Dual Costimulatory Blockades Failed to Achieve Transplant Tolerance Despite Induction of Mixed Chimerism in NHPs.
1Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA
2Department of Pathology, Massachusetts General Hospital, Boston, MA
Meeting: 2017 American Transplant Congress
Abstract number: 396
Keywords: Co-stimulation, Mixed chimerism, Primates, Tolerance
Session Information
Session Name: Concurrent Session: Basic Transplant Tolerance II
Session Type: Concurrent Session
Date: Tuesday, May 2, 2017
Session Time: 2:30pm-4:00pm
Presentation Time: 3:42pm-3:54pm
Location: E350
Background: Our previous studies showed that substantial deletion of CD8+ memory T cells (TMEM) was necessary to induce mixed chimerism (MC) and allograft tolerance when conditioning and donor bone marrow transplant (DBMT) were performed 4 months after kidney transplantation (KTx) (delayed tolerance) (G1/G2). We attempted to replace the anti-CD8/CD154 mAbs (aCD8/aCD154) with the more clinically available agents, anti-CD40 mAb and belatacept (aCD40/bela), in the delayed tolerance models of simultaneous islet and kidney transplantation (SIK) or KTx alone.
Material/Methods: Seven NHP recipients of SIK or KTx were treated with aCD40 and rapamycin for 4 months. Three SIK (G3) and four KTx (G4) recipients received DBMT with a conditioning regimen that includes TBI, TI, horse ATG (hATG), dual costimulatory blockade (CB) with aCD40/bela and a one month course of CNI. The results were compared with KTx recipients that received the DBMT regimen including aCD8/CD154 (G1) or rabbit ATG and bela (rATG/bela) (G5) after tacrolimus/MMF/steroid therapy for 4 months.
Results: Although all SIK and KTx recipients treated with aCD40/bela successfully developed MC without aCD8, achieve allograft tolerance was not achieved in any of them (G3/G4). In contrast, KTx recipients achieved MC and long-term survival, when bela was combined with rATG (R5). Blocking the counter receptor of CD40, CD154 did not inhibit tolerance induction as KTx recipients of aCD8/CD154 achieved allograft tolerance (G1).
Conclusion: Dual CB exhibited potent suppression of CD8+ TMEM, which resulted in successful induction of MC without aCD8. However, blockade of CD40 may be inhibitory to induction of allograft tolerance in our MC approach.
CITATION INFORMATION: Oura T, Hotta K, Rosales I, Dehnadi A, Lei J, James Markmann J, Matsunami M, Paster J, Hanekamp I, Pruner K, Kawai K, Ndishabandi D, Smith R.-N, Cosimi B, Kawai T. Dual Costimulatory Blockades Failed to Achieve Transplant Tolerance Despite Induction of Mixed Chimerism in NHPs. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Oura T, Hotta K, Rosales I, Dehnadi A, Lei J, Markmann JJames, Matsunami M, Paster J, Hanekamp I, Pruner K, Kawai K, Ndishabandi D, Smith R-N, Cosimi B, Kawai T. Dual Costimulatory Blockades Failed to Achieve Transplant Tolerance Despite Induction of Mixed Chimerism in NHPs. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/dual-costimulatory-blockades-failed-to-achieve-transplant-tolerance-despite-induction-of-mixed-chimerism-in-nhps/. Accessed May 13, 2025.« Back to 2017 American Transplant Congress