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Find video protocols related to scientific articles indexed in Pubmed.
Circulating CD34+ Progenitor Cells and Risk of Mortality in a Population with Coronary Artery Disease.
Circ. Res.
PUBLISHED: 10-18-2014
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Rationale: Low circulating progenitor cell (PC) numbers and activity may reflect impaired intrinsic regenerative/reparative potential, but it remains uncertain whether this translates into a worse prognosis. Objective: To investigate whether low numbers of PCs associate with a greater risk of mortality in a population at high cardiovascular risk. Methods and Results: Patients undergoing coronary angiography were recruited into two cohorts (1, n=502 and 2, n=403) over separate time periods. PCs were enumerated by flow cytometry as CD(45med+) blood mononuclear cells expressing CD34, with additional quantification of subsets co-expressing CD133, VEGFR2 and CXCR4. Coefficient of variation for CD34 cells was 2.9% and 4.8%, 21.6% and 6.5% for the respective subsets. Each cohort was followed for a mean of 2.7 and 1.2 years, respectively, for the primary endpoint of all-cause death. There was an inverse association between CD34+ and CD34+/CD133+ cell counts and risk of death in Cohort 1 (?=-0.92, p=0.043 and ?=-1.64, p=0.019, respectively) that was confirmed in Cohort 2 (?=-1.25, p=0.020 and ?=-1.81, p=0.015, respectively). Covariate adjusted HRs in the pooled cohort (n=905) were 3.54 (1.67-7.50) and 2.46 (1.18-5.13), respectively. CD34+/CD133+ cell counts improved risk prediction metrics beyond standard risk factors. Conclusions: Reduced circulating PC counts, identified primarily as CD34+ mononuclear cells or its subset expressing CD133 are associated with risk of death in individuals with coronary artery disease, suggesting that impaired endogenous regenerative capacity is associated with increased mortality. These findings have implications for biological understanding, risk prediction and cell selection for cell based therapies.
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Successful treatment of severe immune hemolytic anemia after allogeneic stem cell transplantation with bortezomib: report of a case and review of literature.
Transfusion
PUBLISHED: 08-25-2014
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Immune hemolytic anemia is a well-known complication after allogeneic hematopoietic stem cell transplantation (HSCT). Posttransplant hemolytic anemia results in increased red blood cell transfusions and medical sequelae including iron overload.
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Incidence and geographic distribution of adult acute leukemia in the state of Georgia.
South. Med. J.
PUBLISHED: 08-02-2014
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We investigated an apparent increase in acute lymphoblastic leukemia (ALL) referrals from northern Georgia to a tertiary care center located in Atlanta.
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Tacrolimus/sirolimus vs tacrolimus/methotrexate as GVHD prophylaxis after matched, related donor allogeneic HCT.
Blood
PUBLISHED: 06-30-2014
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Grades 2-4 acute graft-versus-host disease (GVHD) occurs in approximately 35% of matched, related donor (MRD) allogeneic hematopoietic cell transplantation (HCT) recipients. We sought to determine if the combination of tacrolimus and sirolimus (Tac/Sir) was more effective than tacrolimus and methotrexate (Tac/Mtx) in preventing acute GVHD and early mortality after allogeneic MRD HCT in a phase 3, multicenter trial. The primary end point of the trial was to compare 114-day grades 2-4 acute GVHD-free survival using an intention-to-treat analysis of 304 randomized subjects. There was no difference in the probability of day 114 grades 2-4 acute GVHD-free survival (67% vs 62%, P = .38). Grades 2-4 GVHD was similar in the Tac/Sir and Tac/Mtx arms (26% vs 34%, P = .48). Neutrophil and platelet engraftment were more rapid in the Tac/Sir arm (14 vs 16 days, P < .001; 16 vs 19 days, P = .03). Oropharyngeal mucositis was less severe in the Tac/Sir arm (peak Oral Mucositis Assessment Scale score 0.70 vs 0.96, P < .001), but otherwise toxicity was similar. Chronic GVHD, relapse-free survival, and overall survival at 2 years were no different between study arms (53% vs 45%, P = .06; 53% vs 54%, P = .77; and 59% vs 63%, P = .36). Based on similar long-term outcomes, more rapid engraftment, and less oropharyngeal mucositis, the combination of Tac/Sir is an acceptable alternative to Tac/Mtx after MRD HCT. This study was funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute; and the trial was registered at www.clinicaltrials.gov as #NCT00406393.
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Improved survival after transplantation of more donor plasmacytoid dendritic or naïve T cells from unrelated-donor marrow grafts: results from BMTCTN 0201.
J. Clin. Oncol.
PUBLISHED: 06-30-2014
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To characterize relationships between specific immune cell subsets in bone marrow (BM) or granulocyte colony-stimulating factor-mobilized peripheral blood (PB) stem cells collected from unrelated donors and clinical outcomes of patients undergoing transplantation in BMTCTN 0201.
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Circadian variation in vascular function and regenerative capacity in healthy humans.
J Am Heart Assoc
PUBLISHED: 05-17-2014
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Progenitor cells (PCs) are mobilized in response to vascular injury to effect regeneration and repair. Recruitment of PCs requires intact nitric oxide (NO) synthesis by endothelial cells, and their number and activity correlate with cardiovascular disease risk burden and future outcomes. Whereas cardiovascular vulnerability exhibits a robust circadian rhythm, the 24-hour variation of PCs and their inter-relation with vascular function remain unknown. We investigated the circadian variation of PCs and vascular function with the hypothesis that this will parallel the pattern observed for cardiovascular events (CVEs).
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Intensive chemotherapy and consolidation with high dose therapy and autologous stem cell transplant in patients with mantle cell lymphoma.
Leuk. Lymphoma
PUBLISHED: 05-16-2014
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Mantle cell lymphoma (MCL) remains incurable with conventional chemotherapy without consensus on the optimal initial treatment. We examined our single center experience with frontline therapy for patients with MCL in consecutive cases diagnosed 1995-2011. Among 81 patients, median age was 59 (28% were ? 65 years of age), 95% had stage III/IV disease and 54% had a low risk MCL International Prognostic Index score. Thirty-five percent (n = 28) received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) and 65% received R-HCVAD (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with high-dose methotrexate/cytarabine; n = 53). Forty-one patients were consolidated with autologous stem cell transplant (ASCT). There were no significant differences in 2-year survival for R-CHOP versus R-HCVAD (p = 0.10) or for ASCT versus observation (p = 0.06). After controlling for clinical factors, R-HCVAD followed by ASCT was associated with superior progression-free survival (hazard ratio 0.26, 95% confidence interval 0.09-0.75).
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High incidence of severe acute graft-versus-host disease with tacrolimus and mycophenolate mofetil in a large cohort of related and unrelated allogeneic transplantation patients.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-16-2014
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Both acute and chronic graft-versus-host disease (GVHD) are major causes of morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT). The optimal pharmacological regimen for GVHD prophylaxis is unclear, but combinations of a calcineurin inhibitor (cyclosporin or tacrolimus [Tac]) and an antimetabolite (methotrexate or mycophenolate mofetil [MMF]) are typically used. We retrospectively evaluated the clinical outcomes of 414 consecutive patients who underwent AHSCT from sibling (SD) or unrelated donors (UD) with Tac/MMF combination, between January 2005 and August 2010. The median follow-up was 60 months. Less than one third of the patients received a reduced-intensity chemoregimen. The incidence of grades III and IV acute GVHD was 22.3% and 36.5% in SD and UD groups, respectively (P = .0007). The incidence of chronic GVHD was 47.1% and 52.7% in the SD and UD groups, respectively. Nonrelapse mortality (NRM) at 60 months was 33.3% and 46.5% in the SD and UD groups, respectively (P = .0016). The incidence of relapse was 22.4% for UD and 28.8% for SD. Five-year overall survival was 43% and 34% in the SD and UD groups, respectively (P = .0183). GVHD was the leading cause of death for the entire cohort. Multivariable analysis showed that 8/8 HLA match, patient's age < 60, and low-risk disease were associated with better survival. The use of Tac/MMF for GVHD prophylaxis was associated with a relatively high incidence of severe acute GVHD and NRM in AHSCT from sibling and unrelated donors.
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Outcomes of hematopoietic cell transplantation for diffuse large B cell lymphoma transformed from follicular lymphoma.
Biol. Blood Marrow Transplant.
PUBLISHED: 03-11-2014
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There are limited data on the outcomes of autologous or allogeneic hematopoietic cell transplantation (HCT) in diffuse large B cell lymphoma transformed from follicular lymphoma. We analyzed transplantation outcomes in 141 subjects with biopsy-proven diffuse large B-cell lymphoma transformed from follicular lymphoma reported to the Center for International Blood and Marrow Transplant Research between 1990 and 2009. Two groups were identified: autologous HCT (auto-HCT; n = 108) and allogeneic HCT (allo-HCT; n = 33). Fewer auto-HCTs were done for transformed follicular lymphoma in 2003 to 2009, with a shift favoring allo-HCT. Auto-HCT was associated with a 1-year nonrelapse mortality (NRM) of 8% (95% confidence interval [CI], 4% to 14%), 5-year progression-free survival of 35% (95% CI, 26% to 45%), and 5-year overall survival of 50% (95% CI, 40% to 59%). In contrast, allo-HCT was associated with a 1-year NRM of 41% (95% CI, 23% to 58%), 5-year progression-free survival of 18% (95% CI, 6% to 35%), and 5-year overall survival of 22% (95% CI, 8% to 41%). Auto-HCT for transformed follicular lymphoma achieves sustained remission in a high proportion of subjects. The high NRM of allo-HCT offset any benefit that might be associated with this transplantation modality.
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Evaluation of the spectra Optia® mononuclear cell collection procedure in multiple myeloma patients.
J Clin Apher
PUBLISHED: 02-28-2014
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Background: Peripheral blood stem cell (PBSC) rescue following myeloablative therapy is a mainstay of cancer therapy. To evaluate the ability of the Spectra Optia Apheresis System (SO), a newly developed apheresis device, the device was studied in multiple myeloma patients undergoing a first autologous PBSC transplant. Aim: To demonstrate that neutrophil recovery was not inferior to historical controls when SO harvested PBSCs were reinfused following myeloablative therapy. Methods: Multiple myeloma patients were mobilized according to the standard practice at four clinical sites. Following mobilization, MNC collections were performed on the SO. The collected cells were cryopreserved and reinfused following myeloablative chemotherapy. Neutrophil recovery defined by an absolute neutrophil count exceeding 500/?L (ANC500) was compared to historical data for patients transplanted following apheresis using the COBE Spectra (CS) device. Results: The median day to neutrophil recovery was 12 days (range 10-14 days), with no significant difference in engraftment comparing patients transplanted with stem cells collected using the SO versus historical cohort of patients collected with the CS. CD34+ cell and MNC collection efficiency (CE) were 69.3% and 65.0% for the SO and CS, respectively. Platelet CE, product hematocrit and product granulocytes (as % of WBCs) using the SO were 21%, 2.3% and 28%, respectively. There were no device-related severe adverse events. Conclusions: The study's results confirm that the Spectra Optia Apheresis System's MNC Collection Protocol is safe and effective for its intended use and that engraftment kinetics of cells collected by SO is not inferior to the CS System. J. Clin. Apheresis, 2014. © 2014 Wiley Periodicals, Inc.
