HLA-DR Alpha 2 Mediates Negative Signalling via Binding to Tirc7 Leading to Anti-Inflammatory and Apoptotic Effects in Lymphocytes In Vitro and In Vivo

Classically, HLA-DR expressed on antigen presenting cells (APC) initiates lymphocyte activation via presentation of peptides to TCR bearing CD4+ T-Cells. Here we demonstrate that HLA-DR alpha 2 domain (sHLA-DRα2) also induces negative signals by engaging TIRC7 on lymphocytes. This interaction inhibits proliferation and induces apoptosis in CD4+ and CD8+ T-cells via activation of the intrinsic pathway. Proliferation inhibition is associated with SHP-1 recruitment by TIRC7, decreased phosphorylation of STAT4, TCR-ζ chain & ZAP70, and inhibition of IFN-γ and FasL expression. HLA-DRα2 and TIRC7 co-localize at the APC-T cell interaction site. Triggering HLA-DR - TIRC7 pathway demonstrates that sHLA-DRα2 treatment inhibits proinflammatory-inflammatory cytokine expression in APC & T cells after lipopolysaccaride (LPS) stimulation in vitro and induces apoptosis in vivo. These results suggest a novel antiproliferative role for HLA-DR mediated via TIRC7, revise the notion of an exclusive stimulatory interaction of HLA-DR with CD4+ T cells and highlights a novel physiologically relevant regulatory pathway

Immunohistochemical Characterisation of Cell-Type Specific Expression of CK1δ in Various Tissues of Young Adult BALB/c Mice

BACKGROUND: Casein kinase 1 delta (CK1delta) phosphorylates many key proteins playing important roles in such biological processes as cell growth, differentiation, apoptosis, circadian rhythm and vesicle transport. Furthermore, deregulation of CK1delta has been linked to neurodegenerative diseases and cancer. In this study, the cell specific distribution of CK1delta in various tissues and organs of young adult BALB/c mice was analysed by immunohistochemistry. METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical staining of CK1delta was performed using three different antibodies against CK1delta. A high expression of CK1delta was found in a variety of tissues and organ systems and in several cell types of endodermal, mesodermal and ectodermal origin. CONCLUSIONS: These results give an overview of the cell-type specific expression of CK1delta in different organs under normal conditions. Thus, they provide evidence for possible cell-type specific functions of CK1delta, where CK1delta can interact with and modulate the activity of key regulator proteins by site directed phosphorylation. Furthermore, they provide the basis for future analyses of CK1delta in these tissues

Evidence and evidence gaps - an introduction

Background: Medical treatment requires the implementation of existing evidence in the decision making process in order to be able to find the best possible diagnostic, therapeutic or prognostic measure for the individual patient based on the physician's own expertise. Clinical trials form the evidence base and ideally, their results are assembled, analyzed, summarized, and made available in systematic review articles. Beside planning, conducting, and evaluating clinical trials in conformity with GCP (good clinical practice), it is essential that all results of conducted studies are publicly available in order to avoid publication bias. This includes also the public registration of planned and cancelled trials. History: During the last 25 years, evidence-based medicine became increasingly important in medical care and research. It is closely associated with the names of Archibald Cochrane and David Sackett. About 15 years ago, the Deutsche Cochrane Zentrum (Cochrane Germany) and the Deutsche Netzwerk Evidenzbasierte Medizin e.V. (German Network for Evidence-based Medicine, DNEbM) were founded in Germany. In the International Cochrane Collaboration, clinicians and methodologists come together on an interdisciplinary level to further develop methods of evidence-based medicine and to discuss the topics of evidence generation and processing as well as knowledge transfer.Problem: Evidence is particularly important for physicians in the process of decision making, however, at the same time it is the base of a scientific proof of benefit for the patient and finally for the payers in health care. The closure of evidence gaps requires enormously high staff and financial resources, significant organizational efforts, and it is only successful when clinical and methodical expertise as well as specific knowledge in the field of clinical research are included. On the other hand, the knowledge has to be transferred into practice. For this purpose, practice guidelines, meetings, databases, information portals with processed evidence as well as specific journals and finally teaching are appropriate vehicles. One problem is the multitude of information so that knowledge gaps may affect the clinical routine despite actually existing evidence. Generally, it still takes several years until new knowledge is implemented in daily routine.Tasks: The German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (Deutsche Gesellschaft für Hals-, Nasen- und Ohren-Heilkunde, Kopf- und Hals-Chirurgie e.V., DGHNOKHC) and the Professional Association of Otolaryngologists (Deutscher Berufsverband der HNO-Ärzte e.V., BVHNO) have fundamental interest in supporting their members in generating, processing, and providing evidence as well as accompanying knowledge transfer. It encompasses the fields of diagnostics, therapy, and prognosis in the same way as prevention and applies to medicinal products as well as to medical devices or surgical procedures. The base for this is the regular assessment of evidence gaps, also in the area of established procedures, that has to be followed by a prioritization of research questions and the subsequent initiation of clinical research. In addition, large trials verifying therapies and diagnostics, for example in the context of daily conditions after approval, can only be conducted combining all resources in the ENT community.Method, results, and outlook: Together, the executive committees of the DGHNOKHC and the BVHNO founded the German Study Center of Oto-Rhino-Laryngology, Head and Neck Surgery (Deutsches Studienzentrum für Hals-, Nasen- und Ohren-Heilkunde, Kopf- und Hals-Chirurgie, DSZ-HNO). First projects have been initiated, among those a clinical trial on the therapy of sudden hearing loss supported by the BMBF and a survey on evidence gaps in oto-rhino-laryngology. It seems to be both reasonable and feasible to make available methodological expertise via such an infrastructure of a study center for physicians in hospitals and private practices in order to support clinical research and to implement the principles of evidence-based medicine in daily routine

