Operational Tolerance in Xenotransplantation By Use of Regulatory T Cells with a SLA-specific Chimeric Antigen Receptor

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Abstract

Methods

SLA-specific scFvs were generated by antibody-phage display panning using an swine leucocyte monomer. These were used to generate a highly specific chimeric antigen receptor that specifically recognizes SLA (referred to as X-CAR).

Results

Transduction into nTregs changed the specificity of the nTregs without alteration of their regulatory phenotype and epigenetic stability. Specificity studies using NFAT-GFP hybridoma cells revealed exclusive specificity against porcine target structures. Any cross-reactivity with human cells or self-activation could be ruled out. Xenospecific-mixed lymphocyte reactions were efficiently suppressed by X-CAR nTregs.

Results

Most importantly, X-CAR Tregs completely prevented rejection of allogeneic target cells and tissues in immune reconstituted humanized mice in the absence of any immunosuppression (operational tolerance).

Conclusion

X-CAR Tregs can induce xeno-specific tolerance without perturbation of the general immune competence of the recipient. Therefore, these modified cells have great potential for incorporation into clinical trials using porcine tissues or grafts.

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