Role of IL-4 and Th2 responses in allograft rejection and tolerance

Abstract

Due to the dominance of Th1 cytokines in rejection and the ability of Th2 cytokines, particularly IL-4, to inhibit Th1 responses, it has long been held that Th2 cytokines can improve transplant outcomes. Although there is some support for this, there is mounting evidence that IL-4 and Th2 cytokines can promote graft dysfunction. These disparate effects are reviewed. The role of Th2 cytokines in graft dysfunction is not necessarily due to promotion of humoral immunity, but is due to their ability to drive T-cell and non-T-cell responses including alternative activation of macrophages. Alternatively, activated macrophages compete with classically activated macrophages for arginine and they are mutually exclusive, analogous to mutual competition between Th1 and Th2 cells. Recent findings also point to two subsets of regulatory T cells (Tregs), each dependent on either Th1 or Th2 cytokines. In addition to its effects on bone marrow-derived cells, IL-4 affects parenchymal cells by signalling through the type II receptor, which consists of the IL-4R alpha chain (IL-4Ralpha) and the IL-13Ralpha1, which also binds IL-13. The effects of Th2 cytokines in transplantation depend on their cellular targets, the timing and form of administration and on Th2 cytokine-dependent Tregs.