Selective Blockade of the CD28/B7/CTLA4 Pathway With Monovalent Anti-CD28 Antibodies Versus Targeting of B7 With CTLA4-Ig, in Non-Human Primate Kidney Allograft
1INSERM, UMR1064, ITUN, Nantes, France
2Effimune SAS, Nantes, France.
Meeting: 2015 American Transplant Congress
Abstract number: 490
Keywords: Co-stimulation, Kidney transplantation, Preclinical trails, Primates
Session Information
Session Name: Concurrent Session: New Immunosuppression Strategies: Primate Models
Session Type: Concurrent Session
Date: Tuesday, May 5, 2015
Session Time: 4:00pm-5:30pm
Presentation Time: 4:12pm-4:24pm
Location: Room 119-A
B7 molecules on antigen-presenting cells interact with CD28 and CTLA4 on T lymphocytes to control TCR-mediated signals. Whereas it is highly efficient to block T cell activation, costimulation blockade in kidney transplantation with belatacept, a CTLA4-Ig molecule targeting B7, revealed a high incidence of« belatacept-resistant graft rejection ». This is believed to occur because in addition to inhibiting CD28 signaling, belatacept also blocks co-inhibition mediated by CTLA4, an immune checkpoint inhibitor that is also mandatory for the function of Tregs. The selective targeting of CD28 instead of B7 could have the advantage of maintaining CTLA4-mediated signals.
In the current study, we performed a face to face assessment of FR104, a Fab' antibody antagonist of CD28 versus CTLA4-Ig (LEA29Y) in kidney allograft in the baboon. Biologics were used de novo together with an initial 1 month treatment with low dose of tacrolimus that was weaned between months 1 and 2. Then recipients where left under monotherapy with biologics. Acute rejections were treated with steroids.
In CTLA4-Ig group (n=4), all recipients developed severe acute cellular rejection before, during or just after tacrolimus weaning (day 15, 17, 51, 76) and bolus of steroids were inefficient. In FR104 group- (n=5), only two animals developed an acute rejection episode just after tacrolimus weaning, that could be reversed by steroids. Two recipients were accidentally lost (unrelated to kidney function) and three still had a stable kidney function at 1 year. There was no obvious difference between groups in blood phenotype, including Treg levels. A transcriptional analysis of month 1 biopsies did not reveal significant differences either, including for FoxP3 transcripts, with the remarkable exception of Il-21 which was lower in FR104-treated animals. As the main source of Il-21 is CD4 T follicular helper (Tfh), we assessed proliferation of stimulated “blood Tfh” (CXCR5+), pre-Tfh (CXCR5+ICOS+) and Tfh (CXCR5highICOShigh) using human tonsils and found that inhibition was more effective with FR104 than with CTLA4-Ig.
These results suggest that the selective blockade of CD28 was more efficient to allow reducing immunosuppression and maintaining recipients under monotherapy. The mechanism of action could be dependent of Il-21, a cytokine know to be antitolerogenic.
To cite this abstract in AMA style:
Ville S, Poirier N, Vanhove B, Blancho G. Selective Blockade of the CD28/B7/CTLA4 Pathway With Monovalent Anti-CD28 Antibodies Versus Targeting of B7 With CTLA4-Ig, in Non-Human Primate Kidney Allograft [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/selective-blockade-of-the-cd28b7ctla4-pathway-with-monovalent-anti-cd28-antibodies-versus-targeting-of-b7-with-ctla4-ig-in-non-human-primate-kidney-allograft/. Accessed November 21, 2024.« Back to 2015 American Transplant Congress