**Background:** Organ transplantation is a critical treatment for end-stage diseases, but graft rejection remains the primary obstacle to long-term allograft survival. Rejection involves complex biological processes initiated by both 'danger signals' from the graft itself and the recognition of 'non-self' alloantigens by the host immune system. This review synthesizes the current understanding of immune signal activation during transplantation, focusing on the roles of damage-associated molecular patterns (DAMPs) and allogeneic antigens.
**Methods:** This is a narrative review that synthesizes findings from the existing literature on transplant immunology. The authors discuss the historical development of organ transplantation, the mechanisms of ischemia-reperfusion injury (IRI), the release and recognition of DAMPs, the role of alloantigens in activating adaptive immunity, and the function of various immune receptors, including T cell receptors (TCRs), B cell receptors (BCRs), and immunoglobulin-like receptors (ILRs) on innate immune cells. The review also covers xenotransplantation and the concept of trained immunity.
**Key Results:** The review details that IRI during transplantation leads to metabolic reprogramming, cellular stress, and cell death (apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis), resulting in the release of DAMPs such as HMGB1, ATP, S100 proteins, CIRP, HSPs, and histones. These DAMPs are recognized by pattern recognition receptors (PRRs) like TLRs, RAGE, and NLRP3, activating downstream signaling pathways (e.g., NF-κB, MAPK) and promoting inflammation. For example, HMGB1 binds to TLR2, TLR4, TLR9, and RAGE to induce pro-inflammatory cytokine production. ATP activates the P2X7 receptor, leading to NLRP3 inflammasome activation and IL-1β/IL-18 secretion. The review also highlights that allogeneic MHC molecules are recognized by TCRs and BCRs, providing the first signal for adaptive immune activation. Furthermore, immunoglobulin-like receptors on NK cells (KIRs, NKG2) and myeloid cells (LILRs, PIRs) can recognize allogeneic MHC, contributing to rejection. The concept of 'trained immunity' is discussed, where innate immune cells (monocytes, macrophages) can develop long-term functional reprogramming and memory after exposure to DAMPs or alloantigens, potentially driving chronic rejection. In xenotransplantation, preformed natural antibodies against pig antigens (e.g., α-Gal) cause hyperacute rejection, which can be mitigated by gene editing (e.g., GTKO pigs) and transgenic expression of human complement regulatory proteins (hCD46, hCD55) and coagulation regulators (hTBM).
**Clinical Implications:** Understanding the molecular mechanisms of immune activation during transplantation is crucial for developing new therapeutic strategies to prevent rejection and improve graft survival. Targeting DAMPs and their receptors (e.g., HMGB1, TLRs, NLRP3) could reduce IRI and the subsequent inflammatory cascade. Modulating the function of immunoglobulin-like receptors (e.g., PIR-A, KIRs) may help induce transplant tolerance. The concept of trained immunity suggests that targeting innate immune cell memory could be a novel approach to prevent chronic rejection. In xenotransplantation, multi-gene editing of donor pigs to eliminate xenoantigens and express human protective proteins is a promising strategy to overcome immune barriers, as demonstrated by the first clinical pig-to-human heart transplant in 2022, though challenges remain.