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Prevention of Allograft Rejection by Use of Regulatory T Cells With an MHC ‐Specific Chimeric Antigen Receptor
Author(s) -
Noyan F.,
Zimmermann K.,
HardtkeWolenski M.,
Knoefel A.,
Schulde E.,
Geffers R.,
Hust M.,
Huehn J.,
Galla M.,
Morgan M.,
Jokuszies A.,
Manns M. P.,
Jaeckel E.
Publication year - 2017
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/ajt.14175
Subject(s) - foxp3 , immunology , adoptive cell transfer , chimeric antigen receptor , immune system , transplantation , major histocompatibility complex , humanized mouse , antigen , immunosuppression , medicine , transplant rejection , cancer research , biology , immunotherapy , t cell , surgery
CD 4 + CD 25 high FOXP 3 + regulatory T cells (Tregs) are involved in graft‐specific tolerance after solid organ transplantation. However, adoptive transfer of polyspecific Tregs alone is insufficient to prevent graft rejection even in rodent models, indicating that graft‐specific Tregs are required. We developed a highly specific chimeric antigen receptor that recognizes the HLA molecule A*02 (referred to as A2‐ CAR ). Transduction into natural regulatory T cells (nTregs) changes the specificity of the nT regs without alteration of their regulatory phenotype and epigenetic stability. Activation of nT regs via the A2‐ CAR induced proliferation and enhanced the suppressor function of modified nT regs. Compared with nT regs, A2‐ CAR Tregs exhibited superior control of strong allospecific immune responses in vitro and in humanized mouse models. A2‐ CAR Tregs completely prevented rejection of allogeneic target cells and tissues in immune reconstituted humanized mice in the absence of any immunosuppression. Therefore, these modified cells have great potential for incorporation into clinical trials of Treg‐supported weaning after allogeneic transplantation.