PDLIM2 restricts Th1 and Th17 differentiation and prevents autoimmune disease

Background: PDLIM2 is essential for the termination of the inflammatory transcription factors NF-κB and STAT but is dispensable for the development of immune cells and immune tissues/organs. Currently, it remains unknown whether and how PDLIM2 is involved in physiologic and pathogenic processes. Results: Here we report that naive PDLIM2 deficient CD4+ T cells were prone to differentiate into Th1 and Th17 cells. PDLIM2 deficiency, however, had no obvious effect on lineage commitment towards Th2 or Treg cells. Notably, PDLIM2 deficient mice exhibited increased susceptibility to experimental autoimmune encephalitis (EAE), a Th1 and/or Th17 cell-mediated inflammatory disease model of multiple sclerosis (MS). Mechanistic studies further indicate that PDLIM2 was required for restricting expression of Th1 and Th17 cytokines, which was in accordance with the role of PDLIM2 in the termination of NF-κB and STAT activation. Conclusion: These findings suggest that PDLIM2 is a key modulator of T-cell-mediated immune responses that may be targeted for the therapy of human autoimmune diseases

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Untersuchungen im Mausmodell zu den Effekten von Spenderlymphozyteninfusionen nach allogener Knochenmaktransplantation

Die allogene Stammzelltransplantation ist das Therapieverfahren der Wahl für eine Reihe von malignen und nicht-malignen Erkrankungen des hämatopoetischen Systems. Dies ist darin begründet, daß dieses Verfahren nicht nur die Applikation einer myeloablativen und somit maximalen zytostatischen Therapie erlaubt (oder daß sie verbunden ist dem kompletten Ersatz der Empfängerhämatopoese durch den Spender), sondern vor allem dadurch, daß sie mit einem immunologisch vermittelten Anti-Tumor-Effekt, der Graft-versus-Leukämie-Reaktion (GVL) verbunden ist. In der Klinik ist die Anwendung der allogenen Stammzelltransplantation durch die assoziierten schwerwiegenden Komplikationen, zur Zeit noch erheblich eingeschränkt. Ziel dieser Arbeit war es die Mechanismen dieser T-zellvermittelten anti-Leukämie-Reaktion näher zu untersuchen. Im Mausmodell nach nicht-myeloablativer Konditionierung und alloegenr Kncohenmarktransplantation konnte gezeigt werden, dass die GVL-Reaktion welche durch die Spenderlympozyten vermittelt wird Alloantigen-abhänig ist, da sie in gemischten Chimären wesentlich stärker ausgeprägt ist als in vollen Chimären und ohne dass es zur entwicklung einer GVHD kommt..Weiterhin konnte gezeigt werden, dass diese Alloantigen-abhängige GVL-Reaktion nur kurzlebig ist, keine andauernde Immunität hinterlässt und dieser Verlust an GVL-reaktivität assoziiert ist mit dem verschwinden dieser alloreaktiven T-Zellpopulation.Allogeneic stem cell transplantation is the treatment of choice for a number of malignant and benign hematological diseases. This is due to the fact that this procedure not only allows the administration of a myeloablative and thus maximal cytoreductive therapy, but leads also to the substitution of the recipient hematopoiesis with the donor hematopoeisis. More important however, is the fact that this type of therapy is associated with a significant immunologically-mediated T-cell-dependent anti-tumor response the so called graft-versus - leukemia-reaction (GVL). However, the extensive use of allogeneic stem cell transplantation has been prevented by the considerable treatment-elated morbidity and mortality associated with allogeneic transplantation and the development of Graft-versus-Host-disease (GVHD). Using mouse models it could be observed that in mice following conditioning and allogeneic bone marrow transplantation donor lymphocyte-mediated GVL responses are primarily driven by direct immune recognition of host alloantigen. Furthermore, it could be shown that this GVL response is only transient and that the loss of this GVL effect occurs concomitantly with the contraction of the alloantigen-reactive T cell population

Histopathology of graft-vs-host disease of gastrointestinal tract and liver: An update

© American Society for Clinical Pathology, 2016. All rights reserved. Objectives: Graft-vs-host disease (GVHD) is a donor T-cellmediated disorder affecting the recipient\u27s skin, gastrointestinal tract, lungs, and liver. It complicates up to 70% of hematopoietic cell transplantation and is associated with high morbidity and mortality rates. Methods: An extensive review of the literature has been performed to include the most current consensus on the histopathologic diagnosis of gastrointestinal and liver GVHD. Results: In this review, we present an overview of GVHD, with emphasis on the histopathologic evaluation of gastrointestinal and liver specimens, including the most important differential diagnoses and possible pitfalls. Conclusions: Histopathologic examination remains the mainstay of diagnosis of gastrointestinal and liver GVHD and is interpreted in conjunction with clinical and laboratory data

Fertility Concerns and Access to Care for Stem Cell Transplant Candidates with Sickle Cell Disease.

Sickle cell disease affects 100,000 Americans and causes significant psychiatric illness and poor quality of life in many domains including infertility. Hematopoietic cell transplant (HCT) is the only cure for sickle cell disease, but can have its own chronic toxicities, including psychiatric conditions such as depression and anxiety, and sterility in both men and women. There is scant literature on fertility or psychiatric outcomes for sickle cell disease patients receiving HCT, and none considering the additive ramifications of the stresses of sickle cell disease, transplant, and infertility. Financial toxicity is a significant concern for all patients receiving stem cell transplantation. Treatment for infertility is also very expensive and access to fertility services is variable in the United States, which adds to the medical and quality of life burden for this patient population. Here we review the relevant areas of sickle cell disease and infertility, sickle cell disease and psychiatric wellness, access to care, and infertility and quality of life. These data collectively suggest that the group of patients with sickle cell disease who undergo HCT, and experience infertility are at particularly high risk for poor quality of life, worsening psychiatric health, and poor access to adequate fertility treatment