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.

Immunologic Rejection of Transplanted Retinal Pigmented Epithelium: Mechanisms and Strategies for Prevention

“…However, if the original injury persists, the inflammatory M1 phenotype causes progressive tissue damage (41). To corroborate this in vitro evidence, in vivo studies have indicated that allograft transplantation without immune suppression is associated with persistent M1-type BMM, while macrophages rapidly convert to M2-phenotype with adequate immune suppression (26,46,56). In summary, we hypothesize that surgical trauma causes proliferation of destructive M1 microglia that contribute to acute rejection, and dysregulation of the M1 phenotype leads to macrophage infiltrate surrounding chronically rejected RPE grafts.…”

“…Early work in solid organ transplants demonstrated that Tcells are necessary and sufficient for allograft rejection (24)(25)(26). Subsequently, immunosuppressive regimen were developed that target T-cell activation at three steps: signal 1) binding by APCs, signal 2) costimulatory molecules and ligands, or signal 3) the trigger for cell proliferation (27).…”

“…This is especially true when rejection of RPE occurs within the first week, prior to the development of acquired immunity ( 15 , 16 ). Transplant immunologists have increasingly looked at MNPs to gain a better understanding of allograft rejection ( 26 ).…”

“…As the resident immune cells the graft site, TRM may direct the initial response to transplanted grafts ( 16 , 26 , 45 , 46 ). Depicted in Figure 1 , in vitro studies have demonstrated that DAMPs released as a result of transplantation surgery bind to TLRs and cause IFNγ driven proliferation of M1 microglia, which release TNFα, IL-1β, IL-6, nitric oxide, and reactive oxygen species to propagate inflammation and neural damage ( 48 , 49 ).…”

M2 Macrophages Serve as Critical Executor of Innate Immunity in Chronic Allograft Rejection

“…Inhibiting infiltration or activation of monocytes/macrophages by mycophenolate mofetil (MMF) seems to be a promising therapeutic strategy ( 74 ). Indeed, depletion of monocytes/macrophages attenuate neutrophils-related tissue damage at the early stage of transplant ( 75 – 77 ), while it may also prevent tissue repair and induction of tolerance at late stage due to loss of reprogrammed macrophages that participate in reconstitution of homeostasis ( 17 , 78 ). Moreover, chronic rejection mediated by M2-like macrophages is also an ineligible issue.…”