Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 17, Issue 8, Pages 2020-2032Publisher
WILEY
DOI: 10.1111/ajt.14251
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Funding
- National Institute of Allergy and Infectious Diseases of the National Institutes of Health [UM1 AI109565]
- NIAID [RO1 AI084074]
- NIDDK [RO1 DK106436]
- American Society of Transplantation
- Kidney Research Student Scholar Grant from the American Society of Nephrology
- HONORS award from the American Society of Hematology
- Office of the Director, National Institutes of Health [S10RR027050, S10OD020056]
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We examined tolerance mechanisms in patients receiving HLA-mismatched combined kidney-bone marrow transplantation (CKBMT) that led to transient chimerism under a previously published nonmyeloablative conditioning regimen (Immune Tolerance Network study 036). Polychromatic flow cytometry and high-throughput sequencing of T cell receptor-beta hypervariable regions of DNA from peripheral blood regulatory T cells (Tregs) and CD4 non-Tregs revealed marked early enrichment of Tregs (CD3(+)CD4(+)CD25(high) CD127(low)Foxp3(+)) in blood that resulted from peripheral proliferation (Ki67(+)), possibly new thymic emigration (CD31(+)), and, in one tolerant subject, conversion from non-Tregs. Among recovering conventional T cells, central memory CD4(+) and CD8(+) cells predominated. A large proportion of the T cell clones detected in posttransplantation biopsy specimens by T cell receptor sequencing were detected in the peripheral blood and were not donor-reactive. Our results suggest that enrichment of Tregs by new thymic emigration and lymphopenia-driven peripheral proliferation in the early posttransplantation period may contribute to tolerance after CKBMT. Further, most conventional T cell clones detected in immunologically quiescent posttransplantation biopsy specimens appear to be circulating cells in the microvasculature rather than infiltrating T cells.
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