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Pharmacoeconomic analysis of palifermin to prevent mucositis among patients undergoing autologous hematopoietic stem cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 02-28-2014
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Trials have shown benefits of palifermin in reducing the incidence and severity of oral mucositis in patients with hematological malignancies undergoing autologous hematopoietic stem cell transplantation (HSCT) with total body irradiation (TBI)-based conditioning regimens. Similar outcome data are lacking for patients receiving non-TBI-based regimens. We performed a retrospective evaluation on the pharmacoeconomic benefit of palifermin in the setting of non-TBI-based conditioning and autologous HSCT. Between January 2002 and December 2010, 524 patients undergoing autologous HSCT for myeloma (melphalan 200 mg/m²) and lymphoma (high-dose busulfan, cyclophosphamide, and etoposide) as preparative regimen were analyzed. Use of patient-controlled analgesia (PCA) was significantly lower in the palifermin-treated groups (myeloma: 13% versus 53%, P < .001; lymphoma: 46% versus 68%, P < .001). Median total transplant charges were significantly higher in the palifermin-treated group, after controlling for inflation (myeloma: $167,820 versus $143,200, P < .001; lymphoma: $168,570 versus $148,590, P < .001). Palifermin treatment was not associated with a difference in days to neutrophil engraftment, length of stay, and overall survival and was associated with an additional cost of $5.5K (myeloma) and $14K (lymphoma) per day of PCA avoided. Future studies are suggested to evaluate the cost-effectiveness of palifermin compared with other symptomatic treatments to reduce transplant toxicity using validated measures for pain and quality of life.
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Host bone marrow-derived IL-12 enhances donor T cell engraftment in a mouse model of bone marrow transplantation.
J Hematol Oncol
PUBLISHED: 02-12-2014
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Donor cell engraftment is critical for the success of allogeneic bone marrow transplants. Graft failure is a result of donor cells either failing to engraft initially or being eliminated at later time points. Donor cell engraftment is facilitated by donor T cells, which eliminate residual host hemato-lymphoid effector cells such as NK cells and T cells.
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Allotransplantation for patients age ?40 years with non-Hodgkin lymphoma: encouraging progression-free survival.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-30-2014
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Non-Hodgkin lymphoma (NHL) disproportionately affects older patients, who do not often undergo allogeneic hematopoietic cell transplantation (HCT). We analyzed Center for International Blood and Marrow Transplant Research data on 1248 patients age ?40 years receiving reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning HCT for aggressive (n = 668) or indolent (n = 580) NHL. Aggressive lymphoma was more frequent in the oldest cohort 49% for age 40 to 54 versus 57% for age 55 to 64 versus 67% for age ?65; P = .0008). Fewer patients aged ?65 had previous autografting (26% versus 24% versus 9%; P = .002). Rates of relapse, acute and chronic GVHD, and nonrelapse mortality (NRM) at 1 year post-HCT were similar in the 3 age cohorts (22% [95% confidence interval (CI), 19% to 26%] for age 40 to 54, 27% [95% CI, 23% to 31%] for age 55 to 64, and 34% [95% CI, 24% to 44%] for age ?65. Progression-free survival (PFS) and overall survival (OS) at 3 years was slightly lower in the older cohorts (OS: 54% [95% CI, 50% to 58%] for age 40 to 54; 40% [95% CI, 36% to 44%] for age 55 to 64, and 39% [95% CI, 28% to 50%] for age ?65; P < .0001). Multivariate analysis revealed no significant effect of age on the incidence of acute or chronic GVHD or relapse. Age ?55 years, Karnofsky Performance Status <80, and HLA mismatch adversely affected NRM, PFS, and OS. Disease status at HCT, but not histological subtype, was associated with worse NRM, relapse, PFS, and OS. Even for patients age ?55 years, OS still approached 40% at 3 years, suggesting that HCT affects long-term remission and remains underused in qualified older patients with NHL.
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Similar survival for patients undergoing reduced-intensity total body irradiation (TBI) versus myeloablative TBI as conditioning for allogeneic transplant in acute leukemia.
Int. J. Radiat. Oncol. Biol. Phys.
PUBLISHED: 01-28-2014
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Hematopoietic stem cell transplantation (HSCT) is the mainstay of treatment for adults with acute leukemia. Total body irradiation (TBI) remains an important part of the conditioning regimen for HCST. For those patients unable to tolerate myeloablative TBI (mTBI), reduced intensity TBI (riTBI) is commonly used. In this study we compared outcomes of patients undergoing mTBI with those of patients undergoing riTBI in our institution.
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Silibinin inhibits accumulation of myeloid-derived suppressor cells and tumor growth of murine breast cancer.
Cancer Med
PUBLISHED: 01-20-2014
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Myeloid-derived suppressor cells (MDSC)s increase in blood and accumulate in the tumor microenvironment of tumor-bearing animals, contributing to immune suppression in cancer. Silibinin, a natural flavonoid from the seeds of milk thistle, has been developed as an anti-inflammatory agent and supportive care agent to reduce the toxicity of cancer chemotherapy. The goals of this study were to evaluate the effect of silibinin on MDSCs in tumor-bearing mice and antitumor activity of silibinin in a mouse model of breast cancer. 4T1 luciferase-transfected mammary carcinoma cells were injected into in the mammary fat pad female BALB/c mice, and female CB17-Prkdc Scid/J mice. Silibinin treatment started on day 4 or day 14 after tumor inoculation continued every other day. Tumor growth was monitored by bioluminescent imaging (BLI) measuring total photon flux. Flow cytometry measured total leukocytes, CD11b(+) Gr-1(+) MDSC, and T cells in the blood and tumors of tumor-bearing mice. The effects of silibinin on 4T1 cell viability in vitro were measured by BLI. Treatment with silibinin increased overall survival in mice harboring tumors derived from the 4T1-luciferase breast cancer cell line, and reduced tumor volumes and numbers of CD11b(+) Gr-1(+) MDSCs in the blood and tumor, and increased the content of T cells in the tumor microenvironment. Silibinin failed to inhibit tumor growth in immunocompromised severe combined immunodeficiency mice, supporting the hypothesis that anticancer effect of silibinin is immune-mediated. The antitumor activity of silibinin requires an intact host immune system and is associated with decreased accumulation of blood and tumor-associated MDSCs.
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New molecule for mobilizing marrow stem cells.
Blood
PUBLISHED: 01-18-2014
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In this issue of Blood, Zhang et al describe an exciting new small-molecule antagonist of CXCL12-CXCR4 binding with a potent ability to mobilize hematopoietic stem cells (HSCs). Further clinical development of this new drug,Me6TREN, may have broad applications in stem-cell mobilization for cancer and in regenerative medicine.
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Identification of a permissible HLA mismatch in hematopoietic stem cell transplantation.
Blood
PUBLISHED: 01-09-2014
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In subjects mismatched in the HLA alleles C*03:03/C*03:04 no allogeneic cytotoxic T-lymphocyte responses are detected in vitro. Hematopoietic stem cell transplantation (HSCT) with unrelated donors (UDs) showed no association between the HLA-C allele mismatches (CAMMs) and adverse outcomes; antigen mismatches at this and mismatches other HLA loci are deleterious. The absence of effect of the CAMM may have resulted from the predominance of the mismatch C*03:03/C*03:04. Patients with hematologic malignancies receiving UD HSCT matched in 8/8 and 7/8 HLA alleles were examined. Transplants mismatched in HLA-C antigens or mismatched in HLA-A, -B, or -DRB1 presented significant differences (P < .0001) in mortality (hazard ratio [HR] = 1.37, 1.30), disease-free survival (HR = 1.33, 1.27), treatment-related mortality (HR = 1.54, 1.54), and grade 3-4 acute graft-versus-host disease (HR = 1.49, 1.77) compared with the 8/8 group; transplants mismatched in other CAMMs had similar outcomes with HR ranging from 1.34 to 172 for these endpoints. The C*03:03/C*03:04 mismatched and the 8/8 matched groups had identical outcomes (HR ranging from 0.96-1.05). The previous finding that CAMMs do not associate with adverse outcomes is explained by the predominance (69%) of the mismatch C*03:03/03:04 in this group that is better tolerated than other HLA mismatches.
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Evaluation of peripheral blood stem cell quality in products transported by traditional courier or commercial overnight shipping services.
Transfusion
PUBLISHED: 01-03-2014
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Peripheral blood stem cell (PBSC) products have traditionally been transported from the collection center to a transplant center using validated volunteer courier-based procedures. Evolving airline service strategies and security policies have complicated this model of product transport. This study was designed to evaluate the feasibility of transporting PBSC products using commercial overnight shipping services, while maintaining product quality, compared to courier-transported products.
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Metabolomics of ADSOL (AS-1) red blood cell storage.
Transfus Med Rev
PUBLISHED: 01-02-2014
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Population-based investigations suggest that red blood cells (RBCs) are therapeutically effective when collected, processed, and stored for up to 42 days under validated conditions before transfusion. However, some retrospective clinical studies have shown worse patient outcomes when transfused RBCs have been stored for the longest times. Furthermore, studies of RBC persistence in the circulation after transfusion have suggested that considerable donor-to-donor variability exists and may affect transfusion efficacy. To understand the limitations of current blood storage technologies and to develop approaches to improve RBC storage and transfusion efficacy, we investigated the global metabolic alterations that occur when RBCs are stored in AS-1 (AS1-RBC). Leukoreduced AS1-RBC units prepared from 9 volunteer research donors (12 total donated units) were serially sampled for metabolomics analysis over 42 days of refrigerated storage. Samples were tested by gas chromatography/mass spectrometry and liquid chromatography/tandem mass spectrometry, and specific biochemical compounds were identified by comparison to a library of purified standards. Over 3 experiments, 185 to 264 defined metabolites were quantified in stored RBC samples. Kinetic changes in these biochemicals confirmed known alterations in glycolysis and other pathways previously identified in RBCs stored in saline, adenine, glucose and mannitol solution (SAGM-RBC). Furthermore, we identified additional alterations not previously seen in SAGM-RBCs (eg, stable pentose phosphate pathway flux, progressive decreases in oxidized glutathione), and we delineated changes occurring in other metabolic pathways not previously studied (eg, S-adenosyl methionine cycle). These data are presented in the context of a detailed comparison with previous studies of SAGM-RBCs from human donors and murine AS1-RBCs. Global metabolic profiling of AS1-RBCs revealed a number of biochemical alterations in stored blood that may affect RBC viability during storage as well as therapeutic effectiveness of stored RBCs in transfusion recipients. These results provide future opportunities to more clearly pinpoint the metabolic defects during RBC storage, to identify biomarkers for donor screening and prerelease RBC testing, and to develop improved RBC storage solutions and methodologies.
