Distinct lineages of human T-cell clones, including Th17/Th1 cells, isolated at different stages of anti-factor VIII immune responses (48.26)

Abstract

Abstract Approximately 25% of hemophilia A patients, who lack functional factor VIII (FVIII), develop neutralizing antibodies after receiving therapeutic infusions of FVIII. HLA-DRA-DRB1*0101-restricted T-cell clones that respond to FVIII2194-2213 were isolated from a hemophilia A subject (the proband) ~5 and 21 months following his development of a high-titer FVIII neutralizing antibody response, and from his brother who has not developed a clinically significant antibody response. Three clones obtained from the proband at 5 months were TH17/TH1-polarized and two were TH1/TH2-polarized. The 8 proband clones isolated at 21 months were TH2-polarized, indicating T-cell lineage changes over time. The 6 clones from the brother were TH1-polarized, indicating that B-cell tolerance to FVIII can be maintained even with circulating antigen-specific TH1-polarized cells. Several TCRBV-D-J junction sequences were identified suggesting differences in TCR interaction with the MHC class II-peptide complex. Current investigations are examining the response of clones to altered peptide ligands. This is the first evidence that TH17/TH1-polarized cells play a role in hemophilic immune responses to FVIII; it is also the first detailed characterization of antigen-specific TH17/TH1 clones isolated using standard culture conditions. Research Support: Bayer Hemophilia Award, CSL Behring Hemophilia Research Award, NIH.