Purpose: Despite being a “perfect match”, HLA-identical kidney transplants (HLA-Id KTx) are rejected without sufficient immunosuppression (IS), and hence can also benefit from tolerance induction. We tested whether DHSC infusion could achieve operational tolerance in living donor HLA-id KTx

Methods: Twenty HLA-id KTx recipients were treated with two doses of peri-operative Alemtuzumab and were then given 4 infusions of DHSC over 9 months. Initial IS treatment with tacrolimus/mycophenolate was converted to sirolimus/mycophenolate at 3 months before the final 3 DHSC infusions. IS was totally discontinued by 2 years in recipients without complications. Recipients were designated tolerant (Tol) if protocol biopsies after one year off IS (3 year post-op) did not show rejection and had normal renal function.

Results: Microchimerism was observed in peripheral blood (PBMC) and iliac crest marrow early after DHSC infusions, but disappeared by one year. Five of the 20 originally enrolled were removed from the protocol because of unexpected original disease recurrence (n=3), noncompliance (n=1), or development of an unexpected pre-transplant B cell crossmatch (n=1), but followed as intent to treat. Of the remaining 15, 7 were designated Tol; of these, 5 are still Tol at the 5 year protocol biopsy, 1 Tol died (unrelatedly) beyond the 5 year milestone, and 1 showed Banff 1A rejection at the 5 year biopsy without renal dysfunction after remaining IS free for 3 years. Among the non-Tol, 2 had graft dysfunction and 7 had normal function but evidence of subclinical rejection at 2 or 3 year biopsy, and IS had to be maintained or reinstated. Tol was associated with greater numbers of infused DHSC. Serial immunophenotyping for CD4⁺CD127^–CD25⁺FOXP3⁺ Tregs in PBMC could distinguish between Tol and non-Tol with the Tol group having higher Tregs (p<0.05). Similarly, genomic studies demonstrated Tol recipients to have lower transcripts in >300 immune response genes (P<0.001) and that these gene signatures were predictive of Tol from early on.

Conclusions: This non-chimeric DHSC protocol in HLA-id KTx demonstrated Immunoregulation as a mechanism of tolerance. Therefore, plans for a combinatorial therapy with DHSC and expanded recipient Tregs are underway.

CITATION INFORMATION: Leventhal J, Mathew J, Salomon D, Kurian S, Friedewald J, Gallon L, Huang X, Tambur A, Kanwar Y, Charette J, Abecassis M, Miller J. HLA Identical Renal Transplant Tolerance Using Donor Hematopoietic Stems Cells (DHSC): Role of Immunoregulation. Am J Transplant. 2016;16 (suppl 3).

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