Desensitization and belatacept-based maintenance therapy in pregnancy-sensitized monkeys receiving a kidney transplant

Abstract

Among sensitized patients awaiting a transplant, females are disproportionately represented, partly because of pregnancy-induced sensitization. Using female NHPs sensitized by pregnancy alone, we examined the efficacy of costimulation blockade and proteasome inhibition for desensitization. Three animals received no desensitization (control), and seven animals received weekly carfilzomib (27 mg/m 2 ) and belatacept (20 mg/kg) before kidney transplantation. All animals received renal allografts from crossmatch-positive/maximally MHC-mismatched donors. Controls and three desensitized animals received tacrolimus-based immunosuppression. Four desensitized animals received additional belatacept with tacrolimus-based immunosuppression. Multiparous females had less circulating donor-specific antibody when compared to skin-sensitized males before transplantation. While females receiving desensitization showed only a marginal survival benefit over control females (MST = 11 days versus 63 days), additional belatacept to posttransplant maintenance significantly prolonged graft survival (MST > 164 days) and suppressed posttransplant DSA and circulating follicular helper T-like cells. This combination of therapies demonstrates great potential to reduce antibody-mediated rejection in sensitized recipients.

Belatacept and carfilzomib-based treatment for antibody-mediated rejection in a sensitized nonhuman primate kidney transplantation model

“…Given this stringency, we hypothesize that patients undergoing HLA-compatible transplants may actually have better responses to AMR treatment compared to our NHPs. To address this limitation, we have recently developed a naturally sensitized multiparous female primate model ( 32 ). Additionally, all animals received desensitization therapy prior to transplant to avoid early acute AMR.…”

“…Twelve (12) animals were additionally treated with belatacept (20 mg/kg, IV) and carfilzomib (27 mg/m 2 , IV) weekly for 4 weeks with or without the C3 complement inhibitor, Compstatin (Cp40, 2 mg/kg TID) for 2 weeks ( Table 1 ). Animals in this report have appeared in previous publications with respect to data unrelated to AMR treatment ( 28 , 32 – 34 ). In other words, treatment of AMR and response to treatment data have not previously been reported.…”

Allosensitisation in NHP results in cross‐reactive anti‐SLA antibodies not detected by a lymphocyte‐based flow cytometry crossmatch

“…To investigate if allosensitisation contributes to XAb development, we evaluated 10 NHPs previously reported that were allosensitised via skin transplantation at two timepoints: naïve (pre-sensitisation) and post-allosensitisation (Figure 1). 9 There was no difference in IgG XAb binding between the naïve and sensitised time points as measured in a T cell FXM (TFXM, p = 0.912) or B cell FXM (BFXM, p = 0.739) (Figure 1A). The same was true for IgM XAb binding in the TFXM ( p = 0.529) or B cell crossmatch (BCXM) ( p = 0.971) (Figure 1C).…”

“…We have observed accelerated xenograft rejection kinetics in allosensitised NHP recipients with GGTA1/ CD55Tg pig donor. 9 While alleviated with more advanced pig donor, considering the substantial homology as well as disparity within both amino acid and threedimensional structure among major histocompatibility complex (MHC) across different species, it is hypothesised that allosensitisation and exposure to foreign MHC could lead to the development of cross-reactive antibodies against swine leukocyte antigen (SLA).…”