It is not unreasonable to hypothesize that HA patients with certain HLA class II alleles and/or haplotypes will be more susceptible to T-cell stimulation by particular variant sequences in therapeutic FVIII than patients with other alleles and/or haplotypes. Indeed, the identification of HLA-restricted T-cell responses
in mild HA patients against peptides with the wild-type FVIII sequence at the region corresponding to a haemophilic missense site [45–47] serves as proof-of-principle that even a single amino acid change can cause T-cell stimulation leading to inhibitor development when the patient is infused with FVIII that find more differs at this site. Some higher-risk HLA haplotypes (i.e., those encoding HLA class II molecules that can effectively bind and present particular FVIII sequence variants) may be more prevalent in some racial/ethnic groups than in others. We are currently investigating associations of genetic variations with inhibitor prevalence. Cell-based assays are also being used to directly test the immunogenicity Autophagy Compound Library of FVIII sequence variations due to both haemophilic missense mutations and non-haemophilic ns-SNPs. It is hoped that the results of these and similar
studies will identify immunodominant epitopes in FVIII and thus motivate the development of new therapeutic FVIII products targeted to particular populations. We expect that susceptible patient populations will increasingly be defined
by the results of genetic tests that are more specific, i.e. predictive of potential immune responses. We also expect that some genetic determinants of risk – such as large F8 deletions involving multiple exons, selleck products which occur with comparable frequencies in all human populations – will not correlate with racial self-identification. Future genetic markers will be more predictive of inhibitor risk in more precisely defined sub-populations and they will be more useful than, for example, the general assumption of a higher inhibitor risk in black HA patients. It is important to note that only a subset of HA patients with any racial heritage is likely to be at higher risk for inhibitor development, and the relevant genetic risk factors need to be better defined. Increasing knowledge of immune mechanisms leading to neutralizing antibodies will also suggest new therapeutic approaches targeted to specific at-risk populations. We anticipate that genotyping of HA patients will eventually include testing for the presence of particular SNPs in both F8 and immune regulatory genes, e.g. those encoding the HLA class II antigen-presentation repertoire, in addition to the HA-causing F8 mutation. Appropriate genetic testing will allow better matching of HA patients with FVIII products that are likely to be less immunogenic.