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Recombinant TLR5 agonist CBLB502 promotes NK cell-mediated anti-CMV immunity in mice.
PLoS ONE
PUBLISHED: 01-01-2014
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Prior work using allogeneic bone marrow transplantation (allo-BMT) models showed that peritransplant administration of flagellin, a toll-like receptor 5 (TLR5) agonist protected murine allo-BMT recipients from CMV infection while limiting graft-vs-host disease (GvHD). However, the mechanism by which flagellin-TLR5 interaction promotes anti-CMV immunity was not defined. Here, we investigated the anti-CMV immunity of NK cells in C57BL/6 (B6) mice treated with a highly purified cGMP grade recombinant flagellin variant CBLB502 (rflagellin) followed by murine CMV (mCMV) infection. A single dose of rflagellin administered to mice between 48 to 72 hours prior to MCMV infection resulted in optimal protection from mCMV lethality. Anti-mCMV immunity in rflagellin-treated mice correlated with a significantly reduced liver viral load and increased numbers of Ly49H+ and Ly49D+ activated cytotoxic NK cells. Additionally, the increased anti-mCMV immunity of NK cells was directly correlated with increased numbers of IFN-?, granzyme B- and CD107a producing NK cells following mCMV infection. rFlagellin-induced anti-mCMV immunity was TLR5-dependent as rflagellin-treated TLR5 KO mice had ?10-fold increased liver viral load compared with rflagellin-treated WT B6 mice. However, the increased anti-mCMV immunity of NK cells in rflagellin-treated mice is regulated indirectly as mouse NK cells do not express TLR5. Collectively, these data suggest that rflagellin treatment indirectly leads to activation of NK cells, which may be an important adjunct benefit of administering rflagellin in allo-BMT recipients.
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Autologous or Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Chemotherapy-Sensitive Mantle-Cell Lymphoma: Analysis of Transplantation Timing and Modality.
J. Clin. Oncol.
PUBLISHED: 12-16-2013
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To examine the outcomes of patients with chemotherapy-sensitive mantle-cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course.
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Effect of progenitor cell mobilization with granulocyte-macrophage colony-stimulating factor in patients with peripheral artery disease: a randomized clinical trial.
JAMA
PUBLISHED: 11-20-2013
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Many patients with peripheral artery disease (PAD) have walking impairment despite therapy. Experimental studies in animals demonstrate improved perfusion in ischemic hind limb after mobilization of bone marrow progenitor cells (PCs), but whether this is effective in patients with PAD is unknown.
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Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial.
J. Clin. Oncol.
PUBLISHED: 10-14-2013
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The Programmed Death-1 (PD-1) immune checkpoint pathway may be usurped by tumors, including diffuse large B-cell lymphoma (DLBCL), to evade immune surveillance. The reconstituting immune landscape after autologous hematopoietic stem-cell transplantation (AHSCT) may be particularly favorable for breaking immune tolerance through PD-1 blockade.
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Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI.
Blood
PUBLISHED: 09-24-2013
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Cyclophosphamide combined with total body irradiation (Cy/TBI) or busulfan (BuCy) are the most widely used myeloablative conditioning regimens for allotransplants. Recent data regarding their comparative effectiveness are lacking. We analyzed data from the Center for International Blood and Marrow Transplant Research for 1230 subjects receiving a first hematopoietic cell transplant from a human leukocyte antigen-matched sibling or from an unrelated donor during the years 2000 to 2006 for acute myeloid leukemia (AML) in first complete remission (CR) after conditioning with Cy/TBI or oral or intravenous (IV) BuCy. Multivariate analysis showed significantly less nonrelapse mortality (relative risk [RR] = 0.58; 95% confidence interval [CI]: 0.39-0.86; P = .007), and relapse after, but not before, 1 year posttransplant (RR = 0.23; 95% CI: 0.08-0.65; P = .006), and better leukemia-free survival (RR = 0.70; 95% CI: 0.55-0.88; P = .003) and survival (RR = 0.68; 95% CI: 0.52-0.88; P = .003) in persons receiving IV, but not oral, Bu compared with TBI. In combination with Cy, IV Bu is associated with superior outcomes compared with TBI in patients with AML in first CR.
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Effect of Postremission Therapy before Reduced-Intensity Conditioning Allogeneic Transplantation for Acute Myeloid Leukemia in First Complete Remission.
Biol. Blood Marrow Transplant.
PUBLISHED: 08-19-2013
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The impact of pretransplant (hematopoietic cell transplantation [HCT]) cytarabine consolidation therapy on post-HCT outcomes has yet to be evaluated after reduced-intensity or nonmyeloablative conditioning. We analyzed 604 adults with acute myeloid leukemia in first complete remission (CR1) reported to the Center for International Blood and Marrow Transplant Research who received a reduced-intensity or nonmyeloablative conditioning HCT from an HLA-identical sibling, HLA-matched unrelated donor, or umbilical cord blood donor from 2000 to 2010. We compared transplant outcomes based on exposure to cytarabine postremission consolidation. Three-year survival rates were 36% (95% confidence interval [CI], 29% to 43%) in the no consolidation arm and 42% (95% CI, 37% to 47%) in the cytarabine consolidation arm (P = .16). Disease-free survival was 34% (95% CI, 27% to 41%) and 41% (95% CI, 35% to 46%; P = .15), respectively. Three-year cumulative incidences of relapse were 37% (95% CI, 30% to 44%) and 38% (95% CI, 33% to 43%), respectively (P = .80). Multivariate regression confirmed no effect of consolidation on relapse, disease-free survival, and survival. Before reduced-intensity or nonmyeloablative conditioning HCT, these data suggest pre-HCT consolidation cytarabine does not significantly alter outcomes and support prompt transition to transplant as soon as morphologic CR1 is attained. If HCT is delayed while identifying a donor, our data suggest that consolidation does not increase transplant treatment-related mortality and is reasonable if required.
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From Single Nucleotide Polymorphisms to Constant Immunosuppression: Mesenchymal Stem Cell Therapy for Autoimmune Diseases.
Biomed Res Int
PUBLISHED: 07-17-2013
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The regenerative abilities and the immunosuppressive properties of mesenchymal stromal cells (MSCs) make them potentially the ideal cellular product of choice for treatment of autoimmune and other immune mediated disorders. Although the usefulness of MSCs for therapeutic applications is in early phases, their potential clinical use remains of great interest. Current clinical evidence of use of MSCs from both autologous and allogeneic sources to treat autoimmune disorders confers conflicting clinical benefit outcomes. These varied results may possibly be due to MSC use across wide range of autoimmune disorders with clinical heterogeneity or due to variability of the cellular product. In the light of recent genome wide association studies (GWAS), linking predisposition of autoimmune diseases to single nucleotide polymorphisms (SNPs) in the susceptible genetic loci, the clinical relevance of MSCs possessing SNPs in the critical effector molecules of immunosuppression is largely undiscussed. It is of further interest in the allogeneic setting, where SNPs in the target pathway of MSCs intervention may also modulate clinical outcome. In the present review, we have discussed the known critical SNPs predisposing to disease susceptibility in various autoimmune diseases and their significance in the immunomodulatory properties of MSCs.
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Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-28-2013
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We evaluated outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced-intensity conditioning (RIC). The median age at RIC HCT was 55 yr. Donors were a matched sibling donor (MSD) in 34% of RIC HCTs, an HLA well-matched unrelated donor (URD) in 45%, and a partially matched/mismatched URD in 21%. Risk stratification according to the Dynamic International Prognostic Scoring System (DIPSS) was 12% low, 49% intermediate-1, 37% intermediate-2, and 1% high. The probability of survival at 5 yr was 47% (95% confidence interval [CI], 40% to 53%). In a multivariate analysis, donor type was the sole independent factor associated with survival. Adjusted probabilities of survival at 5-yr were 56% (95% CI, 44% to 67%) for MSD, 48% (95% CI, 37% to 58%) for well-matched URD, and 34% (95% CI, 21% to 47%) for partially matched/mismatched URD (P = .002). The relative risk (RR) for NRM was 3.92 (P = .006) for well-matched URD and 9.37 (P < .0001) for partially matched/mismatched URD. Trends toward increased NRM (RR, 1.7; P = .07) and inferior survival (RR, 1.37; P = .10) were observed in DIPSS intermediate-2/high-risk patients compared with DIPSS low/intermediate-1 risk patients. Our data indicate that RIC HCT is a potentially curative option for patients with MF, and that donor type is the most important factor influencing survival in these patients.
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Providing personalized prognostic information for adult leukemia survivors.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-28-2013
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Prediction of subsequent leukemia-free survival (LFS) and chronic graft-versus-host disease (GVHD) in adults with acute leukemia who survived at least 1 year after allogeneic hematopoietic cell transplantation is difficult. We analyzed 3339 patients with acute myeloid leukemia and 1434 patients with acute lymphoblastic leukemia who received myeloablative conditioning and related or unrelated stem cells from 1990 to 2005. Most clinical factors predictive of LFS in 1-year survivors were no longer significant after 2 or more years. For acute myeloid leukemia, only disease status (beyond first complete remission) remained a significant adverse risk factor for LFS 2 or more years after transplantation. For lymphoblastic leukemia, only extensive chronic GVHD remained a significant adverse predictor of LFS in the second and subsequent years. For patients surviving for 1 year without disease relapse or extensive chronic GVHD, the risk of developing extensive chronic GVHD in the next year was 4% if no risk factors were present and higher if noncyclosporine-based GVHD prophylaxis, an HLA-mismatched donor, or peripheral blood stem cells were used. Estimates for subsequent LFS and extensive chronic GVHD can be derived for individual patients or populations using an online calculator (http://www.cibmtr.org/LeukemiaCalculators). This prognostic information is more relevant for survivors than estimates provided before transplantation.
