HLA Identical Renal Transplant Tolerance with Donor Hematopoietic Stem Cells Absent Chimerism: T and B Regulatory Cell and Genomic Analysis

J. Leventhal, J. Mathew, D. Salomon, S. Kurian, M. Suthanthiran, A. Tambur, J. Friedewald, Y. Kanwar, M. Abecassis, J. Miller

Surgery
Comprehensive Transplant Center, Northwestern University, Chicago, IL
The Scripps Research Institute, La Jolla, CA
Weill Cornell Medical College, New York

Meeting: 2013 American Transplant Congress

Abstract number: 553

Purpose: HLA identical sibling renal transplantation (HLA id RT) still requires continuous immunosuppression (IS) with long term complications. We conducted an HLA id RT tolerance trial in which recipient immunophenotypic T and B regulatory cells and genomic pathways were studied.

Methods: Alemtuzumab induction, donor hematopoietic stem cell (DHSC) infusions, tacrolimus/mycophenolate IS converted early to sirolimus, were followed by total drug withdrawal by 24 months post-operatively. If a subsequent 12 month period elapsed with normal function and transplant biopsies, i.e. at 36 months post-operatively, the recipients were considered tolerant. Sequential T and B cell immunophenotyping and genomic analysis were performed.

Results: Of 20 recipients entered, first 10 have been followed between 39 to 59 months post-operatively and are reported here. The others are earlier in their course (<36 months). Five have had IS successfully withdrawn for between 15 and 32 months with no rejection seen in biopsies 12 months later, i.e. were considered tolerant (Tol). However, 2 others had previously unsuspected disease recurrence and 3 had subclinical rejection in the biopsies; therefore these 5 others had IS continued or reinstated, i.e. were non-tolerant (nTol). Recipient peripheral blood percentages of CD4⁺CD25^highCD127^–FOXP3⁺ T cells and CD19⁺IgD/M⁺CD27^– B cells markedly increased, remaining so up to 59 months post-operatively, whether designated as Tol or not. Peripheral blood microchimerism in either group was only seen up to 1 year post-operatively. However, intriguingly, there were many inflammatory genes downregulated in the blood of the IS-free Tol vs. IS-maintained nTol recipients, while urine CD3, granzyme-B, perforin and IP-10 mRNA levels were equivalent in both groups. All 20 enrollees have normal transplant function.

Summary and Conclusions: In this HLA id RT tolerance trial absent chimerism, marked and prolonged immunophenotypic changes occurred, but were indistinguishable between Tol and nTol recipients. However, genomic changes consistent with an immunoregulatory state occurred unique to the Tol recipients.

To cite this abstract in AMA style:

Leventhal J, Mathew J, Salomon D, Kurian S, Suthanthiran M, Tambur A, Friedewald J, Kanwar Y, Abecassis M, Miller J. HLA Identical Renal Transplant Tolerance with Donor Hematopoietic Stem Cells Absent Chimerism: T and B Regulatory Cell and Genomic Analysis [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/hla-identical-renal-transplant-tolerance-with-donor-hematopoietic-stem-cells-absent-chimerism-t-and-b-regulatory-cell-and-genomic-analysis/. Accessed November 22, 2024.

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