Program: Oral and Poster Abstracts
Type: Oral
Session: 322. Disorders of Coagulation or Fibrinolysis: Inhibitors in Hemophilia
We utilize a well-validated, computational tool, NetMHC-II, to enable large scale, computational comparison of predicted antigen presentation between endogenous, mutated FVIII derived peptides and factor-concentrate derived, wild-type FVIII peptides spanning all 520 F8 missense mutations listed on www.hadb.org. NetMHC-II analyses peptide presentation by 14 class II MHC HLA-DR alleles, resulting in analysis of 7,280 (520 x 14) permutations of F8-MHC-II. We identify 56% (n=4,077) of these permutations to be at low/negligible risk of inhibitor formation, at a binding threshold of 500nM, defined as absence of a novel peptide-MHC surface capable of driving a helper T cell response (p=0.005). When cross referenced with potential homologous sequences buried anywhere in the human proteome (http://www.ebi.ac.uk/reference_proteomes), a further 1,237 F8-MHC-II combinations are afforded “proteome protection” due to direct sequence homology between FVIII-derived peptide and peptide(s) derived from other proteins. This increases the total number of F8-MHC-II combinations predicted to be unable to drive a T cell response to 73% (n=5,314). The residual 1,966 (27%) F8-MHC-II combinations are predicted to retain the ability to present novel-interface FVIII-derived peptides to T cells with an IC50<500nM (higher affinity).
Previous work exploring in silico prediction of FVIII-derived peptide presentation may have overestimated the number of F8-MHC II combinations deemed to be at risk of contributing to inhibitor formation. Our data suggests an additional mechanism “protecting” a larger proportion of those living with non-severe HA from inhibitor formation. The contribution of “proteome protection” further reduces the “at risk” F8-MHC II permutations to be more representative of clinically observed inhibitor rates. We identify a potential novel tolerance mechanism and provide key data for future in vitro validation strategies.
Disclosures: No relevant conflicts of interest to declare.
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