Integrating immunogenetic stratification and follicular immune dynamics: an evolving framework for CAR-Treg therapy in antibody-mediated rejection.

Abstract

One of the leading causes of long-term graft loss following kidney transplantation is antibody-mediated rejection (AMR). In this process, donor-specific antibodies (DSAs), arising either from pre-transplant sensitization or developing de novo after transplantation, induce injury to the graft endothelium. This triggers microvascular inflammation, which may eventually progress to transplant glomerulopathy and graft dysfunction. In recent years, HLA eplet mismatch analysis has provided a more refined approach for predicting de novo DSA development, leading to a more precise assessment of immunogenetic risk in clinical practice. Despite these advances, polyclonal regulatory T cell (Treg) therapies have shown limited efficacy, largely due to their lack of antigen specificity. In contrast, CAR-Treg cells directed against intact donor HLA molecules or other defined alloantigenic targets offer a more targeted strategy. In this framework, HLA eplet mismatch analysis is best interpreted as a high-resolution tool for immunogenetic risk stratification and therapeutic matching rather than as a direct template for eplet-specific CAR construction. These cells engage in complex, localized modulation of Tfh-B cell interactions via cytokine-mediated pathways rather than simple Tfh suppression, thereby limiting germinal center reactions and effectively reducing DSA production. This review examines the immunopathogenesis of AMR, eplet-based risk assessment, the role of the follicular immune network, and the clinical potential of CAR-Treg therapy in light of current evidence. Taken together, by integrating high-resolution immunogenetic stratification with recent insights into the follicular immune network, this review clarifies how CAR-Treg therapies may be positioned within personalized tolerance strategies in transplantation.