دانلود رایگان مقاله انگلیسی بررسی القاء قدرت تحمل ایمنی در بیماری هموفیلی A - الزویر 2018

Abstract

At first sight the bleeding disorder hemophilia A seems to have little in common with immune disorders, but immunology research intersects with other disciplines including hematology. Nowadays, the most important complication in the treatment of hemophilia A is the development of neutralizing antibodies (inhibitors) against exogenous administered factor VIII (FVIII), which occurs in approximately 30% of all patients with severe hemophilia A. This antibody response renders FVIII replacement therapy ineffective, thereby increasing the risk for uncontrollable bleeding and morbidity, decreasing quality of life and increasing healthcare costs. The only proven effective therapy to eradicate these inhibitors is immune-based. Using a protocol called ‘immune tolerance induction’ (ITI), the repeated and frequent administration of FVIII under non-inflammatory conditions downregulates the established antibody response and induces immune tolerance. There has been progress in research clarifying the mechanisms that mediate tolerance induction using ITI, both from patient studies and from research in cell culture and animal-based models. Peripheral tolerance induction to FVIII involves the apoptosis of antigen-specific B-memory cells, anergy induction in antigen-specific effector T-cells (Teff), induction of regulatory T-cells (Treg) and the formation of antiidiotypic antibodies. In this review hemophilia A will be used as an example to discuss current concepts of tolerance induction as they are applied in patient care. Where possible, we will extrapolate tolerance findings in hemophilia A to related pathways known to affect auto-immune disorders or allergy.

7. Conclusion

ITI is until now the only effective therapy to eradicate inhibitors in hemophilia A. Although knowledge about the mechanisms mediating tolerance induction has expanded significantly, much is still to be elucidated. The hypothesized mechanism involved in ITI is that repeated administration of FVIII in a non inflammatory state causes anergy induction of Teffs, induction of Tregs, apoptosis of B-cells and possibly also generation of anti-idiotypic antibodies. Based on ITI in hemophilia, two important paradigms appear as being essential for the induction of tolerance for other allergies and autoimmune diseases/disorders too. First, antigen should be presented by tolerogenic rather than immunogenic APCs. And secondly, this should result in the induction of regulatory cells. Here, regulatory T-cells and their production of suppressive cytokines, like IL-10 and TGF-β, play a central and pivotal role. However, also other regulatory cells are increasingly identified, which include MDSCs, (immature) DCs, mesenchymal stromal cells, and regulatory macrophages, B- and CD8+ T-cells. Further research should clarify the exact role of these cells in the process of tolerance induction. Other interesting future research subjects include unraveling the optimal way to direct allergens to a tolerogenic APC, including the role of FVIII dose and type in this process, and elucidating how to eradicate FVIIIspecific long-living plasma cells (which are less susceptible to tolerance induction due to downregulated antigen receptors).