dynamic-adhesion-assay-for-functional-analysis-anti-adhesion

Dynamic Adhesion Assay for the Functional Analysis of Anti-adhesion Therapies in Inflammatory Bowel Disease

Gut homing of immune cells is important for the pathogenesis of inflammatory bowel diseases (IBD). Integrin-dependent cell adhesion to addressins is a ...

advanced-imaging-lung-homing-human-lymphocytes-an-experimental-vivo

Advanced Imaging of Lung Homing Human Lymphocytes in an Experimental In Vivo Model of Allergic Inflammation Based on Light-sheet Microscopy

Overwhelming tissue accumulation of highly activated immune cells represents a hallmark of various chronic inflammatory diseases and emerged as an ...

University of Erlangen-Nuremberg

University Hospital of Erlangen

Interleukin-12 (IL-12) was the first member of the IL-12 family of cytokines to be identified and has therefore become its eponym. It is a heterodimeric protein of two subunits (p35, p40) secreted by phagocytic cells in response to pathogens and mainly acts through STAT4 to induce IFN-γ production in T and NK cells. IFN-γ in turn mediates proinflammatory functions and activates T-bet. As IL-12 engages in TH1 development, it is believed to represent an important link between innate and adaptive immunity. Following its identification and the finding of its association to TH1 commitment, great hopes were placed in IL-12 to become a target for therapeutic applications in multiple settings of autoimmunity and cancer. Though, the discovery of the related members of the IL-12 family and several rather disappointing attempts to translate experimental results into clinical practice, have relativized these hopes. Nevertheless, IL-12 remains a cytokine of outstanding importance with lots of unresolved questions. In this review, we will first briefly depict the biochemistry of the cytokine, its receptor and the related signal transduction, before summarizing the regulation of IL-12 production and its biological functions. We will then describe the current knowledge about the implication of IL-12 in different murine disease models as well as in the corresponding human conditions and comment on possible consequences for future clinical applications. 

Interleukin-12: Functional activities and implications for disease.

Gut homing of lymphocytes via adhesion molecules has recently emerged as new target for therapy in IBDs. We aimed to analyse the in vivo homing of effector (Teff) and regulatory (Treg) T cells to the inflamed gut via α4β7 and G protein receptor GPR15.

Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo.

Inflammatory bowel diseases (IBD) are believed to arise from a complex interplay of environmental factors, genetic susceptibility, epithelial barrier defects and dysregulation of the intestinal immune system. Although the exact mechanisms of contribution and interference of these players are still not clear, significant advances have been achieved in understanding the immunopathogenesis of IBD in recent years resulting in novel and targeted therapeutic strategies. We will begin this review by giving a brief outline of current pathogenetic concepts of IBD and then focus on the description of the present knowledge of T cell function and regulation in the context of IBD. Moreover, we will summarise the progress on the emerging field of gut homing and delineate some implications for future therapeutic approaches. 

Immunopathogenesis of inflammatory bowel diseases: functional role of T cells and T cell homing.

Fundamental insights into the pathogenesis of inflammatory bowel diseases (IBD) have led to the development of new therapies and lots of experimental compounds in the pipeline. Our treatment of IBD is therefore constantly evolving. In this editorial, we postulate that bi- or even polyspecific therapy will be an important mainstay of future IBD treatment. Moreover, we highlight some promising new therapeutic concepts currently under investigation and point at the outstanding and growing importance of personalized medicine to assign drugs from the increasing pool of options to the individual patient. 

How will new and future therapies change our treatment of IBD?

Potassium channels have been shown to determine wound healing in different tissues, but their role in intestinal epithelial restitution--the rapid closure of superficial wounds by intestinal epithelial cells (IEC)--remains unclear.

K+ Channel Inhibition Differentially Regulates Migration of Intestinal Epithelial Cells in Inflamed vs. Non-Inflamed Conditions in a PI3K/Akt-Mediated Manner.

Pancreatic panniculitis is a rare condition, which has only been described in relation with pancreatic diseases up to now. It is characterized by necrotizing subcutaneous inflammation and is thought to be triggered by adipocyte necrosis due to systemic release of pancreatic enzymes with consecutive infiltration of neutrophils. We present the first case of a patient with pancreatic panniculitis caused by pancreatic-type primary acinar cell carcinoma (ACC) of the liver and without underlying pancreatic disease.

Pancreatic panniculitis in a patient with pancreatic-type acinar cell carcinoma of the liver--case report and review of literature.