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Enrichment of IL-12-producing plasmacytoid dendritic cells in donor bone marrow grafts enhances graft-versus-leukemia activity in allogeneic hematopoietic stem cell transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-18-2013
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A critical question in the field of allogeneic hematopoietic stem cell transplantation (HSCT) is how to enhance graft-versus-leukemia (GVL) activity while limiting graft-versus-host-disease (GVHD). We have previously reported that donor bone marrow (BM) precursors of plasmacytoid dendritic cells (pre-pDCs) can polarize donor T cells toward Th1 immunity and augment the GVL activity of donor T cells while attenuating their GVHD activity in a murine model of allogeneic HSCT. Clinical data on the role of donor pre-pDCs and conventional DCs (cDCs) on transplantation outcomes has been conflicting. To test the effect of increasing the proportion of pre-pDCs versus cDCs in a BM graft, we enriched CD11b(-) pDCs by selectively depleting the CD11b(+) myeloid DC (mDC) population from BM using FACS sorting in a murine model of allogeneic BM transplantation. Donor T cell expansion and GVL activity were greater in mice that received BM depleted of mDCs compared with mice that received undepleted BM. GVHD was not increased by depleting mDCs. To examine the mechanism through which mDC depletion enhances the GVL activity of donor T cells, we used BM and pDCs from IL-12p40KO mice, and found that the increased GVL activity of mDC-depleted BM was IL-12-dependent. This study indicates that a clinically translatable strategy of engineering the DC content of grafts can improve clinical outcomes in allogeneic HSCT through the regulation of donor T cell activation and GVL activity.
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Trends in utilization and outcomes of autologous transplantation as early therapy for multiple myeloma.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-08-2013
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The impact of novel drugs for treating multiple myeloma (MM) on the utilization and outcomes of autologous hematopoietic progenitor cell transplantation (AHPCT) is unknown. We reviewed characteristics and outcomes of 20,278 patients who underwent AHPCT within 12 months of diagnosis of MM in the United States and Canada and registered at the Center for International Blood and Marrow Transplant Research (CIBMTR) in 3 time cohorts reflecting the increasing availability of novel drugs: 1995 to 1999 (n = 2226), 2000 to 2004 (n = 6408), and 2005 to 2010 (n = 11,644). In the United States, the number of AHPCTs performed increased at a greater rate than new MM cases. Patients in recent cohorts were older, less likely to have stage 3 MM, and more likely to have received previous thalidomide, lenalidomide, or bortezomib. On multivariate analysis, AHPCT in the 2000 to 2004 cohort (HR = 0.77) or in the 2005 to 2010 cohort (HR = 0.68) were associated with lower risk of death. Survival at 60 months post-AHPCT improved from 47% in 1995 to 1999 to 55% in 2000 to 2004 and to 57% in 2005 to 2010, owing less to improvement in progression-free survival (50% versus 55% versus 57% at 24 months) than to postrelapse/progression survival (58% versus 65% versus 72% at 24 months). AHPCT and new biological agents are complementary, nonredundant therapies and should be combined in the management of MM in suitable patients.
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The effect of platelet lysate fibrinogen on the functionality of MSCs in immunotherapy.
Biomaterials
PUBLISHED: 05-01-2013
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Human platelet lysate (PL) represents an attractive alternative to fetal bovine serum (FBS) for the ex vivo expansion of human mesenchymal stromal cells (MSCs). However, there is controversy whether MSCs propagated in unfractionated PL retain their immunosuppressive properties. Since fibrinogen can be a major component of PL, we hypothesized that the fibrinogen content in PL negatively affects the suppressor function of MSCs. Pools of outdated plateletpheresis products underwent a double freeze-thaw centrifugation and filtration to produce unfractionated platelet lysates (uPL), followed by a temperature controlled clotting procedure to produce a fibrinogen depleted platelet lysate (fdPL). Fibrinogen depletion affected neither the mitogenic properties of PL or growth factor content, however fdPL was less prone to develop precipitate over time. Functionally, fibrinogen interacted directly with MSCs, dose dependently increased IL-6, IL-8 and MCP-1 protein production, and compromised the ability of MSCs to up-regulate indoleamine dioxygenase (IDO), as well as, mitigate T-cell proliferation. Similarly uPL expanded MSCs showed a reduced capability of inducing IDO and suppressing T-cell proliferation compared to FBS expanded MSCs. Replacing uPL with fdPL largely restored the immune modulating effects of MSCs. Together these data suggest that fibrinogen negatively affects the immunomodulatory functions of MSCs and fdPL can serve as non-xenogenic mitogenic supplement for expansion of clinical grade MSCs for immune modulation.
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Unrelated donor allogeneic transplantation after failure of autologous transplantation for acute myelogenous leukemia: a study from the center for international blood and marrow transplantation research.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-21-2013
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The survival of patients with relapsed acute myelogenous leukemia (AML) after autologous hematopoietic stem cell transplantation (auto-HCT) is very poor. We studied the outcomes of 302 patients who underwent secondary allogeneic hematopoietic cell transplantation (allo-HCT) from an unrelated donor (URD) using either myeloablative (n = 242) or reduced-intensity conditioning (RIC; n = 60) regimens reported to the Center for International Blood and Marrow Transplantation Research. After a median follow-up of 58 months (range, 2 to 160 months), the probability of treatment-related mortality was 44% (95% confidence interval [CI], 38%-50%) at 1-year. The 5-year incidence of relapse was 32% (95% CI, 27%-38%), and that of overall survival was 22% (95% CI, 18%-27%). Multivariate analysis revealed a significantly better overal survival with RIC regimens (hazard ratio [HR], 0.51; 95% CI, 0.35-0.75; P <.001), with Karnofsky Performance Status score ?90% (HR, 0.62; 95% CI, 0.47-0.82: P = .001) and in cytomegalovirus-negative recipients (HR, 0.64; 95% CI, 0.44-0.94; P = .022). A longer interval (>18 months) from auto-HCT to URD allo-HCT was associated with significantly lower riak of relapse (HR, 0.19; 95% CI, 0.09-0.38; P <.001) and improved leukemia-free survival (HR, 0.53; 95% CI, 0.34-0.84; P = .006). URD allo-HCT after auto-HCT relapse resulted in 20% long-term leukemia-free survival, with the best results seen in patients with a longer interval to secondary URD transplantation, with a Karnofsky Performance Status score ?90%, in complete remission, and using an RIC regimen. Further efforts to reduce treatment-related mortaility and relapse are still needed.
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In vivo T cell costimulation blockade with abatacept for acute graft-versus-host disease prevention: a first-in-disease trial.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-17-2013
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We performed a first-in-disease trial of in vivo CD28:CD80/86 costimulation blockade with abatacept for acute graft-versus-host disease (aGVHD) prevention during unrelated-donor hematopoietic cell transplantation (HCT). All patients received cyclosporine/methotrexate plus 4 doses of abatacept (10 mg/kg/dose) on days -1, +5, +14, +28 post-HCT. The feasibility of adding abatacept, its pharmacokinetics, pharmacodynamics, and its impact on aGVHD, infection, relapse, and transplantation-related mortality (TRM) were assessed. All patients received the planned abatacept doses, and no infusion reactions were noted. Compared with a cohort of patients not receiving abatacept (the StdRx cohort), patients enrolled in the study (the ABA cohort) demonstrated significant inhibition of early CD4(+) T cell proliferation and activation, affecting predominantly the effector memory (Tem) subpopulation, with 7- and 10-fold fewer proliferating and activated CD4(+) Tem cells, respectively, at day+28 in the ABA cohort compared with the StdRx cohort (P < .01). The ABA patients demonstrated a low rate of aGVHD, despite robust immune reconstitution, with 2 of 10 patients diagnosed with grade II-IV aGVHD before day +100, no deaths from infection, no day +100 TRM, and with 7 of 10 evaluable patients surviving (median follow-up, 16 months). These results suggest that costimulation blockade with abatacept can significantly affect CD4(+) T cell proliferation and activation post-transplantation, and may be an important adjunct to standard immunoprophylaxis for aGVHD in patients undergoing unrelated-donor HCT.
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Temporal changes in plerixafor administration and hematopoietic stem cell mobilization efficacy: results of a prospective clinical trial in multiple myeloma.
Biol. Blood Marrow Transplant.
PUBLISHED: 04-04-2013
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Plerixafor with granulocyte colony-stimulating factor (G-CSF) is effective for hematopoietic stem cell (HSC) mobilization in patients with non-Hodgkin Lymphoma and myeloma; however, labeling requires dosing 11 hours before apheresis. Pharmacodynamic studies show peak blood CD34(+) cell counts at 10 to 14 hours; limited data are available for later time points. To address the effect of afternoon plerixafor dosing on CD34(+) cell yields, we conducted a prospective clinical trial in myeloma patients undergoing stem cell collection. Thirty-one patients received plerixafor 17 hours before apheresis; blood CD34(+) cells were measured before the first plerixafor dose and 1, 3, and 17 ± 1 hours after treatment. The target HSC number (?10 × 106 CD34(+) cells/kg) was collected from 22 subjects (73%) in 1 day and from all subjects within 3 days. Hematopoietic engraftment after transplantation and adverse events were similar to previous studies. Plerixafor given 17 hours before apheresis yields desired HSC collection efficiencies after induction treatment in myeloma patients.
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Autologous haematopoietic cell transplantation for non-Hodgkin lymphoma with secondary CNS involvement.
Br. J. Haematol.
PUBLISHED: 03-04-2013
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Pre-existing central nervous system (CNS) involvement may influence referral for autologous haematopoietic cell transplantation (AHCT) for patients with non-Hodgkin lymphoma (NHL). The outcomes of 151 adult patients with NHL with prior secondary CNS involvement (CNS(+) ) receiving an AHCT were compared to 4688 patients without prior CNS lymphoma (CNS(-) ). There were significant baseline differences between the cohorts. CNS(+) patients were more likely to be younger, have lower performance scores, higher age-adjusted international prognostic index scores, more advanced disease stage at diagnosis, more aggressive histology, more sites of extranodal disease, and a shorter interval between diagnosis and AHCT. However, no statistically significant differences were identified between the two groups by analysis of progression-free survival (PFS) and overall survival (OS) at 5 years. A matched pair comparison of the CNS(+) group with a subset of CNS(-) patients matched on propensity score also showed no differences in outcomes. Patients with active CNS lymphoma at the time of AHCT (n = 55) had a higher relapse rate and diminished PFS and OS compared with patients whose CNS lymphoma was in remission (n = 96) at the time of AHCT. CNS(+) patients can achieve excellent long-term outcomes with AHCT. Active CNS lymphoma at transplant confers a worse prognosis.
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Bortezomib-containing induction regimens in transplant-eligible myeloma patients: a meta-analysis of phase 3 randomized clinical trials.
Cancer
PUBLISHED: 02-26-2013
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The objective of this meta-analysis in patients with myeloma was to test the hypothesis that the addition of bortezomib to induction therapy not only improves the depth of response but also improves post-transplant progression-free survival (PFS) and overall survival (OS) outcomes.
