[Background] De novo donor-specific antibody (DSA) after organ transplantation promotes antibody-mediated rejection (AMR) and causes late graft loss. Nearly a third of transplant recipients develop de novo antibodies, for which no established therapies are effective at preventing. Previously, we demonstrated that depletion using anti-CD3 immunotoxin (IT) combined with Tacrolimus and Alefacept (AMR regimen) reliably induced early DSA production with antibody-mediated injury in a nonhuman primate kidney transplant model.

[Methods] All rhesus macaques received the AMR regimen of CD3-IT × 4 days, alefacept × 8 weeks, and tacrolimus maintenance. Five animals were assigned as positive AMR controls, four received additional belatacept (20mg/kg weekly × 8 weeks), and four received additional anti-CD40 mAb 2c10 (20mg/kg weekly × 8 weeks).

[Results] Notably, production of early de novo DSA was completely attenuated (*p<0.05) at 4 and 6 weeks post transplantation with additional Belatacept (n=4) or 2C10 (n=4) treatment compared to the AMR control group (n=5). In accordance with this, while positive controls experienced a decrease in peripheral IgM⁺CD20⁺ B cells by day 28, bela- and 2c10-added groups maintained a predominant population of IgM⁺CD20⁺ B cells, potentially indicating decreased isotype switching. Central memory T cells (CD4⁺CD28⁺CD95⁺) as well as follicular helper T (Tfh) cells (PD-1^hiCD4⁺CD3⁺) were decreased in both bela-added and 2c10-added groups compared to the AMR controls. In analyzing Tfh cells and germinal center reactions in situ, immunostained lymph nodes further revealed a reduction of B cell clonal expansion (% of Ki67⁺CD20⁺ in the follicle; 2.11±0.31 or 3.37±2.34 vs. 9.08±2.71%; p<0.05)), Tfh Cells (# of PD-1^hiCD4⁺ per mm2; 33.80±24.23 or 195.90±242.81 vs. 502.72±169.34 mm2;p<0.05), and IL-21 production (% CD3⁺IL-21⁺ area in the follicle; 2.52±0.53 or 3.54±1.01 vs. 7.42±2.23%; P<0.05) inside germinal centers with additional belatacept or 2C10 treatment compared to AMR controls.

[Conclusions] Here we provide evidence that Belatacept and 2C10 selectively suppresses the humoral response via regulating follicular helper T cells (Tfh) and prevents AMR in this non-human primate model. These results support the translation of selective supplementation with belatacept for AMR prevention.

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