Autologous immune system reset for kidney allograft acceptance: mechanisms, evidence, and a testable...

Autologous hematopoietic stem cell transplantation (AHSCT)-based immune system reset (ISR) is conceptually distinct from donor-hematopoietic chimerism: recipient immunity is deeply depleted and rebuilt from recipient-derived hematopoietic stem/progenitor cells, without intended donor hematopoiesis. This review evaluates whether that platform could support kidney-allograft acceptance under reduced immunosuppression and, in exceptional responders, justify later testing of operational tolerance. We separate four evidence levels: mechanistic observations after AHSCT for autoimmune disease, preclinical hematopoietic-rescue models without intended donor chimerism, human partial-reset/minimization studies, and true drug-free tolerance. Autoimmune-disease data establish repertoire renewal and regulatory rebalancing, but do not prove alloantigen-specific tolerance. Experimental and early clinical transplant evidence remains limited and heterogeneous. We refine the proposed immune reconstitution-window model as a falsifiable framework in which continuous graft-derived donor-antigen exposure must coincide with a transient period of heightened immune plasticity. Donor antigen may enter this window through kidney transplantation during reconstitution after pretransplant ISR, or may already be present when ISR is applied to a stable recipient with an established allograft. Antigen presence is hypothesized to be necessary, but not sufficient, for donor-specific hyporesponsiveness. The model is linked to measurable targets: reduction of circulating and memory lymphocytes, turnover of donor-reactive clones, recovery of thymic output and naive repertoires, HLA-antibody trajectories interpreted against pretransplant donor-specific antibody status and specificity, absence of molecular or histologic graft injury, and reduced immunosuppression requirements. We also address resistant plasma cells, tissue-resident memory, pathogen-specific immunity, natural-killer-cell missing-self responses, age-dependent thymic recovery, stem-cell source, organ- and donor-type constraints, and kidney-specific safety. Current evidence supports biomarker-gated mechanistic testing in highly selected patients, not routine AHSCT or unmonitored immunosuppression withdrawal.