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Vinorelbine, paclitaxel, etoposide, cisplatin, and cytarabine (VTEPA) is an effective second salvage therapy for relapsed/refractory Hodgkin lymphoma.
Clin Lymphoma Myeloma Leuk
PUBLISHED: 02-22-2013
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For Hodgkin lymphoma (HL) patients with refractory or relapsed (R/R) disease after primary therapy, the standard of care is a salvage regimen followed by autologous stem cell transplant (ASCT). However, patients who fail to respond to a salvage regimen have limited options. Our phase I study of cytarabine combined with fixed doses of vinorelbine, paclitaxel, etoposide, and cisplatin (VTEPA) for patients with R/R lymphoma showed an overall response rate (ORR) of 33%.
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Who is the better donor for older hematopoietic transplant recipients: an older-aged sibling or a young, matched unrelated volunteer?
Blood
PUBLISHED: 01-29-2013
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Older patients are increasingly undergoing allogeneic hematopoietic transplantation. A relevant question is whether outcomes can be improved with a younger allele-level 8/8 HLA-matched unrelated donor (MUD) rather than an older HLA-matched sibling (MSD). Accordingly, transplants in leukemia/lymphoma patients age ?50 years were analyzed comparing outcomes for recipients of MSD ?50 (n = 1415) versus MUD <50 years (n = 757). Risks of acute graft-versus-host disease (GVHD) grade 2 to 4 (hazard ratio [HR], 1.63; P < .001), 3 to 4 (HR, 1.85; P < .001), and chronic GVHD (HR, 1.48; P < .0001) were higher after MUD compared with MSD transplants. The effect of donor type on nonrelapse mortality (NRM), relapse, and overall mortality was associated with performance score. For patients with scores of 90 or 100, NRM (HR, 1.42; P = .001), relapse (HR, 1.45; P < .001), and overall mortality (HR, 1.28; P = .001) risks were higher after MUD transplants. For patients with scores below 90, NRM (HR, 0.96; P = .76), relapse (HR, 0.86; P = .25), and overall mortality (HR, 0.90; P = .29) were not significantly different after MUD and MSD transplants. These data favor an MSD over a MUD in patients age ?50 years.
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Impact of pretransplantation conditioning regimens on outcomes of allogeneic transplantation for chemotherapy-unresponsive diffuse large B cell lymphoma and grade III follicular lymphoma.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-26-2013
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Patients with chemorefractory non-Hodgkin lymphomas generally have a poor prognosis. We used the observational database of the Center for International Blood and Marrow Transplant Research to study the outcome of 533 patients with refractory diffuse large B cell lymphoma (DLBCL) or grade III follicular lymphoma (FL-III) who underwent allogeneic hematopoietic cell transplantation (allo-HCT) using either myeloablative (MA; n = 307) or reduced-intensity/nonmyeloablative conditioning (RIC/NST; n = 226) between 1998 and 2010. We analyzed nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Only 45% of the patients at transplantation had a Karnofsky performance score of ?90%. Median follow-up of surviving patients after MA and RIC/NST allo-HCT is 35 months and 30 months, respectively. At 3 years, MA allo-HCT was associated with a higher NRM compared with RIC/NST (53% versus 42%; P = .03), similar PFS (19% versus 23%; P = .40), and lower OS (19% versus 28%; P = .02), respectively. On multivariate analysis, FL-III histology was associated with lower NRM (relative risk [RR], .52), reduced risk of relapse/progression (RR, .42), and superior PFS (RR, .51) and OS (RR, .53), whereas MA conditioning was associated with reduced risk of relapse/progression (RR, .66). Despite a refractory state, a small subset of DLBCL and FL-III patients can attain durable remissions after allo-HCT. Conditioning regimen intensity was not associated with PFS and OS despite a higher risk of relapse/progression with RIC/NST allo-HCT.
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Birth order and transplantation outcome in HLA-identical sibling stem cell transplantation: an analysis on behalf of the Center for International Blood and Marrow Transplantation.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-25-2013
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Allogeneic stem cell transplantation (SCT) is the most effective treatment option for many hematologic malignancies, but graft-versus-host disease (GVHD) remains a major cause of treatment failure. Along with well-established risk factors for transplantation outcomes, recent single-center studies have identified a birth order effect in HLA-identical sibling SCT, with lower rates of acute and chronic GVHD and improved overall survival when the donor is younger than the recipient. One hypothesized mechanism for this effect is microchimerism due to fetomaternal and transmaternal sibling cell trafficking during pregnancy as the donor is exposed to recipient antigens in utero. The aim of the present study was to validate previously reported single-center data in a large, multicenter cohort provided by the Center for International Blood and Marrow Transplantation. All adult and pediatric patients (n = 11,365) with a hematologic malignancy who underwent allogeneic SCT with a graft from an HLA-identical sibling donor between 1990 and 2007 were included. When donors were younger than recipients, there was a significantly lower rate of acute GVHD grade II-IV and chronic GVHD in children, as well as a lower rate of chronic GVHD in adolescents. However, the hypothesized overall positive effect of lower relapse and better survival when donors are younger than recipients was not observed. Our data suggest that if otherwise equally matched, a graft from a younger sibling may be superior to a graft from an older sibling for children and adolescents undergoing SCT.
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Soluble FAS ligand as a biomarker of disease recurrence in differentiated thyroid cancer.
Cancer
PUBLISHED: 01-22-2013
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Reliable predictive biomarkers are required to address the challenge of disease recurrence after thyroid cancer surgery. For this study, the authors assessed the association of cellular-based and serum-based immunologic mediators with thyroid cancer recurrence.
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Pharmacological inhibition of VIP signaling enhances antiviral immunity and improves survival in murine cytomegalovirus-infected allogeneic bone marrow transplant recipients.
Blood
PUBLISHED: 01-16-2013
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Cytomegalovirus (CMV) infection following allogeneic bone marrow transplant (allo-BMT) is controlled by donor-derived cellular immunity. Vasoactive intestinal peptide (VIP) suppresses Th1 immunity. We hypothesized that blocking VIP-signaling would enhance anti-CMV immunity in murine recipients of allo-BMT. Recipients were transplanted with bone marrow (BM) and T-cells from major histocompatibility complex (MHC)-mismatched VIP-knockout (KO) or wild-type donors, and treated with 7 daily subcutaneous injections of VIPhyb (peptidic VIP-antagonist) or phosphate-buffered saline (PBS). Genetic and pharmacological blockade of VIP-signaling protected allo-BMT recipients from lethal murine CMV (mCMV) infection, improving survival without increasing graft-versus-host disease. Mice treated with VIPhyb or transplanted with VIP-KO allografts had significantly lower viral loads, increased numbers of mCMV-M45-peptide-MHC-tetramer(+) CD8(+) T-cells, with lower PD-1 expression, and enhanced primary and secondary cellular immune responses after mCMV infection than did PBS-treated mice. These results demonstrate that administration of a VIP antagonist after allo-BMT is a promising safely therapeutic approach to enhance antiviral cellular immunity.
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Allogeneic hematopoietic cell transplantation for chemotherapy-unresponsive mantle cell lymphoma: a cohort analysis from the center for international blood and marrow transplant research.
Biol. Blood Marrow Transplant.
PUBLISHED: 01-15-2013
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Patients with chemorefractory mantle cell lymphoma (MCL) have a poor prognosis. We used the Center for International Blood and Marrow Transplant Research database to study the outcome of 202 patients with refractory MCL who underwent allogeneic hematopoietic cell transplantation (allo-HCT) using either myeloablative (MA) or reduced-intensity/nonmyeloablative conditioning (RIC/NST), during 1998-2010. We analyzed nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS). Seventy-four patients (median age, 54 years) received MA, and 128 patients (median age, 59 years) received RIC/NST. Median follow-up after allo-HCT was 35 months in the MA group and 43 months in the RIC/NST group. At 3 years post-transplantation, no significant between-group differences were seen in terms of NRM (47% in MA versus 43% in RIC/NST; P = .68), relapse/progression (33% versus 32%; P = .89), PFS (20% versus 25%; P = .53), or OS (25% versus 30%; P = .45). Multivariate analysis also revealed no significant between-group differences in NRM, relapse, PFS, or OS; however, receipt of a bone marrow or T cell-depleted allograft was associated with an increased risk of NRM and inferior PFS and OS. Our data suggest that despite a refractory disease state, approximately 25% of patients with MCL can attain durable remission after allo-HCT, and conditioning regimen intensity does not influence outcome of allo-HCT.
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Properties of immature myeloid progenitors with nitric-oxide-dependent immunosuppressive activity isolated from bone marrow of tumor-free mice.
PLoS ONE
PUBLISHED: 01-01-2013
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Myeloid derived suppressor cells (MDSCs) from tumor-bearing mice are important negative regulators of anti-cancer immune responses, but the role for immature myeloid cells (IMCs) in non-tumor-bearing mice in the regulation of immune responses are poorly described. We studied the immune-suppressive activity of IMCs from the bone marrow (BM) of C57Bl/6 mice and the mechanism(s) by which they inhibit T-cell activation and proliferation. IMCs, isolated from BM by high-speed FACS, inhibited mitogen-induced proliferation of CD4(+) and CD8(+) T-cells in vitro. Cell-to-cell contact of T-cells with viable IMCs was required for suppression. Neither neutralizing antibodies to TGF?1, nor genetic disruption of indolamine 2,3-dioxygenase, abrogated IMC-mediated suppressive activity. In contrast, suppression of T-cell proliferation was absent in cultures containing IMCs from interferon-? (IFN-?) receptor KO mice or T-cells from IFN-? KO mice (on the C57Bl/6 background). The addition of NO inhibitors to co-cultures of T-cells and IMC significantly reduced the suppressive activity of IMCs. IFN-? signaling between T-cells and IMCs induced paracrine Nitric Oxide (NO) release in culture, and the degree of inhibition of T-cell proliferation was proportional to NO levels. The suppressive activity of IMCs from the bone marrow of tumor-free mice was comparable with MDSCs from BALB/c bearing mice 4T1 mammary tumors. These results indicate that IMCs have a role in regulating T-cell activation and proliferation in the BM microenvironment.
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VIPhyb, an antagonist of vasoactive intestinal peptide receptor, enhances cellular antiviral immunity in murine cytomegalovirus infected mice.
