A Pilot Study Of The Immunological Mechanism Of Allograft Tolerance Induction By Donor Apoptotic Lymphocyte Transfusion

One of the ultimate goals for transplantation is the induction of immune tolerance. The protocols currently used for allograft tolerance are generally based on the classical theory of central and peripheral tolerance, but unfortunately the efforts to achieve clinical tolerance is enormously challenged up front, given the complicated transplant antigen reactivities and the other clinical reasons.Apoptosis, or programmed cell death, is a basic physiologic phenomenon in organisms and plays a pivotal role in the regulation of tissue growth and homeostasis. According to the understanding of apoptotic cell death, it is acknowledged that apoptosis is important to the immune system development and homeostasis as well. In addition, apoptotic cells can actively confer immunosuppressive effects on inflammation: they can present "eat-me" signals on the surface and secrete chemotactic factors, by which monocytes or macrophages can be attracted and stimulated to recognize and remove the apoptotic cells; at the same time, the presence of apoptotic cells increases secretion of anti-inflammatory and immunoregulatory cytokines by monophagocytes, such as TGFβ, IL-10, PGE₂, which creates an immunosuppressive microenvironment. Under physiologic conditions, the consequence of apoptotic cell phagocytosis is not an antigen-specific adaptiveimmune response but a tolerance induction.Therefore, Sun Erwei et al speculated that "...The finding that apoptotic cells are not only rapidly scavenged by phagocytes but also actively transmit immunoregulatory signals to phagocytes suggests the uniqueness of apoptotic cells in transplantation tolerance induction. Since phagocytes devouring apoptotic cells secrete immunoregulatory cytokines, there is a strong possibility that antigens derived from apoptotic cells are presented to cognate T cells within the context of local immune regulatory factors..." (Cell Death Differ, 2004.11(2): 1258). The speculation is validated by our previous study with a series of heart or liver transplantation rat models that immune tolerance and long-term survival are achieved in recipients by pre-transfusion of donor apoptotic splenocytes. But there remain even more questions: how the donor apoptotic cells induce transplantation tolerance; what the key point is; and what mechanism underlies them. So far there are no studies to resolve or be referred to those questions. However, only if the mechanisms are clarified is it possible to design more effective and practical protocols for clinical allograft tolerance induction by donor apoptotic cells. The present pilot study is conducted to explore the traffic of in vivo transfused allogeneic apoptotic lymphocytes. The results are summaried as follows:...