Abstract: TH-OR54
Vaccination with Class-Ib MHC Binding Synthetic Superagonist and Adoptive Transfer of Antigen-Specific CD8 Tregs Prolong Cardiac Allograft Survival in Alloantigen-Sensitized Hosts
Session Information
- Kidney Transplantation: Breakthroughs from Basic to Translational to Clinical Research
November 04, 2021 | Location: Simulive, Virtual Only
Abstract Time: 04:30 PM - 06:00 PM
Category: Transplantation
- 1901 Transplantation: Basic
Authors
- 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
- 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
Previously, we showed Qa-1 (HLA-E in human) restricted regulatory CD8 T cells (CD8 Treg) are highly suppressive of follicular helper T cells (Tfh), and play a critical role in suppressing donor-specific antibodies (DSA) and antibody-mediated rejection (AMR). Alloreactive CD4 T cells upregulate Qa-1 in association with stress peptides such as FL9 that are recognized by CD8 Treg. Therefore, we hypothesized that vaccinating hosts with a superagonist that mobilizes CD8 Treg, and adoptive transfer of antigen-specific CD8 Treg may protect heart allografts from antibody-mediated injury.
Methods
We used a tetramer to sort FL9-Qa-1 specific CD8 T cells and sequenced their T cell receptors (TCR). We screened over 100 peptides synthesized with FL9 backbone and identified a superagonist that induces the strongest CD8 T cell response. We also generated FL9-Qa-1 TCR Transgenic mice (FL9-Tg mice). We then sensitized B6 hosts with Balb/c skin allograft with or without vaccinating with superagonist, AND with or without transferring CD8 T cells isolated from FL9-Tg. Following the sensitization with different treatments, each group received BALB/c heart allografts and was monitored for graft survival.
Results
The superagonist induced a strong CD8 Treg response that suppresses Tfh, activated B cells, plasma cells and DSA in vivo. Allograft retrieved from the treatment group showed less C4d deposit and attenuated graft injury. The treatment group also showed prolonged allograft survival; the superagonist and the adoptive transfer showed a synergistic effect.
Conclusion
Allo-sensitized, cardiac transplantation is a stringent model in which allografts undergo a robust process of AMR. While antibody-mediated graft injury in clinical transplantation is a major barrier to long-term kidney allograft survival, we believe the graft protection using the superagonist and antigen-specific CD8 Treg is biologically significant with a high translational potential. Further investigation is needed to maximize the efficacy of CD8 Treg therapy, such as co-administration of CD8 Treg-specific co-stimulator. In addition, we are investigating the human equivalent of FL9 peptide, and examining the potential unwanted toxicity of FL9-Qa-1 specific CD8 T cells on allografts.
Funding
- Other NIH Support