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JCI Insight. 2018 Nov 15;3(22). pii: 124086. doi: 10.1172/jci.insight.124086. [Epub ahead of print]

Early expansion of donor-specific Tregs in tolerant kidney transplant recipients.

Author information

1
Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
2
Department of Surgery, University of California San Francisco, San Francisco, California, USA.
3
Center for Translational Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA.
4
Immune Tolerance Network, Bethesda, Maryland, USA.
5
Center for Computational Biology and Bioinformatics, Department of Systems Biology, Columbia University, New York, New York, USA.
6
Department of Microbiology & Immunology, Columbia University Medical Center, Columbia University, New York, New York, USA.
7
Department of Surgery, Columbia University Medical Center, Columbia University, New York, New York, USA.

Abstract

Allograft tolerance, in which a graft is accepted without long-term immunosuppression, could overcome numerous obstacles in transplantation. Human allograft tolerance has been intentionally induced across HLA barriers via combined kidney and bone marrow transplantation (CKBMT) with a regimen that induces only transient chimerism. Tregs are enriched early after CKBMT. While deletional tolerance contributes to long-term tolerance, the role of Tregs remains unclear. We have optimized a method for identifying the donor-specific Treg repertoire and used it to interrogate the fate of donor-specific Tregs after CKBMT. We expanded Tregs with several different protocols. Using functional analyses and T cell receptor sequencing, we found that expanding sorted Tregs with activated donor B cells identified the broadest Treg repertoire with the greatest potency and donor specificity of suppression. This method outperformed both alloantigen stimulation with CTLA4Ig and sequencing of CFSElo cells from the primary mixed lymphocyte reaction. In 3 tolerant and 1 nontolerant CKBMT recipients, we sequenced donor-specific Tregs before transplant and tracked them after transplant. Preexisting donor-specific Tregs were expanded at 6 months after CKBMT in tolerant patients and were reduced in the nontolerant patient. These results suggest that early expansion of donor-specific Tregs is involved in tolerance induction following CKBMT.

KEYWORDS:

Immunology; Organ transplantation; T-cell receptor; Tolerance; Transplantation

PMID:
30429370
DOI:
10.1172/jci.insight.124086
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