optimization-of-the-cuff-technique-for-murine-heart-transplantation

Optimization of the Cuff Technique for Murine Heart Transplantation

Murine cardiac transplantation has been performed for more than 40 years. With advancements in microsurgery, certain new techniques have been used to ...

Xiamen University

Fujian Key Laboratory of Organ and Tissue Regeneration

Donor-reactive memory T cells are major barriers to long-term survival of transplanted organs due to their capacity to accelerate rejection. In this study we investigated the ability of 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] to inhibit accelerated rejection mediated by alloreactive CD4(+) memory T cells and to prolong cardiac allograft survival in an adoptive T cell memory/heart transplant model of nude mice. In vitro, the proliferation of CD4(+) memory T cells was significantly inhibited by 1,25(OH)(2)D(3) and was restored following addition of exogenous IL-2. Compared with the control group, the mean survival time of cardiac allografts in the 1,25(OH)(2)D(3) group was prolonged from 6.5±0.3 to 20.2±0.8 days in vivo. Five days after transplantation, the levels of IL-2 and IFN-γ were reduced in the grafts and the recipient sera by 1,25(OH)(2)D(3) treatment, while that of IL-10 increased. The proportions of CD4(+) memory T cells and CD4(+)Foxp3(+) T cells, both in recipient spleen and lymph nodes, were lowered by 1,25(OH)(2)D(3) treatment when compared with the control group. Our data suggests that 1,25(OH)(2)D(3) inhibits expansion of CD4(+) memory T cells, possibly by inducing clonal anergy and/or clonal deletion, resulting in prolongation of cardiac allograft survival in nude mice. These results may provide a rational basis for exploiting 1,25(OH)(2)D(3) as a novel immunosuppressant targeting CD4(+) memory T cells.

Inhibiting accelerated rejection mediated by alloreactive CD4(+) memory T cells and prolonging allograft survival by 1α,25-dihydroxyvitamin D(3) in nude mice.

The aim of this study was to evaluate and determine the potential mechanisms of As₂O₃ in accelerated rejection mediated by alloreactive CD4⁺ memory T cells. Vascularized heterotopic cardiac transplantation from C57BL/6 mice to nude mice (pre-transferred CD4⁺ memory T cells) was performed on Day 0, and As₂O₃ was administered to recipient mice from Day 0 to 10. As a result, As₂O₃ could reduce the proliferation of allo-primed CD4⁺ memory T cells in vitro in MLR and the baseline rate of proliferation was restored by the addition of exogenous IL-2. In vivo, compared with the control[+] group, the mean survival time of cardiac allografts in the As₂O₃ group was prolonged from 5.8 ± 0.7 to 14.2 ± 2.5 days. Five days after transplantation, the relative gene expression of IL-2, IFN-γ and Foxp3 was reduced in the grafts by As₂O₃ treatment, but the expression of IL-10 and TGF-β was increased. Correspondingly, the proportions of CD4⁺ T cells, CD4⁺ memory T cells and regulatory T cells (Tregs), both in recipient spleens and lymph nodes, were lowered. These results indicate the potential of As2O3 as a novel immunosuppressant targeting CD4⁺ memory T cells.

Inhibition of accelerated rejection mediated by alloreactive CD4⁺ memory T cells and prolonged allograft survival by arsenic trioxide.

We report a case of a 44-year-old male patient with ectopic drainage from the inferior vena cava to the left atrium accompanied by partial anomalous pulmonary venous drainage. After the patient was hospitalized, his diagnosis was confirmed by Doppler echocardiography and angiography. A pericardial patch was used to divert the blood to the atrium. The surgical procedure was successful, and the patient began a rehabilitation program 8 days later. This type of ectopic drainage pattern is an unusual and infrequent clinical finding. The definitive diagnosis should be made by Doppler ultrasound combined with angiography. 

Ectopic drainage from the inferior vena cava to the left atrium together with a partial anomalous pulmonary venous connection.

Dendritic cells (DCs) have the tolerogenic potential to regulate adaptive immunity and induce allografts acceptance. Here we investigated whether blockade of the CD40 pathway could enhance the immune tolerance induced by DC2.4 cells modified to express Jagged-1 (JAG1-DC) in heart transplantation. Results showed that JAG1-DC treatment combined with anti-CD40L monoclonal antibody (mAb) administration significantly prolonged cardiac allograft survival in mice, with long-term survival (>110 days) of 50% of the allografts in the recipients. The therapy specifically inhibited the immune response, induced alloantigen-specific T-cell hyporesponsiveness, upregulated transforming growth factor-β synthesis and increased the population of regulatory T cells (Tregs) driven by Jagged-1-Notch activation. These results highlight the potential application of gene therapy to induce alloantigen-specific Tregs effectively by providing the Jagged-1 stimulation. 