Cytokines are believed to be crucial mediators of chronic intestinal inflammation in inflammatory bowel diseases (IBD) such as Crohn's disease (CD) and ulcerative colitis (UC). Many of these cytokines trigger cellular effects and functions through signaling via janus kinase (JAK) and signal transducer and activator of transcription (STAT) molecules. In this way, JAK/STAT signaling controls important events like cell differentiation, secretion of cytokines or proliferation and apoptosis in IBD in both adaptive and innate immune cells. Moreover, JAK/STAT signaling, especially via the IL-6/STAT3 axis, is believed to be involved in the transition of inflammatory lesions to tumors leading to colitis-associated cancer (CAC). In this review, we will introduce the main cellular players and cytokines that contribute to pathogenesis of IBD by JAK/STAT signaling, and will highlight the integrative function that JAK/STATs exert in this context as well as their divergent role in different cells and processes. Moreover, we will explain current concepts of the implication of JAK/STAT signaling in CAC and finally discuss present and future therapies for IBD that interfere with JAK/STAT signaling. 

Integrating Immunologic Signaling Networks: The JAK/STAT Pathway in Colitis and Colitis-Associated Cancer.

Therapeutically targeting lymphocyte adhesion is of increasing relevance in IBD. Yet, central aspects of the action of antiadhesion compounds are incompletely understood. We investigated the role of αEβ7 and α4β7 integrins and their blockade by vedolizumab and etrolizumab for trafficking of IBD T lymphocytes in an in vivo model of homing to and retention in the inflamed gut.

Blockade of αEβ7 integrin suppresses accumulation of CD8 and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo.

The precise mechanisms controlling homing of T effector (Teff) cells to the inflamed gut in Crohn's disease (CD) are still unclear, and clinical outcome data from patients with inflammatory bowel disease treated with the anti-α4β7 integrin antibody vedolizumab suggest differences between ulcerative colitis and CD.

The α4β1 Homing Pathway Is Essential for Ileal Homing of Crohn's Disease Effector T Cells In Vivo.

Therapeutic compounds interfering with T cell trafficking are a new column of inflammatory bowel disease (IBD) treatment. Currently, the anti-α4β7 integrin antibody vedolizumab is successfully used in the clinic and further drugs are likely to follow. Despite these clinical advances, the precise mechanistic background of their action is only gradually elucidated and still a matter of intensive research. Only recently, advances made with the help of new in vivo models and human studies have contributed to shape our concept of T cell trafficking in IBD by deciphering some important and so far unanswered questions. At the same time, basic and clinical data have generated new issues to be addressed on the way toward a clear perception of trafficking mechanisms and toward elucidation of the action of compounds interfering with this process. In this review, we will give a comprehensive outline of all components of T cell trafficking in regard to IBD before discussing the current knowledge concerning targeted interference with integrins in this complex network. Moreover, we will summarize remaining ambiguity and give an outlook on potential future targets.

Novel Insights into the Mechanisms of Gut Homing and Antiadhesion Therapies in Inflammatory Bowel Diseases.

Homeostasis in the gastrointestinal tract relies on a sensitive equilibrium between permissive and protective functions. This is closely reflected in the regulation of the intestinal immune system and especially T cells in the gut. This balance, however, is susceptible to disturbances as demonstrated by pathological conditions like food allergy, celiac disease, or inflammatory bowel disease. In these allergic and chronic inflammatory bowel disorders, luminal antigens get access to the lamina propria where they trigger a dysregulated immune response with crucial involvement of different T cell subsets. We will begin this review with some comprehensive remarks on current concepts on the pathogenesis of these diseases before taking a closer look at the life cycle of intestinal T cells consisting of priming, homing, differentiation and proliferation and apoptosis respectively. Subsequently we will discuss the specific implication of distinct T cell subsets in allergic and chronic inflammatory conditions of the gastrointestinal tract in detail and comment on current and future approaches to targeted therapy in this context.

Pathogenic T cell subsets in allergic and chronic inflammatory bowel disorders.

The number of biologicals for the therapy of immunologically mediated diseases is constantly growing. In contrast to other agents that were previously introduced in rheumatologic or dermatologic diseases and only later adopted for the treatment of inflammatory bowel diseases (IBDs), the field of IBD was ground breaking for the concept of anti-adhesion blockade. Anti-adhesion antibodies selectively target integrins controlling cell homing to the intestine, which leads to reduction of inflammatory infiltration to the gut in chronic intestinal inflammation. Currently, the anti-α4β7-antibody vedolizumab is successfully used for both Crohn's disease and ulcerative colitis worldwide. In this mini-review, we will summarize the fundamental basis of intestinal T cell homing and explain the molecular groundwork underlying current and potential future anti-adhesion therapies. Finally, we will comment on noteworthy clinical aspects of anti-adhesion therapy and give an outlook to the future of anti-integrin antibodies and inhibitors.

Anti-Adhesion Therapies in Inflammatory Bowel Disease-Molecular and Clinical Aspects.

