Mast cell-mediated mechanistic pathways in organ transplantation

Adaptive immunity has gained importance in transplant immunology for years, based on models in which T-cells orchestrate the immune responses during rejection. Most recently, researches revealed that innate immune cells, including mast cells (MCs) also play a pivotal role in allograft rejection. MC mediated immunoregulatory responses influence the innate and adaptive immune responses. Their capability to produce an array of both pro-inflammatory and anti-inflammatory mediators, expressing a wide range of costimulatory molecules in addition to acting as antigen-presenting cells (APCs), make them effective immune cells far beyond their classical role as primary orchestrator cells of allergy. Activated regulatory Tcells (Treg) cells contribute to MC recruitment into grafts by releasing interleukin (IL)-9. Tregs are capable of stabilizing MCs and suppressing IgE mediated degranulation through interaction of Treg expressing OX40 with MCs expressing OX40L. MCs in turn release transforming growth factor (TGF)-β and IL-10 which possess suppressive properties. Thus, these cells can suppress the proliferation of T-cells and support the generation of Tregs. MCs in addition to orchestrating immune responses in grafts by cell-to-cell interactions with variety of immune cells, cause histologic changes, mainly fibrosis by releasing mediators such as histamine, fibroblast growth factor-2 (FGF-2), TGF-β, chymase, and cathepsin G. The role of MCs in transplant rejection remains controversial. The accumulation of MCs in rejected grafts suggests that they play a role in preventing graft tolerance, and contribute to the progression of chronic rejection of allografts. However, high expression of MC-related gene products in tolerant grafts and their known interaction with Tregs on the other hand, support the notion that they are an integral component in achieving peripheral tolerance.