PLoS ONE
PUBLISHED: 01-01-2013
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Vasoactive intestinal peptide (VIP) is a neuropeptide hormone that suppresses Th1-mediated cellular immunity. We previously reported that VIP-knockout (VIP-KO) mice have enhanced cellular immune responses and increased survival following murine cytomegalovirus (mCMV) infection in C57BL/6 mice. In this study, we tested whether treatment with a VIP receptor antagonistic peptide protects C57BL/6 and BALB/c mice from mCMV-infection. One week of daily subcutaneous injections of VIPhyb was non-toxic and did not alter frequencies of immune cell subsets in non-infected mice. VIPhyb administration to mCMV-infected C57BL/6 and BALB/c mice markedly enhanced survival, viral clearance, and reduced liver and lung pathology compared with saline-treated controls. The numbers of effector/memory CD8+ T-cells and mature NK cells were increased in VIPhyb-treated mice compared with PBS-treated groups. Pharmacological blockade of VIP-receptor binding or genetic blockade of VIP-signaling prevented the up-regulation of PD-L1 and PD-1 expression on DC and activated CD8+ T-cells, respectively, in mCMV-infected mice, and enhanced CD80, CD86, and MHC-II expression on conventional and plasmacytoid DC. VIPhyb-treatment increased type-I IFN synthesis, numbers of IFN-?- and TNF-?-expressing NK cells and T-cells, and the numbers of mCMV-M45 epitope-peptide-MHC-I tetramer CD8+ T-cells following mCMV infection. VIP-treatment lowered the percentage of Treg cells in spleens compared with PBS-treated WT mice following mCMV infection, while significantly decreasing levels of serum VEGF induced by mCMV-infection. The mice in all treated groups exhibited similar levels of anti-mCMV antibody titers. Short-term administration of a VIP-receptor antagonist represents a novel approach to enhance innate and adaptive cellular immunity in a murine model of CMV infection.
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IFN-? and indoleamine 2,3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity.
Blood
PUBLISHED: 11-30-2011
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Allogeneic hematopoietic stem cell transplantation (HSCT) can eradicate chemorefractory leukemia through the graft-versus-leukemia (GVL) activity of donor T cells. However, the clinical success of allo-HSCT is limited by the graft-versus-host disease (GVHD) activity of donor T cells. We have reported previously that donor bone marrow precursors of plasmacytoid dendritic cells (pre-pDCs) can activate donor T cells toward T-helper 1 immune polarization in murine allogeneic HSCT. To optimize the GVL activity of these activated donor T cells and limit their graft versus host activity, we engineered the cellular constituents of an allogeneic hematopoietic stem cell graft with highly purified hematopoietic stem cells, T cells, and pre-pDCs and studied their GVL and GVHD activities in a murine model of allogeneic HSCT. Transplanted donor pre-pDCs expanded in vivo for 2 weeks after transplant, and they markedly augmented the activation and GVL activity of donor T cells while attenuating their GVHD activity, leading to an improved therapeutic index. Bidirectional signaling between donor T cells and donor pDCs with IFN-? synthesis by donor T cells inducing indoleamine 2,3-dioxygenase synthesis by donor pDCs limited GVHD by altering the balance between donor T-reg and inflammatory T cells. Manipulating the content of donor DC precursors in allogeneic HSCT is a novel method to optimize the balance between GVL and GVHD.
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Cryopreserved mesenchymal stromal cells display impaired immunosuppressive properties as a result of heat-shock response and impaired interferon-? licensing.
Cytotherapy
PUBLISHED: 10-27-2011
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Human mesenchymal stromal cells (MSC) can suppress T-cell activation in vitro in an indoleamine 2,3-dioxygenase (IDO)-dependent manner. However, their clinical effects on immune ailments have been inconsistent, with a recent phase III study showing no benefit in acute graft-versus-host disease (GvHD). We here tested the hypothesis that the banked, cryopreserved MSC often used in clinical trials display biologic properties distinct from that of MSC in the log phase of growth typically examined in pre-clinical studies. In freshly thawed cryopreserved MSC derived from normal human volunteers, we observed that MSC up-regulate heat-shock proteins, are refractory to interferon (IFN)-?-induced up-regulation of IDO, and are compromised in suppressing CD3/CD28-driven T cell proliferation. Immune suppressor activity, IFN-? responsiveness and induction of IDO were fully restored following 24 h of MSC tissue culture post-thaw. These results highlight a possible cause for the inefficacy of MSC-based immunotherapy reported in clinical trials using cryopreserved MSC thawed immediately prior to infusion.
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Flagellin, a TLR5 agonist, reduces graft-versus-host disease in allogeneic hematopoietic stem cell transplantation recipients while enhancing antiviral immunity.
J. Immunol.
PUBLISHED: 10-17-2011
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Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in patients treated with allogeneic hematopoietic stem cell transplantation (HSCT). Posttransplant immunosuppressive drugs incompletely control GVHD and increase susceptibility to opportunistic infections. In this study, we used flagellin, a TLR5 agonist protein (?50 kDa) extracted from bacterial flagella, as a novel experimental treatment strategy to reduce both acute and chronic GVHD in allogeneic HSCT recipients. On the basis of the radioprotective effects of flagellin, we hypothesized that flagellin could ameliorate GVHD in lethally irradiated murine models of allogeneic HSCT. Two doses of highly purified flagellin (administered 3 h before irradiation and 24 h after HSCT) reduced GVHD and led to better survival in both H-2(b) ? CB6F1 and H-2(K) ? B6 allogeneic HSCT models while preserving >99% donor T cell chimerism. Flagellin treatment preserved long-term posttransplant immune reconstitution characterized by more donor thymic-derived CD4(+)CD25(+)Foxp3(+) regulatory T cells and significantly enhanced antiviral immunity after murine CMV infection. The proliferation index and activation status of donor spleen-derived T cells and serum concentration of proinflammatory cytokines in flagellin-treated recipients were reduced significantly within 4 d posttransplant compared with those of the PBS-treated control recipients. Allogeneic transplantation of radiation chimeras previously engrafted with TLR5 knockout hematopoietic cells showed that interactions between flagellin and TLR5 expressed on both donor hematopoietic and host nonhematopoietic cells were required to reduce GVHD. Thus, the peritransplant administration of flagellin is a novel therapeutic approach to control GVHD while preserving posttransplant donor immunity.
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T cell-depleted partial matched unrelated donor transplant for advanced myeloid malignancy: KIR ligand mismatch and outcome.
Biol. Blood Marrow Transplant.
PUBLISHED: 10-04-2011
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To evaluate the applicability of high-dose conditioning, CD34 selection, and enhanced natural killer (NK) cell alloreactivity reported as promising after haploidentical transplantation, we tested the same strategy for patients with advanced/high-risk myeloid leukemia lacking either related or well-matched unrelated donors (URD). In a prospective multicenter clinical trial using pretransplantation conditioning of thiotepa (5 mg/kg/day × 2), fludarabine (40 mg/mg/M(2)/day × 5), and total body radiation (800 cGy) plus thymoglobulin (2.5 mg/kg/day × 2), as well as a CD34 selected filgrastim stimulated peripheral blood graft from a partial matched URD, we treated 24 patients. The patients (median age 40 [range: 22-61]) were mismatched at 1-3 of 10 HLA loci with their donors; all were mismatched at HLA-C. Thirty-seven percent were ethnic or racial minorities. Twenty-one of 24 engrafted promptly with 1 primary graft failure and 2 early deaths. The cumulative incidence of grade II-IV acute graft-versus-host disease (aGVHD) (34%, 95% confidence interval [CI], 14-54%), chronic GVHD (20%, 95% CI, 2%-38%), and relapse (26%, 95% CI, 8%-84%) were unaffected by KIR ligand donor:recipient mismatch (n = 5) versus KIR ligand match (n = 19). Only 3 (12%) had grade III-IV GVHD. Nonrelapse occurred in 17% (95% CI, 30%-31%) by 100 days and in 35% (95% CI, 15%-55%) by 1 year. Two-year survival and leukemia-free survival were each 40% (95% CI, 21%-59%) and was similar in KIR ligand matched or mismatched patients. Infections, mostly in the first 2 months, were frequent, and were the cause of death in 5 patients (35% of deaths). T cell recovery and NK cell proliferation and functional maturation were not altered by KIR ligand match or mismatch status. For these high-risk patients, this high intensity regimen and T depleted approach yielded satisfactory outcomes, but logistical difficulties in arranging URD grafts for patients with high-risk, unstable leukemia limited accrual. Improvements in peritransplantation disease control and additional measures to augment the allogeneic graft-versus-leukemia effect are still required.
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NK cell education after allogeneic transplantation: dissociation between recovery of cytokine-producing and cytotoxic functions.
Blood
PUBLISHED: 07-14-2011
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Natural killer (NK) cells mediate GVL effects after allogeneic hematopoietic cell transplantation (allo-HCT) by the production of inflammatory cytokines and by direct target lysis. The acquisition of both functions was presumed to be developmentally linked, but this linkage remained unstudied after allo-HCT. We tested the cytokine production and degranulation of reconstituting NK cells after adult unrelated donor or umbilical cord blood grafting. Recipients of T cell-depleted transplants, receiving no immune suppression, showed diminished NK cell degranulation. In contrast, degranulation was normal or increased after T-cell replete transplants given with immune suppression. Strikingly, target cell-induced IFN? production was markedly diminished in all transplant settings, especially with T cell-depleted or naive T cell-containing umbilical cord blood grafts, suggesting a role for T cells in NK education. Although degranulation was similar in the KIR(+) and KIR(-) populations that coexpressed NKG2A, target cell-induced IFN? production was limited to the subset of NK cells expressing KIR inhibited by self-ligands. Thus, cytokine production and cytotoxic function do not consistently coexist in NK cells reconstituting after allo-HCT. Exposure to IL-15 rapidly increased target-inducible IFN? production, indicative of IL-15s potential as a therapeutic tool to enhance NK cell function to protect against infection and relapse after allo-HCT.
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Absence of vasoactive intestinal peptide expression in hematopoietic cells enhances Th1 polarization and antiviral immunity in mice.
J. Immunol.
PUBLISHED: 06-15-2011
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Vasoactive intestinal peptide (VIP) induces regulatory dendritic cells (DC) in vitro that inhibit cellular immune responses. We tested the role of physiological levels of VIP on immune responses to murine CMV (mCMV) using VIP-knockout (VIP-KO) mice and radiation chimeras engrafted with syngenic VIP-KO hematopoietic cells. VIP-KO mice had less weight loss and better survival following mCMV infection compared with wild-type (WT) littermates. mCMV-infected VIP-KO mice had lower viral loads, faster clearance of virus, with increased numbers of IFN-?(+) NK and NKT cells, and enhanced cytolytic activity of NK cells. Adaptive antiviral cellular immunity was increased in mCMV-infected VIP-KO mice compared with WT mice, with more Th1/Tc1-polarized T cells, fewer IL-10(+) T cells, and more mCMV-M45 epitope peptide MHC class I tetramer(+) CD8(+) T cells (tetramer(+) CD8 T cells). mCMV-immune VIP-KO mice had enhanced ability to clear mCMV peptide-pulsed target cells in vivo. Enhanced antiviral immunity was also seen in WT transplant recipients engrafted with VIP-KO hematopoietic cells, indicating that VIP synthesized by neuronal cells did not suppress immune responses. Following mCMV infection there was a marked upregulation of MHC-II and CD80 costimulatory molecule expression on DC from VIP-KO mice compared with DC from WT mice, whereas programmed death-1 and programmed death ligand-1 expression were upregulated in activated CD8(+) T cells and DC, respectively, in WT mice, but not in VIP-KO mice. Because the absence of VIP in immune cells increased innate and adaptive antiviral immunity by altering costimulatory and coinhibitory pathways, selective targeting of VIP signaling represents an attractive therapeutic target to enhance antiviral immunity.
