Induction of immune tolerance in living related human leukocyte antigen-matched kidney transplantation: A phase 3 randomized clinical trial
In a phase 3 trial, a donor-derived cellular product (MDR-101) that induces mixed chimerism allowed 95% of HLA-matched living-sibling kidney transplant recipients to stop all immunosuppression, with 75% remaining drug-free for over 2 years and no graft loss, donor-specific antibody, or graft-versus-host disease.
Background
Lifelong immunosuppression after kidney transplantation causes cumulative toxicity. Inducing donor-specific immune tolerance — graft acceptance without ongoing drugs — has long been a goal, achievable through mixed-chimerism protocols. This trial tested a standardized cellular product to make tolerance reproducible.
Study design
Phase 3 multicenter randomized controlled trial. Adult recipients of kidneys from 2-haplotype HLA-matched living siblings were randomized 2:1 to MDR-101 (n=20) or standard-of-care immunosuppression (n=10). Treated recipients underwent nonmyeloablative conditioning (rabbit antithymocyte globulin and low-dose total lymphoid irradiation) with MDR-101 infused on day 11; immunosuppression was withdrawn over the first year if donor chimerism was ≥5%.
Key findings
All 20 MDR-101 recipients achieved donor mixed chimerism with no graft-versus-host disease. Nineteen (95%) discontinued all immunosuppression about 1 year post-transplant, and 15 (75%) met the primary endpoint of being immunosuppression-free for more than 2 years. Four resumed immunosuppression (recurrent IgA nephropathy and/or rejection). There were no deaths, graft losses, or donor-specific antibodies, and quality of life improved versus standard care.
Clinical implications
A reproducible cell-therapy protocol can deliver durable, functional immune tolerance and freedom from immunosuppression in HLA-matched living-sibling kidney transplantation. Extending this approach to HLA-mismatched and deceased-donor settings, where stable chimerism is harder to achieve, is the next challenge.
Category
Transplant
Source
American Journal of Transplantation
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