Macrophages in Organ Transplantation

Abstract

Current immunosuppressive therapy has led to excellent short-term survival rates in organ transplantation. However, long-term graft survival rates are suboptimal, and a vast number of allografts are gradually lost in the clinic. An increasing number of animal and clinical studies have demonstrated that monocytes and macrophages play a pivotal role in graft rejection, as these mononuclear phagocytic cells recognize alloantigens and trigger an inflammatory cascade that activate the adaptive immune response. Moreover, recent studies suggest that monocytes acquire a feature of memory recall response that is associated with a potent immune response. This form of memory is called "trained immunity," and it is retained by mechanisms of epigenetic and metabolic changes in innate immune cells after exposure to particular ligands, which have a direct impact in allograft rejection. In this review article, we highlight the role of monocytes and macrophages in organ transplantation and summarize therapeutic approaches to promote tolerance through manipulation of monocytes and macrophages. These strategies may open new therapeutic opportunities to increase long-term transplant survival rates in the clinic.

Keywords: immune tolerance; macrophages; nanotherapy; organ transplantation; trained immunity.

Figure 1

Interfering with binding of the TCR to antigenic peptide complexed with MHC (signal 1) and engagement of co-stimulatory molecules (signal 2) prevents T cell activation. (A) Prolonged allograft survival and induction of tolerance has been achieved in experimental animal models buy targeting signals 1 and 2 in both T cells and antigen presenting cells (APC). (B) The clinical translation of therapeutic approaches that specifically target APC in vivo remain largely elusive.

Figure 2

Macrophages polarization in the transplanted allograft is influenced by various stimuli. The image indicates the expression of macrophage genes encoding cytokine receptors, cell activation markers and cell adhesion molecules. Data was acquired from published microarray obtained from graft-infiltrating macrophages on day 5 post-transplantation in either untreated rejecting or anti-CD40L mAb treated mice. The GEO accession number for the microarray data reported in this figure is GSE68648.