Polyarthritis can have numerous reasons and may thus constitute a challenge for differential diagnosis. One rare potential reason for sterile polyarthritis is underlying pancreatic disease with systemic hyperlipasemia, most often accompanied by painful skin lesions caused by a subcutaneous inflammatory process known as panniculitis. Systematic evidence on pancreatic panniculitis and polyarthritis is limited, particularly regarding its feature as facultative paraneoplasia with underlying intra- or even extra-pancreatic malignancy. Therefore, we will summarize the current knowledge about this orphan disease including epidemiological, pathophysiological, diagnostic, and treatment aspects in the present review.

Pancreatic Panniculitis and Polyarthritis.

Three-Dimensional Cross-Sectional Light-Sheet Microscopy Imaging of the Inflamed Mouse Gut.

Acute graft-versus-host disease (GVHD) represents a severe, T cell-driven inflammatory complication following allogeneic hematopoietic cell transplantation (allo-HCT). GVHD often affects the intestine and is associated with a poor prognosis. Although frequently detectable, proinflammatory mechanisms exerted by intestinal tissue-infiltrating Th cell subsets remain to be fully elucidated. Here, we show that the Th17-defining transcription factor basic leucine zipper transcription factor ATF-like (BATF) was strongly regulated across human and mouse intestinal GVHD tissues. Studies in complete MHC-mismatched and minor histocompatibility-mismatched (miHA-mismatched) GVHD models revealed that BATF-expressing T cells were functionally indispensable for intestinal GVHD manifestation. Mechanistically, BATF controlled the formation of colon-infiltrating, IL-7 receptor-positive (IL-7R+), granulocyte-macrophage colony-stimulating factor-positive (GM-CSF+), donor T effector memory (Tem) cells. This T cell subset was sufficient to promote intestinal GVHD, while its occurrence was largely dependent on T cell-intrinsic BATF expression, required IL-7-IL-7R interaction, and was enhanced by GM-CSF. Thus, this study identifies BATF-dependent pathogenic GM-CSF+ effector T cells as critical promoters of intestinal inflammation in GVHD and hence putatively provides mechanistic insight into inflammatory processes previously assumed to be selectively Th17 driven.

BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease.

Although anti-adhesion therapies are a novel mainstay in the treatment of inflammatory bowel diseases (IBDs), the mechanisms controlling integrin-dependent gut homing are poorly elucidated, and the available techniques for translational functional investigations are limited.

ArticleTotal : 2	Year
Publication title Cited by 4	2018
Publication title Cited by 4	2019

Article	Year
Interleukin-12: Functional activities and implications for disease. Cytokine & growth factor reviews\| PubMed ID: 26182974	2015
Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo. Gut\| PubMed ID: 26209553	2016
Immunopathogenesis of inflammatory bowel diseases: functional role of T cells and T cell homing. Clinical and experimental rheumatology\| PubMed ID: 26458165	2015
How will new and future therapies change our treatment of IBD? Expert review of clinical immunology\| PubMed ID: 26558407	2016
K+ Channel Inhibition Differentially Regulates Migration of Intestinal Epithelial Cells in Inflamed vs. Non-Inflamed Conditions in a PI3K/Akt-Mediated Manner. PloS one\| PubMed ID: 26824610	2016
Pancreatic panniculitis in a patient with pancreatic-type acinar cell carcinoma of the liver--case report and review of literature. BMC cancer\| PubMed ID: 26895632	2016
Integrating Immunologic Signaling Networks: The JAK/STAT Pathway in Colitis and Colitis-Associated Cancer. Vaccines\| PubMed ID: 26938566	2016
Blockade of αEβ7 integrin suppresses accumulation of CD8 and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo. Gut\| PubMed ID: 27543429	2017
The α4β1 Homing Pathway Is Essential for Ileal Homing of Crohn's Disease Effector T Cells In Vivo. Inflammatory bowel diseases\| PubMed ID: 28221249	2017
Novel Insights into the Mechanisms of Gut Homing and Antiadhesion Therapies in Inflammatory Bowel Diseases. Inflammatory bowel diseases\| PubMed ID: 28296823	2017
Pathogenic T cell subsets in allergic and chronic inflammatory bowel disorders. Immunological reviews\| PubMed ID: 28658546	2017
Anti-Adhesion Therapies in Inflammatory Bowel Disease-Molecular and Clinical Aspects. Frontiers in immunology\| PubMed ID: 28804488	2017
Pancreatic Panniculitis and Polyarthritis. Current rheumatology reports\| PubMed ID: 28844095	2017
Three-Dimensional Cross-Sectional Light-Sheet Microscopy Imaging of the Inflamed Mouse Gut. Gastroenterology\| PubMed ID: 28870528	2017
BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease. The Journal of clinical investigation\| PubMed ID: 29376889	2018
Similar Inhibition of Dynamic Adhesion of Lymphocytes From IBD Patients to MAdCAM-1 by Vedolizumab and Etrolizumab-s. Inflammatory bowel diseases\| PubMed ID: 29788362	2018

Sebastian Zundler

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