Evidence and evidence gaps - an introduction

Background: Medical treatment requires the implementation of existing evidence in the decision making process in order to be able to find the best possible diagnostic, therapeutic or prognostic measure for the individual patient based on the physician's own expertise. Clinical trials form the evidence base and ideally, their results are assembled, analyzed, summarized, and made available in systematic review articles. Beside planning, conducting, and evaluating clinical trials in conformity with GCP (good clinical practice), it is essential that all results of conducted studies are publicly available in order to avoid publication bias. This includes also the public registration of planned and cancelled trials. History: During the last 25 years, evidence-based medicine became increasingly important in medical care and research. It is closely associated with the names of Archibald Cochrane and David Sackett. About 15 years ago, the Deutsche Cochrane Zentrum (Cochrane Germany) and the Deutsche Netzwerk Evidenzbasierte Medizin e.V. (German Network for Evidence-based Medicine, DNEbM) were founded in Germany. In the International Cochrane Collaboration, clinicians and methodologists come together on an interdisciplinary level to further develop methods of evidence-based medicine and to discuss the topics of evidence generation and processing as well as knowledge transfer.Problem: Evidence is particularly important for physicians in the process of decision making, however, at the same time it is the base of a scientific proof of benefit for the patient and finally for the payers in health care. The closure of evidence gaps requires enormously high staff and financial resources, significant organizational efforts, and it is only successful when clinical and methodical expertise as well as specific knowledge in the field of clinical research are included. On the other hand, the knowledge has to be transferred into practice. For this purpose, practice guidelines, meetings, databases, information portals with processed evidence as well as specific journals and finally teaching are appropriate vehicles. One problem is the multitude of information so that knowledge gaps may affect the clinical routine despite actually existing evidence. Generally, it still takes several years until new knowledge is implemented in daily routine.Tasks: The German Society of Oto-Rhino-Laryngology, Head and Neck Surgery (Deutsche Gesellschaft für Hals-, Nasen- und Ohren-Heilkunde, Kopf- und Hals-Chirurgie e.V., DGHNOKHC) and the Professional Association of Otolaryngologists (Deutscher Berufsverband der HNO-Ärzte e.V., BVHNO) have fundamental interest in supporting their members in generating, processing, and providing evidence as well as accompanying knowledge transfer. It encompasses the fields of diagnostics, therapy, and prognosis in the same way as prevention and applies to medicinal products as well as to medical devices or surgical procedures. The base for this is the regular assessment of evidence gaps, also in the area of established procedures, that has to be followed by a prioritization of research questions and the subsequent initiation of clinical research. In addition, large trials verifying therapies and diagnostics, for example in the context of daily conditions after approval, can only be conducted combining all resources in the ENT community.Method, results, and outlook: Together, the executive committees of the DGHNOKHC and the BVHNO founded the German Study Center of Oto-Rhino-Laryngology, Head and Neck Surgery (Deutsches Studienzentrum für Hals-, Nasen- und Ohren-Heilkunde, Kopf- und Hals-Chirurgie, DSZ-HNO). First projects have been initiated, among those a clinical trial on the therapy of sudden hearing loss supported by the BMBF and a survey on evidence gaps in oto-rhino-laryngology. It seems to be both reasonable and feasible to make available methodological expertise via such an infrastructure of a study center for physicians in hospitals and private practices in order to support clinical research and to implement the principles of evidence-based medicine in daily routine