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Ex Vivo ‐Expanded Natural CD4 + CD25 + Regulatory T Cells Synergize With Host T‐Cell Depletion to Promote Long‐Term Survival of Allografts
Author(s) -
Xia G.,
He J.,
Leventhal J. R.
Publication year - 2008
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/j.1600-6143.2007.02088.x
Subject(s) - foxp3 , il 2 receptor , ex vivo , immunology , medicine , cd28 , in vivo , transplantation , t cell , immunotherapy , immune system , biology , cancer research , microbiology and biotechnology
Foxp3 + CD4 + CD25 + natural regulatory T (nT reg ) cells have been shown in immunodeficient mice to suppress allograft rejection after adoptive cotransfer. We hypothesized that immunotherapy using ex vivo ‐expanded nT reg could suppress allograft rejection in wild‐type mice. Donor alloantigen (alloAg) specificity of naive splenic nT reg was enriched in vitro by culturing with anti‐CD3/CD28‐coated Dynabeads plus bone marrow‐derived dendritic cells (BM‐DC) in the presence of interleukin (IL)‐2 or IL‐2 plus transforming growth factor (TGF)‐β. On average, 96.2% fresh CD4 + CD25 + nT reg were intracellular Foxp3 + . By d+20 in culture, 6.4% nT reg were Foxp3 + following expansion with IL‐2 alone, and 14.4% or 19.7% nT reg were Foxp3 + when expanded with IL‐2 plus 0.5 or 2.5 ng/mL TGF‐β, respectively. In vitro , alloAg‐enriched, TGF‐β/IL‐2‐conditioned nT reg exerted stronger donor alloAg‐specific suppression than cells with IL‐2 alone in mixed lymphocyte reaction (MLR) assays. In vivo , alloAg‐enriched, TGF‐β/IL‐2‐conditioned nT reg expressed high‐level Foxp3 following infusion, effectively overcame acute rejection and induced long‐term survival of donor but not third‐party heart allografts in peritransplant host T‐cell‐depleted mice. Long‐term surviving allografts were noted to possess Foxp3 + graft‐infiltrating cells of exogenous and endogenous origins. In conjunction with transient host T‐cell depletion, therapeutic use of ex vivo ‐expanded nT reg may be a practical means of preventing acute allograft rejection.