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

Anandharaman Veerapathran, Joseph Pidala, Francisca Beato, Brian Betts, Jongphil Kim, Joel G. Turner, Marc K. Hellerstein, Xue Zhong Yu, William Janssen, Claudio Anasetti

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Alloreactive donor T cells against host minor histocompatibility antigens (mHAs) cause graft-versus-host disease (GVHD) after marrow transplantation from HLAidentical 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 b 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.

Original languageEnglish (US)
Pages (from-to)2251-2261
Number of pages11
JournalBlood
Volume122
Issue number13
DOIs
StatePublished - 2013

Fingerprint Dive into the research topics of 'Human regulatory T cells against minor histocompatibility antigens: Ex vivo expansion for prevention of graft-versus-host disease'. Together they form a unique fingerprint.

  • Cite this

    Veerapathran, A., Pidala, J., Beato, F., Betts, B., Kim, J., Turner, J. G., Hellerstein, M. K., Yu, X. Z., Janssen, W., & Anasetti, C. (2013). Human regulatory T cells against minor histocompatibility antigens: Ex vivo expansion for prevention of graft-versus-host disease. Blood, 122(13), 2251-2261. https://doi.org/10.1182/blood-2013-03-492397