Overexpression of Jagged-1 combined with blockade of CD40 pathway prolongs allograft survival.

The development of a suitable extracellular matrix (ECM) scaffold is the first step in vascular tissue engineering (VTE). Synthetic vascular grafts are available as an alternative to autologous vessels in large-diameter arteries (>8 mm) and medium-diameter arteries (6-8 mm). In small-diameter vessels (<6 mm), synthetic vascular grafts are of limited use due to poor patency rates. Compared with a vascular prosthesis, natural tissue ECM has valuable advantages. Despite considerable progress in recent years, identifying an optimal protocol to create a scaffold for use in small-diameter (<6 mm) fully natural tissue-engineered vascular grafts (TEVG), remains elusive. Although reports on different decellularization techniques have been numerous, combination of and comparison between these methods are scarce; therefore, we have compared five different decellularization protocols for making small-diameter (<6 mm) ECM scaffolds and evaluated their characteristics relative to those of fresh vascular controls.

Preparation and characterization of small-diameter decellularized scaffolds for vascular tissue engineering in an animal model.

To develop tissue-engineered arteries (TEAs) with collateral arteries(CAs) in ischemic hind limb goat models(IHLMs). The IHLMs created by removing femoral arteries were divided into non-treated control group(NG); non-catheter group (NCG) in which TEA was anastomosed to external iliac artery(EIA), and surrounded with collagen sponge containing autologous MSCs and VEGF-gelatin microspheres, the distal end of TEA was ligated; catheter group(CG) which received the same procedure as NCG, also received heparin infusion through catheter in EIA. TEA patency was assessed weekly by Ultrasound. The TEA and CAs were assessed by angiography, gross examination, histology and electron microscopy. In CG, TEAs remained patent for 1 month, but became partly occluded 1 week after catheter withdrawn. In NCG, TEAs were occluded 1 week after implantation. Angiography demonstrated that communication between CAs arising from the TEAs and the native vessels was established in both groups. NCG had fewer CAs than CG (P < 0.01). At 40 days, TEAs in CG demonstrated of endothelium formation, smooth muscle cells infiltration and collagen regeneration. The CG had more capillaries and mature vessels in adventia of TEAs than NCG (P < 0.01). CG group also had more vessels around TEAs than NCG (P < 0.01) or NG (P < 0.001).

The development of an extra-anatomic tissue-engineered artery with collateral arteries for therapeutic angiogenesis in ischemic hind limb.

Accelerated transplant rejection mediated by donor reactive memory T cells is another barrier to the induction of graft tolerance. The aim of this study was to investigate the immunosuppressing effects of vitamin D (1,25(OH)2D3), administered alone or in combination with a costimulatory blockade treatment, on rejection of secondary heart allografts in a mouse model.

Article	Year
Inhibiting accelerated rejection mediated by alloreactive CD4(+) memory T cells and prolonging allograft survival by 1α,25-dihydroxyvitamin D(3) in nude mice. Immunology letters\| PubMed ID: 23147102	2013
Inhibition of accelerated rejection mediated by alloreactive CD4⁺ memory T cells and prolonged allograft survival by arsenic trioxide. Immunological investigations\| PubMed ID: 23802174	2013
Ectopic drainage from the inferior vena cava to the left atrium together with a partial anomalous pulmonary venous connection. Annals of vascular surgery\| PubMed ID: 24333195	2014
Overexpression of Jagged-1 combined with blockade of CD40 pathway prolongs allograft survival. Immunology and cell biology\| PubMed ID: 25287443	2015
Preparation and characterization of small-diameter decellularized scaffolds for vascular tissue engineering in an animal model. Biomedical engineering online\| PubMed ID: 28494781	2017
The development of an extra-anatomic tissue-engineered artery with collateral arteries for therapeutic angiogenesis in ischemic hind limb. Scientific reports\| PubMed ID: 29545563	2018
Combined treatment with vitamin D3 and antibody agents suppresses secondary heart transplant rejection in the early postoperative period. Transplant immunology\| PubMed ID: 31953155	2020

Shuangyue Xu

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