Transplant Immunobiology – Mechanisims of Graft Rejection

Abstract

Graft rejection is a complex process involving the interplay between innate and adaptive immunity. Many factors including the nature of the tissue transplanted, donor factors, the ischaemia time, the genetic disparities between the donor and recipient, the site of transplantation, and the immune status of the recipient as well as others all contribute to determining the character of the rejection response. Donor derived passenger leukocytes, immature dendritic cells, are present within solid organ grafts at the time of transplantation. These cells are triggered to migrate out of the graft as a result of the inflammation caused by removing the organ from the donor and transplanting it into the recipient. When the donor passenger cells migrate from the graft to the recipient lymphoid tissue they change their functional properties, including the acquisition of costimulatory molecules, and become potent antigen presenting cells (APC). As a result T cells recognizing the mismatched donor major histocompatibility antigens will be activated thereby triggering acute rejection via the direct pathway of allorecognition. Donor histocompatibility antigens can also be recognized by T cells after processing and presentation by recipient antigen presenting cells. This pathway of allorecognition, the indirect pathway, can also be responsible for acute rejection but has also been shown to play a key role in the development of transplant arteriosclerosis that results in delayed graft loss, often referred to as chronic allograft rejection. In general, activation of CD4+ T cells leads to the orchestration of the effector mechanisms that lead to graft destruction. CD8+ T cells with cytotoxic activity, macrophages, antibody and complement and cytokines have all been implicated in the graft destruction. The precise combination of effector cells and their relative contributions to the destruction of a particular graft will depend on the circumstances that have lead to the initiation of the response.