ABSTRACT
The development of neutralizing FVIII antibodies is the most serious complication of hemophilia A treatment. The currently known patient- and treatment-related risk factors for inhibitor development do not accurately predict this adverse event in all patients. The composition of the gut microbiota has been shown to influence immune-mediated diseases at distant anatomical sites (eg, lungs, brain, and joints). We demonstrate that a disrupted gut microbiota can be created in a mouse model of hemophilia A using a broad-spectrum antibiotic. Under controlled conditions, this sustained dysbiosis was associated with an increase in splenic B cells and the development of higher titer, FVIII-specific immunoglobulin G antibodies after FVIII challenge. Splenic and mesenteric lymph node cytokines, T cells, and dendritic cells were unaffected before administration of FVIII. However, the immune transcriptome of both aforementioned secondary lymphoid organs was significantly modified. Short-chain fatty acids (SCFAs), which are immunomodulatory microbial metabolites, were depleted in cecal contents of the dysbiotic mice. Furthermore, supplementation of the drinking water with butyrate, the most immunologically active SCFA, successfully achieved attenuation of the FVIII immune response. Collectively, data from this exploratory study suggest that the composition of the gut microbiota alters the FVIII immune response via the action of specific microbial metabolites on the immune cell transcriptome and that oral supplementation with butyrate effectively reduces the FVIII immune response.
Subject(s)
Gastrointestinal Microbiome , Hemophilia A , Animals , Dysbiosis , Factor VIII , Hemophilia A/drug therapy , Humans , Immunity , Mice , Mice, Inbred C57BLABSTRACT
Anti-drug antibody formation following factor VIII (FVIII) replacement therapy is the most important treatment-related complication in patients with severe haemophilia A. A significant number of these antibodies show neutralising activity against FVIII and are referred to as FVIII inhibitors. Alloimmunity to FVIII, given the absence of endogenous circulating FVIII protein, may be predictable to some extent; however, only 30% of patients develop inhibitors. Genetic and environmental risk factors have been identified, contributing to the likelihood of inhibitor development. Multiple immunological theories have been proposed which in part explain the outcomes of many epidemiological studies. Significant differences exist among replacement therapies, including the source, FVIII sequence, glycosylation, formulation components, impurities and aggregation potential, which significantly complicate interpretation of the results from these studies. In this review, we present recent advances in the understanding of the cellular mechanisms of inhibitor formation and highlight some areas of uncertainty requiring further investigation.
Subject(s)
Autoantibodies , Blood Coagulation Factor Inhibitors , Factor VIII , Autoantibodies/genetics , Autoantibodies/immunology , Blood Coagulation Factor Inhibitors/genetics , Blood Coagulation Factor Inhibitors/immunology , Factor VIII/genetics , Factor VIII/immunology , Factor VIII/therapeutic use , Hemophilia A/drug therapy , Hemophilia A/genetics , Hemophilia A/immunology , Hemophilia A/pathology , Humans , Male , Risk FactorsABSTRACT
In hemophilia A, the most severe complication of factor VIII (FVIII) replacement therapy involves the formation of FVIII neutralizing antibodies, also known as inhibitors, in 25% to 30% of patients. This adverse event is associated with a significant increase in morbidity and economic burden, thus highlighting the need to identify methods to limit FVIII immunogenicity. Inhibitor development is regulated by a complex balance of genetic factors, such as FVIII genotype, and environmental variables, such as coexistent inflammation. One of the hypothesized risk factors of inhibitor development is the source of the FVIII concentrate, which could be either recombinant or plasma derived. Differential immunogenicity of these concentrates has been documented in several recent epidemiologic studies, thus generating significant debate within the hemophilia treatment community. To date, these discussions have been unable to reach a consensus regarding how these outcomes might be integrated into enhancing clinical care. Moreover, the biological mechanistic explanations for the observed differences are poorly understood. In this article, we complement the existing epidemiologic investigations with an overview of the range of possible biochemical and immunologic mechanisms that may contribute to the different immune outcomes observed with plasma-derived and recombinant FVIII products.
