ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

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

Category: Transplantation

  • 2001 Transplantation: Basic

Authors

  • Choi, John Yongjoon, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Zhang, Hengcheng, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Saad, Anis Joseph, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Solhjou, Zhabiz, Brigham and Women's Hospital, Boston, Massachusetts, United States
  • Deban, Christa A., Brigham and Women's Hospital, 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., Dana-Farber Cancer Institute, Boston, Massachusetts, United States
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-2d) was recovered with a full-length ureter and transplanted into B6 hosts (H-2b). 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