Current State of Tolerance: The Holy Grail

Abstract

Research in Tolerance and Chimerism by Transplant immunologists for over half a century is akin to the pursuit of the Holy Grail. Animal experiments for inducing tolerance may not have been successful initially but in that process, our knowledge of the fascinating immune system has been greatly enriched. Understanding of innate and adaptive immune systems has paved the way for development of potent immunosuppression. However, achieving clinical or operational tolerance long term in renal transplant recipients in the absence of immunosuppression is the ultimate goal for clinicians. Reduction in immunosuppression will lower morbidity and mortality associated with heavy burden of immunosuppression. This review article will be of particular interest to clinicians involved in delivering care to renal transplant recipients. We have elucidated mechanisms of self-tolerance through central and peripheral tolerance, evolution of tolerogenic strategies, difference between macro and micro-chimerism, overview of successful protocols for inducing tolerance and recent work in the development of expanding regulatory cell lines. It is most encouraging to note progress using cellular therapies as reported by Immune Tolerance Network and by Transplant Research & Immunology group at Oxford. We may not be far from achieving clinical tolerance albeit with minimal if not completely immunosuppression free regimens in the longer term. Review Article Tolerance in TransplantationThe highest result of education is toleranceHelen Keller [1], Tolerance is derived from 'tolero' in Latin, which means to endure. Achieving transplant tolerance has been the subject of research for over half a century and our current understanding of tolerance has evolved during that time. It is by no means complete and the search for true tolerance continues.Tolerance is the ability of a foreign tissue or organ to survive in a host without immunosuppression. It can be described as donor specifi c non-reactivity in experimental models [2]. "Clinical operational tolerance" is described as a well-functioning graft lacking histological signs of rejection in absence of immunosuppression for at least 1 year in an immunocompetent host capable of responding to other challenges including infections [3,4].In contrast, "Immunological tolerance" is no detectable immune reaction towards the allograft in absence of immunosuppression. It is a state of permanent and specifi c immunological acceptance of the allograft by the host immune system in the absence of immunosuppression. Self-toleranceThe concept of tolerance towards transplanted organs is best understood through learning about self-tolerance. The lymphoid system, which consists of T and B-lymphocytes, controls the immune system protecting the host from foreign pathogens. In the developmental pathway of the lymphoid system, T cells and B cells undergo education and maturation in the central lymphoid organs; the thymus and bone marrow. During this maturation process, T and B cells learn to differentiate between s...