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Abstract: TH-PO653

Universal Antigen Specific CD8 Treg to Suppress Alloreactive T Cells

Session Information

  • Transplantation: Basic
    November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Transplantation

  • 2001 Transplantation: Basic

Authors

  • Saad, Anis Joseph, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
  • Choi, John Yongjoon, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
  • Kim, Hye-jung, Dana Farber Cancer Institute, Boston, Massachusetts, United States
  • Younis, Nour Khaled, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
  • Zhang, Hengcheng, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
  • Deban, Christa A., Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
  • Solhjou, Zhabiz, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
  • Halawi, Ahmad, Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
  • Cantor, Harvey, Dana Farber Cancer Institute, Boston, Massachusetts, United States
  • Azzi, Jamil R., Brigham and Women's Hospital Department of Medicine, Boston, Massachusetts, United States
Background

We have previously shown that alloreactive T cells upregulate their expression of Qa-1(HLA-E in human)-FL9 peptide complex, making them susceptible to killing by Qa1 restricted CD8 Treg. Mobilization and activation of CD8 Treg in vivo by immunization with an engineered FL9 peptide superagonist, dampens Tfh-dependent Ab mediated injury and prolongs allograft survival. Therefore, we hypothesized that adoptively transferred FL9-antigen specific CD8 Treg may preferentially suppress the alloimmune response, and delay allograft rejection, opening new horizons for the use of CD8 Treg in cellular therapies.

Methods

We generated FL9-Qa-1 TCR Transgenic mice (FL9-Tg). We then transplanted B6 hosts with BALB/c skin allografts with or without vaccinating with FL9 superagonist AND with or without adoptively transferring CD8 T cells isolated from FL9 TCR Tg mice. One group of skin allograft recipient was subsequently transplanted with BALB/c hearts. Allograft survival was monitored and CD8 Treg migration was tracked in allograft and lymphoid organs. Mechanistic analysis was performed in the spleen, LN and allograft.

Results

FL9 specific CD8 Tregs significantly suppressed Tfh, GC B cell differentiation and DSA production, prolonging skin and heart allograft survivals compared to FL-9 superagonist alone or untreated recipients (p<0.05). Furthermore, the superagonist vaccine and CD8 Treg adoptive transfer group showed a synergistic effect(p<0.05), prolonging mean survival time of heart allografts from 4 to up to 15 days in a stringent sensitized transplant model.

Conclusion

Implementation of Tg CD8 Treg in cellular therapies has provided proof of concept data for the role of CD8 Treg in allo-immune response with high translational potential.

Funding

  • Other NIH Support