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- W2771126912 abstract "Novel biologic therapies directed against alternate T cell costimulatory pathways could synergize with currently available CD28/B7 costimulation blockade agents to improve allograft survival after kidney transplantation. One potential target is the ICOS (inducible costimulator)-ICOS-L pathway. ICOS-Ig is a human Fc-fusion protein composed of an ICOS extracellular domain and IgG1 tail that binds ICOS-L, blocking ICOS-ICOS-L interaction. We hypothesized that ICOS-Ig would synergize with CD28/B7 costimulation blockade with belatacept to prolong allograft survival in a nonhuman primate kidney transplant model. Therefore, nine rhesus monkeys underwent MHC-mismatched kidney allotransplantation, with 3 animals receiving ICOS-Ig alone, 3 receiving belatacept alone, and 3 receiving ICOS-Ig and belatacept. Belatacept (20 mg/kg) was given on days 0, 3, 7, and 14, then every 2 weeks until day 180, and monthly thereafter. ICOS-Ig (10 mg/kg) was given on day 0, and 5 mg/kg on days 3, 7, 14, 21, and 28. Rejection-free survivals were 6, 6, and 6 days with ICOS-Ig alone; 44, 71, and >385 days with belatacept alone; and 36, 44, and 45 days with ICOS-Ig and belatacept. ICOS-Ig, with or without belatacept, did not prolong rejection-free survival compared to belatacept alone or untreated animals, respectively. Acute rejections were graded Banff 2a to 3. Lymphocytes from peripheral blood, lymph node, spleen and the kidney allograft were isolated at the time of rejection and analyzed for CD28, ICOS, and PD-1 expression by flow cytometry. In the ICOS-Ig alone group, a large percentage of CD8 (60-76%) and CD4 (58-73%) graft infiltrating T cells co-expressed high levels of ICOS and PD-1. The addition of belatacept significantly decreased the proportion of CD8 and CD4 ICOS+PD-1+ T cells (26-54% and 10-16%, respectively). Similar patterns were observed in peripheral blood. The proportions of CD8 CD28- memory T cells were notably higher in the animals receiving belatacept, both in the kidney and peripheral blood. However, T cells that were ICOS+PD-1+ were overwhelmingly CD28+ (80-99%). We concluded that ICOS-Ig, with or without belatacept, did not effectively prolong renal allograft survival in nonhuman primates in this study. DISCLOSURES:Chapin, S.: Employee, Perseid Therapeutics. Devens, B.: Employee, Perseid Therapeutics. Karrer, E.: Employee, Perseid Therapeutics." @default.
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- W2771126912 date "2014-07-01" @default.
- W2771126912 modified "2023-09-25" @default.
- W2771126912 title "A Pilot Trial Targeting the ICOS-ICOS-L Pathway in Nonhuman Primate Kidney Transplantation." @default.
- W2771126912 doi "https://doi.org/10.1097/00007890-201407151-00896" @default.
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