The HLA-DR2 haplotype is associated with an increased proliferative response to the immunodominant CD4+ T-cell epitope in human interferon-β

Abstract

Human CD4 þ T-cell epitopes were identified in interferon-beta (IFN-b)-1b. A prominent peptide epitope region was found that induced a proliferative response in 16% of all donors tested. Responses corresponded to the presence of the HLA-DR2 haplotype. Responsive donors expressing the HLA-DQ6 allele showed an increased level of proliferation to the epitope as compared to peptide-responsive HLA-DQ6 negative donors. A similar result was found for HLA-DR15-expressing donors. PBMC from donors expressing HLA-DR15 were more likely to proliferate in response to IFN-b in a whole-protein in vitro assay than donors who did not carry this haplotype. It is striking that the common DQ6 allele HLA-DQB1*0602 is found in linkage disequilibrium with HLA-DRB1*1501, and this combination defines the HLA genotype associated with the development of multiple sclerosis. The HLA association between a response to IFN-b and MS might explain the prevalence of neutralizing antibody development, and may underlie the etiology of the disease.

Elimination of an Immunodominant CD4+ T Cell Epitope in Human IFN-β Does Not Result in an In Vivo Response Directed at the Subdominant Epitope

“…Amino acids 118 -132 represent the dominant CD4 ϩ T cell epitope found in a human population-based test of the IFN-␤ peptides (21). We have previously tested alanine scan variants of this region using human CD4 ϩ T cells and found that the response to this epitope peptide was severely inhibited by changes to the isoleucine at position 129 (21).…”

“…We have previously tested alanine scan variants of this region using human CD4 ϩ T cells and found that the response to this epitope peptide was severely inhibited by changes to the isoleucine at position 129 (21). As the BALB/cByJ mouse also responded to the 118 -132 region, we immunized mice with human IFN-␤ protein and tested proliferative responses to the parent peptide (118 -132) and a series of alanine mutant peptides based on the sequence of the parent peptide.…”

“…The effect of neutralizing Abs on IFN-␤ efficacy is controversial (16, 18 -20). An immunodominant epitope was defined at amino acid position 118 -132 in the protein (21). To test our ability to modify immune reactivity of protein therapeutic molecules while leaving their activity intact, we undertook an animal model proof-of-concept project using human IFN-␤.…”

The immunogenicity of humanized and fully human antibodies

“…This empirical method was selected due to the utility of the assay in identifying CD4 + T cell epitopes in other proteins 82,83 with a very good specificity and sensitivity. 84 This method identifies CD4 + T cell epitope responses within a test population of community donors.…”

Immunogenicity of Protein Therapeutics: Risk Assessment and Risk Mitigation

“…Stickler et al have observed that the DRB1 * 1501/DQB1 * 0602 haplotype is associated with a high potential of naïve CD4 + T cells to react against human IFN-β in vitro [60]. In accordance, the C-terminal IFN-β peptide 147-161 was eluted from HLA-DR molecules after IFN-β exposure of human dendritic cells expressing the DRB1 * 1501 allele (H. Kropshofer, unpublished).…”