Human regulatory T cells against minor histocompatibility antigens: ex vivo expansion for prevention of graft-versus-host disease
2013
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
siblingsin the presence of interleukin 2,
interleukin 15, and rapamycin. Male-specific Treg clones against
H-Y antigensDBY, 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
siblingmHAs. 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
Foxp3gene promoter,
Foxp3expression, and transforming growth
factorβ
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
siblingsin sufficient numbers for application in human transplant trials.
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