Sensitization in Transplantation Assessment of Risk 2025 innate working group: The potential role of innate...

In solid organ transplantation, the alloimmune response is traditionally attributed to the action of alloreactive T cells that recognize mismatched human leukocyte antigens, as well as antibody formation and antibody-mediated rejection. However, recent evidence indicates that these paradigms of involvement of the adaptive immune system in organ transplant rejection do not explain all cases of graft inflammation and that innate cell allorecognition plays a role. This review, conducted by the innate team of the Sensitization in Transplantation Assessment of Risk workgroup, summarizes the concepts and empirical evidence supporting innate allorecognition. The focus is on natural killer cell activation via missing self and monocyte activation through the signal regulatory protein α-CD47 pathway and SIRPα gene polymorphisms. A consensus definition of genetic missing self is proposed, necessitating both donor and recipient human leukocyte antigen class I genotyping and evaluation of the recipient inhibitory killer-cell immunoglobulin-like receptor genotype. Although in vitro studies and preclinical validations corroborate the potential of innate allorecognition concepts, further research is required to establish clinical utility. This article delineated future research directions to bridge the gap between theoretical promise and practical application in clinical transplantation.