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Abstract: TH-OR54

Targeting the Archetypal Innate Immune Receptor Integrin CD11b Prolongs Kidney Allograft Survival in Nonhuman Primates (NHPs)

Session Information

Category: Transplantation

  • 2001 Transplantation: Basic

Authors

  • Dehnadi, Abbas, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Lassiter, Grace, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Hirose, Takayuki, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Kawai, Tatsuo, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Cosimi, Anthony Benedict, Massachusetts General Hospital, Boston, Massachusetts, United States
  • Arnaout, M. Amin, Massachusetts General Hospital, Boston, Massachusetts, United States
Background

Peri-transplant IRI activates innate immunity leading to delayed graft function, inferior long-term transplant outcomes, and interferes with tolerance induction. mAb107 is a first-in-class orthosteric antagonist of CD11b that blocks on-target conformational activation and proinflammatory outside-in signaling in an NHP model of IRI (Nature Comm, 2017). We have now evaluated the effect of mAb107 on allograft survival in NHPs receiving subtherapeutic tacrolimus (Tac) in our well-studied transplant model.

Methods

The donor's kidney from each of 8 NHPs was subjected to a 20-min WIT, followed by a 2-hour CIT before transplanting into each of 8 right nephrectomized MHC-mismatched recipients (half receiving IV mAb107 before allograft reperfusion and the other half receiving saline). The left native ureter was ligated on day 8 post-transplant (Tx). Recipients were followed by blood tests, transabdominal ultrasound, and Tac trough levels (adjusted to <10ng/ml, previously determined to result in acute rejection within 4-5 weeks in controls). Protocol biopsies were performed on days 8-10 and 30 post-Tx and all surviving animals were to be sacrificed on day 60 post-Tx.

Results

Following revascularization, immediate uniform reperfusion was observed only in mAb107-treated allografts, suggesting rapid termination of the maladaptive responses to ischemia. mAb107 induced significant prolongation of allograft survival in recipients (Fig. 1), with sustained vascular perfusion on day 20 post-Tx, reduced C4d staining, and ACR.

Conclusion

Suppressing the peri-transplant inflammatory response significantly prolonged NHP allograft survival, suggesting the potential of mAb107 in preventing/mitigating delayed graft function and enhancing tolerance.

Funding

  • NIDDK Support