FcγR3A genotype influences the inhibition of activated T cell proliferation by infliximab and adalimumab (HUM1P.313)

Abstract

Abstract The anti-tumor necrosis factor (TNF) antibodies, infliximab and adalimumab are efficacious in Crohn’s disease (CD) patients but their relevant mechanism(s) of action (MOA) are not fully elucidated. Neutralization of TNF activity is a key efficacy mechanism, but may not be the only relevant MOA for efficacy in CD. Fc receptor-mediated dampening of the immune response has been proposed as one of the alternative hypotheses. Two FcγR3A-158 polymorphisms (158V and 158F) have been shown to influence binding affinity of IgG1 antibodies, and CD patients with V/V genotypes have increased biological responses to infliximab. Previous work by others showed that in a mixed lymphocyte reaction (MLR), infliximab and adalimumab induced formation of immunosuppressive macrophages in an Fc region-dependent manner and that these macrophages inhibited proliferation of activated T cells. We ran MLRs with FcγR3A genotype-matched donor pairs to determine if Fc receptor genotype influenced the anti-inflammatory response by infliximab and adalimumab. Our results showed that regulatory macrophages were induced regardless of FcγR3A genotype but that decreases in T cell proliferation were more pronounced with V/V donor pairs than with V/F or F/F genotypes. In conclusion, our work suggests that infliximab and adalimumab may be more effective at inducing an anti-inflammatory state in individuals with the 158V polymorphism of FcγR3A.