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Characterization of mechanical dyssynchrony measured by gated single photon emission computed tomography phase analysis after acute ST-elevation myocardial infarction.
J Nucl Cardiol
PUBLISHED: 06-04-2011
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Left ventricular dyssynchrony is an adverse consequence of ST-elevation myocardial infarction (STEMI) and bears an unfavorable prognosis. Mechanical dyssynchrony as measured by phase analysis from gated single photon emission computed tomography (GSPECT) correlates well with other imaging methods of assessing dyssynchrony but has not been studied in STEMI. We hypothesized that systolic dyssynchrony as measured by GSPECT would correlate with adverse remodeling after STEMI.
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Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: a Center for International Blood and Marrow Transplant Research study.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-26-2011
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Cytogenetics play a major role in determining the prognosis of patients with acute myelogenous leukemia (AML). However, existing cytogenetics classifications were developed in chemotherapy-treated patients and might not be optimal for patients undergoing allogeneic hematopoietic cell transplantation (HCT). We studied 821 adult patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) who underwent HCT for AML in first or second complete remission between 1999 and 2004. We compared the ability of the 6 existing classifications to stratify patients by overall survival. We then defined a new scheme specifically applicable to patients undergoing HCT using this patient cohort. Under this scheme, inv(16) is favorable, a complex karyotype (4 or more abnormalities) is adverse, and all other classified abnormalities are intermediate in predicting survival after HCT (5-year overall survival, 64%, 18%, and 50%, respectively; P = .0001). This scheme stratifies patients into 3 groups with similar nonrelapse mortality, but significantly different incidences of relapse, overall and leukemia-free survival. It applies to patients regardless of disease status (first or second complete remission), donor type (matched related or unrelated), or conditioning intensity (myeloablative or reduced intensity). This transplantation-specific classification could be adopted for prognostication purposes and to stratify patients with AML and karyotypic abnormalities entering HCT clinical trials.
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Effectiveness and cost analysis of "just-in-time" salvage plerixafor administration in autologous transplant patients with poor stem cell mobilization kinetics.
Transfusion
PUBLISHED: 04-14-2011
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Plerixafor is a recently Food and Drug Administration (FDA)-approved CXCR4 antagonist, which is combined with granulocyte-colony-stimulating factor (G-CSF) to facilitate stem cell mobilization of lymphoma and myeloma patients.
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Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies.
Blood
PUBLISHED: 04-04-2011
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The success of reduced intensity conditioning (RIC) transplantation is largely dependent on alloimmune effects. It is critical to determine whether immune modulation with anti-T-cell antibody infusion abrogates the therapeutic benefits of transplantation. We examined 1676 adults undergoing RIC transplantation for hematologic malignancies. All patients received alkylating agent plus fludarabine; 792 received allografts from a human leukocyte antigen-matched sibling, 884 from a 7 or 8 of 8 HLA-matched unrelated donor. Using Cox regression, outcomes after in vivo T-cell depletion (n = 584 antithymocyte globulin [ATG]; n = 213 alemtuzumab) were compared with T cell- replete (n = 879) transplantation. Grade 2 to 4 acute GVHD was lower with alemtuzumab compared with ATG or T cell- replete regimens (19% vs 38% vs 40%, P < .0001) and chronic GVHD, lower with alemtuzumab, and ATG regimens compared with T-replete approaches (24% vs 40% vs 52%, P < .0001). However, relapse was more frequent with alemtuzumab and ATG compared with T cell-replete regimens (49%, 51%, and 38%, respectively, P < .001). Disease-free survival was lower with alemtuzumab and ATG compared with T cell-replete regimens (30%, 25%, and 39%, respectively, P < .001). Corresponding probabilities of overall survival were 50%, 38%, and 46% (P = .008). These data suggest adopting a cautious approach to routine use of in vivo T-cell depletion with RIC regimens.
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CD34(+) cell infusion after ST elevation myocardial infarction is associated with improved perfusion and is dose dependent.
Am. Heart J.
PUBLISHED: 02-24-2011
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the objective of the study was to determine whether the effects of infarct-related artery (IRA) infusion of autologous bone marrow-derived CD34(+) cells after ST elevation myocardial infarction (STEMI) are dependent on the dose (quantity and mobility) of the cells infused. Beneficial effects of IRA infusion of mononuclear cells after STEMI have been inconsistent, possibly because of differences in timing, cell type, quantity, and mobility of infused cells.
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Prevention of transfusion-transmitted cytomegalovirus in low-birth weight infants (?1500 g) using cytomegalovirus-seronegative and leukoreduced transfusions.
Transfus Med Rev
PUBLISHED: 02-23-2011
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The transfusion-transmitted cytomegalovirus (TT-CMV) can cause serious morbidity and mortality in low-birth weight infants (LBWIs). Transfusion-transmitted cytomegalovirus can be minimized in LBWIs born to cytomegalovirus (CMV)-seronegative mothers with the use of CMV-seronegative blood components. Despite evidence that has independently shown that either leukoreduction or the use of CMV-seronegative components mitigates TT-CMV, the potential efficacy of combining these 2 strategies has not been substantiated in very LBWIs (<1500 g) born to either CMV-seronegative or CMV-seropositive mothers. Nonetheless, the serious risks of CMV infection posed by allogeneic transfusions and the broad implementation of universal leukoreduction have made this combination strategy the de facto clinical standard for transfusion of LBWIs. Although preferred, this combined approach has not been validated in clinical trials and, thus, warrants a large prospective study to determine whether this is the optimal transfusion tactic or if additional safety measures are necessary to prevent TT-CMV in LBWIs born to both CMV- seronegative and CMV-seropositive mothers. The aim of this prospective birth cohort study, therefore, is to estimate the incidence of TT-CMV in 1300 LBWIs (?1500 g) who receive CMV-seronegative plus leuko-reduced blood products to evaluate the effectiveness of this coupled strategy. Conducted in Atlanta, GA, this study has been registered at the US National Institutes of Health (ClinicalTrials.gov no. NCT00907686).
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A randomized clinical trial comparing granulocyte-colony-stimulating factor administration sites for mobilization of peripheral blood stem cells for patients with hematologic malignancies undergoing autologous stem cell transplantation.
Transfusion
PUBLISHED: 02-18-2011
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A study was undertaken to investigate whether granulocyte-colony-stimulating factor (G-CSF) injection in lower adipose tissue-containing sites (arms and legs) would result in a lower exposure and reduced stem cell collection efficiency compared with injection into abdominal skin.
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Treatment of severe neutropenia with high-dose pyridoxine in a patient with chronic graft versus host disease and squamous cell carcinoma: a case report.
J Med Case Rep
PUBLISHED: 02-09-2011
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The differential diagnosis of neutropenia includes medications, infections, autoimmune diseases, and deficiencies of Vitamin B12 and folate. The association of Vitamin B6 deficiency with severe neutropenia is a rare finding.
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A phase I/II trial combining high-dose melphalan and autologous transplant with bortezomib for multiple myeloma: a dose- and schedule-finding study.
Clin. Cancer Res.
PUBLISHED: 08-25-2010
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We did a randomized phase I/II trial designed to evaluate the safety and efficacy of combining the proteasome inhibitor bortezomib with high-dose melphalan as the conditioning for high-dose therapy and autologous transplant for myeloma.
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Comparison of outcomes after transplantation of G-CSF-stimulated bone marrow grafts versus bone marrow or peripheral blood grafts from HLA-matched sibling donors for patients with severe aplastic anemia.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-18-2010
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We compared outcomes of patients with severe aplastic anemia (SAA) who received granulocyte-colony stimulating factor (G-CSF)-stimulated bone marrow (G-BM) (n = 78), unstimulated bone marrow (BM) (n = 547), or peripheral blood progenitor cells (PBPC) (n = 134) from an HLA-matched sibling. Transplantations occurred in 1997 to 2003. Rates of neutrophil and platelet recovery were not different among the 3 treatment groups. Grade 2-4 acute graft-versus-host disease (aGVHD) (relative risk [RR] = 0.82, P = .539), grade 3-4 aGVHD (RR = 0.74, P = .535), and chronic GVHD (cGVHD) (RR = 1.56, P = .229) were similar after G-BM and BM transplants. Grade 2-4 aGVHD (RR = 2.37, P = .012) but not grade 3-4 aGVHD (RR = 1.66, P = .323) and cGVHD (RR = 5.09, P < .001) were higher after PBPC transplants compared to G-BM. Grade 2-4 (RR = 2.90, P < .001), grade 3-4 (RR = 2.24, P = .009) aGVHD and cGVHD (RR = 3.26, P < .001) were higher after PBPC transplants compared to BM. Mortality risks were lower after transplantation of BM compared to G-BM (RR = 0.63, P = .05). These data suggest no advantage to using G-BM and the observed higher rates of aGVHD and cGVHD in PBPC recipients warrants cautious use of this graft source for SAA. Taken together, BM is the preferred graft for HLA-matched sibling transplants for SAA.
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Comparable survival after HLA-well-matched unrelated or matched sibling donor transplantation for acute myeloid leukemia in first remission with unfavorable cytogenetics at diagnosis.
