Kidney Week

Abstract: TH-OR53

Mobilizing MHC Class Ib-Restricted Regulatory CD8 T Cells (CD8 Treg) With a Peptide Agonist Promotes Allograft Tolerance in a Fully Mismatched Mouse Kidney Transplant Model

Session Information

• Transplantation: Basic Research
  November 03, 2022 | Location: W314, Orange County Convention Center‚ West Building
  Abstract Time: 05:15 PM - 05:24 PM

Category: Transplantation

• 2001 Transplantation: Basic

Authors

• Choi, John Yongjoon, Brigham and Women's Hospital, Boston, Massachusetts, United States

John Yongjoon Choi, MD

• Zhang, Hengcheng, Brigham and Women's Hospital, Boston, Massachusetts, United States

Hengcheng Zhang,

• Saad, Anis Joseph, Brigham and Women's Hospital, Boston, Massachusetts, United States

Anis Joseph Saad,

• Solhjou, Zhabiz, Brigham and Women's Hospital, Boston, Massachusetts, United States

Zhabiz Solhjou,

• Deban, Christa A., Brigham and Women's Hospital, Boston, Massachusetts, United States

Christa A. Deban,

• Kim, Hye-jung, Dana-Farber Cancer Institute, Boston, Massachusetts, United States

Hye-jung Kim,

• Cantor, Harvey, Dana-Farber Cancer Institute, Boston, Massachusetts, United States

Harvey Cantor,

• Azzi, Jamil R., Dana-Farber Cancer Institute, Boston, Massachusetts, United States

Jamil R. Azzi,

Background

A subset of CD8 T cells that express TCR restricted to Qa-1 - a Class-Ib MHC molecule - plays a critical regulatory function. CD8 Tregs kill activated CD4 T cells, which significantly upregulate Qa-1 during allograft rejection. We previously showed that allograft recipients with dysfunctional CD8 Treg undergo severe antibody-mediated rejection.
We have engineered a Qa-1-binding 9-mer peptide superagonist (FL9-SA) that strongly activates CD8 Treg. We hypothesized that vaccinating hosts with FL9-SA may mobilize CD8 Treg and promote allograft tolerance by suppressing alloreactive CD4 T cells in the kidney transplant model.

Methods

The kidney of BALB/c mice (H-2^d) was recovered with a full-length ureter and transplanted into B6 hosts (H-2^b). The ureter of the remaining native kidneys was then ligated to inhibit native kidney function. Transplanted B6 hosts were treated intraperitoneally FL9-SA, or PBS emulsified in Adjuvant, once a week, starting POD2. Rapamycin was provided to certain groups on POD 0-4.

Results

Hosts treated with FL9-SA showed prolonged allograft survival compared to the control group (40 days vs 20.5 days). We also observed the indefinite survival of the kidney allograft when FL9-SA is combined with an mTOR inhibitor compared to the mTOR inhibitor only (38.5 days). Mechanistic analysis showed a diminished germinal center response and suppressed DSA level in hosts treated with FL9-SA compared to the control group. The allograft retrieved from the FL9-SA treated group showed a significant reduction in C4d deposit and cellular infiltrate. The overall memory CD4 T cells between the two groups remained similar; however, CD4 T cells from hosts treated with FL9-SA showed less proliferative capacity when co-cultured with irradiated donor splenocytes.

Conclusion

Our study suggests that mobilizing CD8 Tregs with a tolerogenic peptide vaccine is a novel method to promote kidney allograft tolerance. CD8 Treg-specific superagonist showed a synergistic effect with an mTOR inhibitor. Finally, mobilized CD8 Treg specifically suppresses alloreactive CD4 T cells while sparing the rest of the memory CD4 T cells that may play important role in host defense against pathogens.

Funding

• Other NIH Support