Background. We previously described 3-year results of a non-chimeric tolerance protocol in HLA-identical living donor renal transplant (RT) recipients and now report on longer term, more definitive findings.

Methods. Recipients with alemtuzumab induction and tacrolimus/mycophenolic acid therapy were multiply infused with donor hematopoietic CD34⁺ stem cells (DHSC) following early conversion to sirolimus. All immunosuppression was withdrawn by 24 months. Twelve months later tolerance was documented by rejection-free transplant biopsies.

Results. Five of the first 8 enrollees were initially shown as tolerant at 3 years, 1-year off immunosuppression. Biopsies of 3 patients after total withdrawal showed Banff 1A acute cellular rejection without renal dysfunction. With longer follow-up of the 8 original patients including 5-year post-transplant biopsies (5 to 6.5 years), 4 of the 5 tolerant recipients remain without rejection evidence while one revealed Banff 1A rejection at 5 years without renal dysfunction. By including the next 7 more newly entered subjects (2 tolerant at 3 years), we demonstrate sequentially elevated numbers of circulating CD4⁺CD25⁺⁺⁺CD127^–FOXP3⁺ Tregs in tolerant subjects vs. a loss of Tregs in non-tolerant subjects (see figure, p≤0.001), with concrete evidence of DHSC dose-related immunoregulation in tolerant patients. We also demonstrated signatures for tolerance by global gene expression profiling of sequential samples of whole blood. The sequential measures reveal a 357-gene signature for immunoquiescence predicting as early as one year postoperatively the successful achievement of tolerance after drug withdrawal (p≤0.001).

Conclusion. These prospective longer term HLA-identical RT non-chimeric tolerance studies clarify, for the first time, tolerance predictive signatures based on both immunophenotypes for Tregs and serial monitoring of gene expression profiles.

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