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Mixed chimerism and acceptance of kidney transplants after immunosuppressive drug withdrawal

Persistent mixed chimerism protects against rejection of HLA-matched and mismatched kidney transplants without graft-versus-host disease. Staving off immunosuppression Kidney transplant recipients are continually at risk of rejection despite intense immunosuppressive regimens that can have detrimental side effects. Busque et al. conducted kidney transplants with a selected composition of donor hematopoietic cells to attempt to evade graft-versus-host disease. They monitored mixed chimerism, defined as at least 1% of circulating cells being of donor origin, and kidney graft health. Most patients in the fully human leukocyte antigen (HLA)–matched cohort experienced persistent chimerism and no rejection episodes after removal of immunosuppressive drugs. Persistent chimerism was less prevalent in a partially HLA-matched cohort, and long-term withdrawal of immunosuppressants was not feasible in these patients. These findings indicate that methods to promote mixed chimerism may improve kidney transplant outcomes. Preclinical studies have shown that persistent mixed chimerism is linked to acceptance of organ allografts without immunosuppressive (IS) drugs. Mixed chimerism refers to continued mixing of donor and recipient hematopoietic cells in recipient tissues after transplantation of donor cells. To determine whether persistent mixed chimerism and tolerance can be established in patients undergoing living donor kidney transplantation, we infused allograft recipients with donor T cells and hematopoietic progenitors after posttransplant lymphoid irradiation. In 24 of 29 fully human leukocyte antigen (HLA)–matched patients who had persistent mixed chimerism for at least 6 months, complete IS drug withdrawal was achieved without subsequent evidence of rejection for at least 2 years. In 10 of 22 HLA haplotype–matched patients with persistent mixed chimerism for at least 12 months, reduction of IS drugs to tacrolimus monotherapy was achieved. Withdrawal of tacrolimus during the second year resulted in loss of detectable chimerism and subsequent rejection episodes, unless tacrolimus therapy was reinstituted. Posttransplant immune reconstitution of naïve B cells and B cell precursors was more rapid than the reconstitution of naïve T cells and thymic T cell precursors. Robust chimerism was observed only among naïve T and B cells but not among memory T cells. No evidence of rejection was observed in all surveillance graft biopsies obtained from mixed chimeric patients withdrawn from IS drugs, and none developed graft-versus-host disease. In conclusion, persistent mixed chimerism established in fully HLA- or haplotype-matched patients allowed for complete or partial IS drug withdrawal without rejection.