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Human regulatory T cells against minor histocompatibility antigens: ex vivo expansion for prevention of graft-versus-host disease. Blood 2013 Sep 26;122(13):2251-61

Date

08/03/2013

Pubmed ID

23908471

Pubmed Central ID

PMC3785121

DOI

10.1182/blood-2013-03-492397

Scopus ID

2-s2.0-84887347546 (requires institutional sign-in at Scopus site)   38 Citations

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.

Author List

Veerapathran A, Pidala J, Beato F, Betts B, Kim J, Turner JG, Hellerstein MK, Yu XZ, Janssen W, Anasetti C

Author

Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Cell Culture Techniques
Coculture Techniques
Female
Flow Cytometry
Graft vs Host Disease
Humans
Male
Minor Histocompatibility Antigens
Siblings
T-Lymphocytes, Regulatory
Transplantation, Homologous