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.
Original language | English |
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Pages (from-to) | 10-18 |
Number of pages | 9 |
Journal | American Journal of Transplantation |
Volume | 20 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Jan 2020 |
Funding
The authors’ work is supported by National Institutes of Health grants R01 AI139623AI (JO); R01 CA220234, R01 HL144072, P01 HL131478, and Netherlands Organization for Scientific Research (NWO) grant ZonMW Vici 91818622 (WJMM); R01 HL143814 and P01HL131478 (ZAF); European Research Council (ERC) Consolidator Grant (310372) and Spinoza Grant of the Netherlands Organization for Scientific Research (MGN); and UO1 AI131470 (JCM).
Keywords
- immunobiology
- immunosuppression/immune modulation
- infection and infectious agents
- infectious disease
- macrophage/monocyte biology: activation
- rejection
- tolerance: mechanisms
- translational research/science