Blood
PUBLISHED: 06-10-2010
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We compared the outcomes of unrelated donor (URD, n = 358) with human leukocyte antigen (HLA)-matched sibling donor (MSD, n = 226) transplantations in patients with acute myeloid leukemia (AML) in first complete remission (CR1) having unfavorable cytogenetics at diagnosis. Unfavorable cytogenetic abnormalities were: complex (? 3 abnormalities), 32%; and noncomplex involving chromosome 7, 25%; chromosome 5, 9%; 11q or MLL rearrangements, 18%; t(6;9), 5%; and other noncomplex, 10%. URDs were HLA-well-matched (n = 254; 71%) or partially-matched (n = 104; 29%). Three-year leukemia-free survival (LFS) for MSD was 42% (95% confidence interval [CI], 35%-48%) compared with 34% (95% CI, 28%-41%) for HLA-well-matched URD and 29% (95% CI, 20%-39%) for partially-matched URD (P = .08). In multivariate analysis, HLA-well-matched URD and MSD yielded similar LFS (relative risk [RR] = 1.1, 95% CI, 0.86-1.40, P = .44) and overall survival (OS; RR = 1.06, 95% CI, 0.83-1.37, P = .63). LFS and OS were significantly inferior for HLA-partially-matched URD recipients, those with prior myelodysplastic syndrome, and those older than 50 years. All cytogenetic cohorts had similar outcomes. Patients with chronic graft-versus-host disease had a significantly lower risk of relapse (RR = 0.68, 95% CI, 0.47-0.99, P = .05). Hematopoietic cell transplantation (HCT) using HLA-well-matched URD and MSD resulted in similar LFS and OS in AML patients in CR1 with unfavorable cytogenetics. Outcomes of HCT from HLA-partially- matched URD were inferior.
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Receiver operating characteristic curve analysis of circulating blood dendritic cell precursors and T cells predicts response to extracorporeal photopheresis in patients with chronic graft-versus-host disease.
Transfusion
PUBLISHED: 06-10-2010
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One proposed mechanism of extracorporeal photopheresis (ECP) in reducing chronic graft-versus-host disease (cGVHD) is alteration in numbers of circulating dendritic cells (DCs). This hypothesis was tested by correlating numbers of DC precursors and T cells in the blood before and during ECP therapy with response of cGVHD.
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One-antigen mismatched related versus HLA-matched unrelated donor hematopoietic stem cell transplantation in adults with acute leukemia: Center for International Blood and Marrow Transplant Research results in the era of molecular HLA typing.
Biol. Blood Marrow Transplant.
PUBLISHED: 06-07-2010
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Approximately 13% of patients lacking an HLA-identical sibling have a one-antigen-mismatched related donor (MMRD). Historically, outcomes from the use of a one-antigen MMRD were considered equivalent to those from the use of a matched unrelated donor (UD). Recent improvements in UD stem cell transplantation (SCT) resulting from better molecular HLA matching justifies investigating whether UD should be preferred over MMRD in adult patients with acute leukemia. Here, we compared the outcomes of MMRD (n = 89) and HLA-A, -B, -C, and -DRB1 allele-matched UD (n = 700) SCT reported to the Center for International Blood and Marrow Transplant Research between 1995 and 2005. The patients underwent transplantation for acute myelogenous leukemia or acute lymphoblastic leukemia in first or second complete remission. Donor type was not associated with hematologic recovery. Univariate and multivariate comparisons of MMRD versus HLA-matched UD transplants showed no statistically significant differences in overall survival, disease-free survival, treatment-related mortality, relapse, or 100-day grade III-IV acute graft-versus-host disease (GVHD). MMRD SCT was associated with a lower rate of chronic GVHD at 1 year (35% vs 47%; P = .03), which was confirmed by multivariate analysis (relative risk, 0.58; 95% confidence interval, 0.39-0.85; P < .01). According to our data, HLA-matched UD and MMRD SCT are associated with comparable survival. Given that less chronic GVHD was observed in the MMRD transplantations, this option, when available, remains the first choice in patients with acute leukemia without an HLA-identical sibling in need of allogeneic SCT.
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Deep venous thromboses in patients with hematological malignancies after peripherally inserted central venous catheters.
Leuk. Lymphoma
PUBLISHED: 05-07-2010
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The incidence of deep venous thromboses (DVTs) associated with peripherally inserted central catheters (PICCs) in patients with hematological malignancies is not well described. We sought to determine the incidence, characteristics, and outcomes of PICC-related DVTs in this patient population. Retrospective, single center cohort analysis of patients with hematological malignancies with upper extremity PICCs and symptomatic upper extremity DVTs were identified by electronic medical record databases search. Between April 2001 and February 2006, 899 PICCs were placed in 498 patients, and ultrasound documented DVTs were observed in 39 (7.8%) a median of 26 days after PICC placement. Twenty-three (59%) had a new diagnosis of hematological malignancy at the time of PICC placement. DVT management included PICC removal (71%), thrombectomy/thrombolysis (13%), and 3-month anticoagulation. No pulmonary emboli or hemorrhages were observed. A change to centrally inserted tunneled internal jugular (IJ) catheters was instituted February 2006, and the incidence of DVTs was 0.4% among 843 tunneled IJ catheters placed in a subsequent cohort of 667 patients with hematological malignancies. Patients with hematological malignancies have a high incidence of PICC-associated DVTs. Internal jugular vein tunneled PICCs are associated with a very low incidence of DVTs in this patient population.
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Effect of age on outcome of reduced-intensity hematopoietic cell transplantation for older patients with acute myeloid leukemia in first complete remission or with myelodysplastic syndrome.
J. Clin. Oncol.
PUBLISHED: 03-08-2010
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PURPOSE Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) primarily afflict older individuals. Hematopoietic cell transplantation (HCT) is generally not offered because of concerns of excess morbidity and mortality. Reduced-intensity conditioning (RIC) regimens allow increased use of allogeneic HCT for older patients. To define prognostic factors impacting long-term outcomes of RIC regimens in patients older than age 40 years with AML in first complete remission or MDS and to determine the impact of age, we analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR). PATIENTS AND METHODS We reviewed data reported to the CIBMTR (1995 to 2005) on 1,080 patients undergoing RIC HCT. Outcomes analyzed included neutrophil recovery, incidence of acute or chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, disease-free survival (DFS), and overall survival (OS). RESULTS Univariate analyses demonstrated no age group differences in NRM, grade 2 to 4 acute GVHD, chronic GVHD, or relapse. Patients age 40 to 54, 55 to 59, 60 to 64, and > or = 65 years had 2-year survival rates as follows: 44% (95% CI, 37% to 52%), 50% (95% CI, 41% to 59%), 34% (95% CI, 25% to 43%), and 36% (95% CI, 24% to 49%), respectively, for patients with AML (P = .06); and 42% (95% CI, 35% to 49%), 35% (95% CI, 27% to 43%), 45% (95% CI, 36% to 54%), and 38% (95% CI, 25% to 51%), respectively, for patients with MDS (P = .37). Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS (all P > .3). Greater HLA disparity adversely affected 2-year NRM, DFS, and OS. Unfavorable cytogenetics adversely impacted relapse, DFS, and OS. Better pre-HCT performance status predicted improved 2-year OS. CONCLUSION With these similar outcomes observed in older patients, we conclude that older age alone should not be considered a contraindication to HCT.
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Activation, immune polarization, and graft-versus-leukemia activity of donor T cells are regulated by specific subsets of donor bone marrow antigen-presenting cells in allogeneic hemopoietic stem cell transplantation.
J. Immunol.
PUBLISHED: 11-23-2009
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We investigated the roles of specific subsets of donor APCs purified from bone marrow in donor T cell activation and graft-vs-leukemia (GvL) activity in murine models of hemopoietic stem cell transplantation. Lineage(-)CD11c(+) APC precursors were separated from donor bone marrow based on expression of CD11b. Transplanting lineage(-)CD11c(+)CD11b(-) APC (CD11b(-) APC) in combination with c-kit(+)Sca-1(+)lineage(-) hemopoietic stem cells (HSC) and congenic donor T cells led to increased donor CD4(+) and CD8(+) T cell proliferation and higher donor T cell chimerism than with transplanting grafts containing HSC, T cells, and lineage(-)CD11c(+)CD11b(+) APCs (CD11b(+) APC), or grafts containing only HSC and T cells. Transplanting CD11b(-) APCs induced Th1/type 1 cytotoxic T lymphocyte donor T cell immune polarization and enhanced GvL activity of donor T cells without increased graft-vs-host disease in both MHC- and minor histocompatibility Ag-mismatched murine hemopoietic stem cell transplantation models, whereas CD11b(+) APCs led to Th2/type 2 cytotoxic T lymphocyte donor T cell immune polarization. Donor CD11b(-) APCs were plasmacytoid dendritic cell progenitors (>90% CD317; PDCA-1(+)) and up-regulated CD80, CD86, and IL-12 during alloantigen presentation, whereas CD11b(+) APCs expressed Gr-1 and up-regulated expression of programmed death ligands-1 and 2 after activation. These results are the first to show that manipulation of the content of donor APCs in allogeneic HSC grafts can regulate donor T cell immunity and enhance GvL without increasing graft-vs-host disease activity.
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Separating graft-versus-leukemia from graft-versus-host disease in allogeneic hematopoietic stem cell transplantation.
Immunotherapy
PUBLISHED: 07-08-2009
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Routine methods to maximize the graft-versus-leukemia (GvL) activity of allogeneic hematopoietic stem cell transplantation (HSCT) without the detrimental effects of graft-versus-host disease (GvHD) are lacking. Depletion or inhibition of alloreactive T cells is partially effective in preventing GvHD, but usually leads to decreased GvL activity. The current model for the pathophysiology of acute GvHD describes a series of immune pathways that lead to activation of donor T cells and inflammatory cytokines responsible for tissue damage in acute GvHD. This model does not account for how allotransplant can lead to GvL effects without GvHD, or how the initial activation of donor immune cells may lead to counter-regulatory effects that limit GvHD. In this review, we will summarize new findings that support a more complex model for the initiation of GvHD and GvL activities in allogeneic HSCT, and discuss the potential of novel strategies to enhance GvL activity of the transplant.
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Dichotomous role of interferon-gamma in allogeneic bone marrow transplant.
Biol. Blood Marrow Transplant.
PUBLISHED: 05-06-2009
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Interferon (IFN)-gamma is a pleiotropic cytokine with a central role in innate and adaptive immunity. As a potent pro-inflammatory and antitumor cytokine, IFN-gamma is conventionally thought to be responsible for driving cellular immune response. On the other hand, accumulating evidence suggests that IFN-gamma also has immunosuppressive activity. An important role for IFN-gamma in inhibiting graft-versus-host disease (GVHD) has been demonstrated in murine models, despite IFN-gamma being one of the key factors amplifying T cell activation during the process of acute GVHD (aGVHD), the major complication and cause of post-transplant mortality in allogeneic bone marrow transplantation (BMT). At the same time, IFN-gamma facilitates graft-versus-leukemia (GVL) activity. Dissociation of GVL effects from GVHD has been the ultimate goal of allogeneic BMT in the treatment of hematologic malignancies. This paradoxic role of IFN-gamma makes modulating its activity a promising strategy to maximize GVL while minimizing GVHD and improve clinical outcomes in BMT. In this review, the effects of IFN-gamma on GVHD and GVL are discussed with consideration of the mechanism of IFN-gamma action.
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