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Prevention of Allograft Rejection by Use of Regulatory T Cells With an MHC‐Specific Chimeric Antigen Receptor |
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| Authors: | F Noyan K Zimmermann M Hardtke‐Wolenski A Knoefel E Schulde R Geffers M Hust J Huehn M Galla M Morgan A Jokuszies M P Manns E Jaeckel |
| Institution: | 1. Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, Hannover, Germany;2. Integrated Research and Treatment Center, Transplantation (IFB‐Tx), Hannover Medical School, Hannover, Germany;3. Department of Cardiothoracic, Transplantation and Vascular Surgery, Hannover Medical School, Hannover, Germany;4. RG of Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany;5. Department of Biotechnology, Institute for Biochemistry, Biotechnology and Bioinformatics, Technische Universit?t Braunschweig, Braunschweig, Germany;6. Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany;7. Institute of Experimental Haematology, Hannover Medical School, Hannover, Germany;8. Department of Plastic, Aesthetic, Hand and Reconstructive Surgery, Hannover Medical School, Hannover, Germany |
| Abstract: | CD4+CD25highFOXP3+ 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 nTregs without alteration of their regulatory phenotype and epigenetic stability. Activation of nTregs via the A2‐CAR induced proliferation and enhanced the suppressor function of modified nTregs. Compared with nTregs, 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. |
| Keywords: | basic (laboratory) research/science translational research/science immunobiology immunosuppression/immune modulation tissue (nonvascularized) transplantation tolerance tolerance: experimental T cell biology gene therapy |