Studying The Immune Tolerance Mechanism Induced By Regulatory T Cells In Skin Transplantation

Transplantation has become a mainstay of therapy for most patients with end-stage organ dysfunction. During the past 30 years, organ transplantation has developed from a highly experimental procedure into an important part of routine clinical practice. This is reflected by the fact that graft survival time has been significantly prolonged, and such survival depends on a number of factors but the most significant of these is the administration of powerful immunosuppressive drugs. Transplantation between genetically disparate individuals (transplantation of an allograft or xenograft) evokes a rapid and potentially destructive immune response that, if left unchecked, can lead to almost complete destruction of the transplanted organ within a matter of days. Administration of immunosuppressive drugs (such as the purine analogue azathioprine, the steroid methylprednisolone, the cyclic peptide cyclosporin A and a variety of anti-lymphocyte antibody preparations) attenuates this response and thus prevents acute graft rejection. However, continued graft survival depends on life-long immunosuppression because, except for a very small number of cases (the majority of which involve liver transplantation and should probably be regarded as a special case), withdrawal of immunosuppression results in re-activation of the rejection response, leading to rapid graft destruction. Although the immunosuppressive drugs that are currently available and very effective in the short term, substantial problems in four specific areas indicate a pressing need to develop alternative and more sophisticated ways of preventing graft rejection. These areas can be summarised as follows: â‘ chronic graft rejection, â‘¡transplant-associated vasculopathy, â‘¢infection and â‘£ cancer.Clinical success continues to be limited by the ongoing need in the majority of patients for nonspecific immunosuppressive therapy that reduces the risk of graft rejection but also brings with it unwanted effects, such as increased susceptibility to infection and malignancy. In addition, the majority of immunosuppressive drugs in current clinical use act by inhibiting T cell activation and thus prevent graft rejection; however, this may be counter-productive, as under appropriate circumstances, T cell activation may lead to the induction of processes facilitating the development of graft-specific tolerance. The finaldestruction of an allograft might involve most, or perhaps all, of the cellular and non-cellular components of the immune system, but many studies have shown that T lymphocytes and particularly CD4+ T cells play an essential pivotal role in graft rejection. Therefore, the majority of protocols aimed at providing true transplantation tolerance are designed to tolerise T cells. In order to assess the possibilities for the induction of T-cell tolerance to transplanted organs, it is necessary to consider some fundamental aspects of T-cell function and examine the basis of tolerance to self. That is to say, all strategies for transplantation tolerance must target T cells, and the major aim of transplantation immunology is to develop protocols that prevent immune responses towards the graft but leave the rest of the immune system intact.Most important of all is that, the immunosuppressive agents currently used in clinical transplantation are non-specific in nature and cannot distinguish between beneficial immune responses against infectious pathogens and destructive immune responses against the graft. Thus, the administration of immunosuppressive drugs necessary to prevent graft rejection can lead to an increased risk of opportunistic infection. While current procedures for burn injury management have improved patient prognosis, increased morbidity and mortality remain major concerns. Thus, identification of the mechanisms responsible for post-burn immune dysfunction and increased susceptibility to subsequent sepsis and multiple organ failure under such conditions are essential for the development of improved treatment modalities. Thermal injury induces a...