Human regulatory T cells against minor histocompatibility antigens: ex vivo expansion for prevention of graft-versus-host disease.

TitleHuman regulatory T cells against minor histocompatibility antigens: ex vivo expansion for prevention of graft-versus-host disease.
Publication TypeJournal Article
Year of Publication2013
AuthorsVeerapathran A, Pidala J, Beato F, Betts B, Kim J, Turner JG, Hellerstein MK, Yu X-Z, Janssen W, Anasetti C
JournalBlood
Volume122
Issue13
Pagination2251-61
Date Published2013 Sep 26
Abstract

Alloreactive donor T cells against host minor histocompatibility antigens (mHAs) cause graft-versus-host disease (GVHD) after marrow transplantation from HLA-identical siblings. We sought to identify and expand regulatory CD4 T cells (Tregs) specific for human mHAs in numbers and potency adequate for clinical testing. Purified Tregs from normal donors were stimulated by dendritic cells (DCs) from their HLA-matched siblings in the presence of interleukin 2, interleukin 15, and rapamycin. Male-specific Treg clones against H-Y antigens DBY, UTY, or DFFRY-2 suppressed conventional CD4 T cell (Tconv) response to the specific antigen. In the blood of 16 donors, we found a 24-fold (range, 8-fold to 39-fold) excess Tconvs over Tregs reactive against sibling mHAs. We expanded mHA-specific Tregs from 4 blood samples and 4 leukaphereses by 155- to 405-fold. Cultured Tregs produced allospecific suppression, maintained demethylation of the Treg-specific Foxp3 gene promoter, Foxp3 expression, and transforming growth factor β production. The rare CD4 T conv and CD8 T cells in the end product were anergic. This is the first report of detection and expansion of potent mHA-specific Tregs from HLA-matched siblings in sufficient numbers for application in human transplant trials.

DOI10.7861/clinmedicine.13-4-374
Alternate JournalBlood