Trained immunity in organ transplantation

Abstract

Consistent induction of donor-specific unresponsiveness in the absence of continuous immunosuppressive therapy and toxic effects remains a difficult task in clinical organ transplantation. Transplant immunologists have developed numerous experimental treatments that target antigen-presentation (signal 1), costimulation (signal 2), and cytokine production (signal 3) to establish transplantation tolerance. While promising results have been obtained using therapeutic approaches that predominantly target the adaptive immune response, the long-term graft survival rates remain suboptimal. This suggests the existence of unrecognized allograft rejection mechanisms that contribute to organ failure. We postulate that trained immunity stimulatory pathways are critical to the immune response that mediates graft loss. Trained immunity is a recently discovered functional program of the innate immune system, which is characterized by nonpermanent epigenetic and metabolic reprogramming of macrophages. Since trained macrophages upregulate costimulatory molecules (signal 2) and produce pro-inflammatory cytokines (signal 3), they contribute to potent graft reactive immune responses and organ transplant rejection. In this review, we summarize the detrimental effects of trained immunity in the context of organ transplantation and describe pathways that induce macrophage training associated with graft rejection.

Keywords: immunobiology; immunosuppression/immune modulation; infection and infectious agents; infectious disease; macrophage/monocyte biology: activation; rejection; tolerance: mechanisms; translational research/science.

Figure 1

Trained immunity danger signals that compromise organ transplantation. Trained immunity–inducing agents, such as infection (viral, bacterial, and fungical), activation of the NLRP3 inflammasome, Western diet, sugar, OxLDL, and cell death are associated with increased morbidity and mortality in organ transplant patients. HMGB1, high mobility group box 1; IL, interleukin; mTOR, mammalian target of rapamycin; NOD2, Nod‐like receptor 2; NLRP, NOD‐like receptor pyrin domain‐containing‐3; OxLDL, oxidized low‐density lipoprotein; TLR4, Toll‐like receptor 4; TNFα, tumor necrosis factor α