Lineages of human T-cell clones, including T helper 17/T helper 1 cells, isolated at different stages of anti-factor VIII immune responses.
The development of neutralizing antibodies (inhibitors) after factor VIII (FVIII) infusions is a serious complication that affects approximately one-quarter of hemophilia A patients who have access to replacement therapy. To investigate the differentiation of naive T cells into FVIII-specific helper T cells that promote B-cell activation and antibody secretion, HLA-DRA-DRB1*0101-restricted T-cell clones that respond to a specific epitope in FVIII were isolated from a mild hemophilia A subject (the proband) 19 weeks and 21 months after his development of a high-titer inhibitor. Clones responding to the same epitope were also isolated from his multiply infused brother, who has not developed a clinically significant inhibitor. The 19-week proband clones were T helper (T(H))17/T(H)1- or T(H)1/T(H)2-polarized, whereas all 8 clones isolated 21 months postinhibitor development were T(H)2-polarized cells. In contrast, all 6 clones from the brother who did not develop an inhibitor were T(H)1-polarized, indicating that tolerance to FVIII can be maintained even with circulating T(H)1-polarized cells that respond vigorously to in vitro FVIII stimulation. This is the first evidence that T(H)17/T(H)1-polarized cells play a role in hemophilic immune responses to FVIII. Furthermore, this is the first report of successful isolation and expansion of antigen-specific human T(H)17/T(H)1 clones using standard culture conditions.
Ettinger
Ruth A
RA
Puget Sound Blood Center, Seattle, WA 98104, USA.
James
Eddie A
EA
Kwok
William W
WW
Thompson
Arthur R
AR
Pratt
Kathleen P
KP
D000906:Antibodies / Q000276:immunology*; D019774:Blood Coagulation Factor Inhibitors / Q000276:immunology*; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002478:Cells, Cultured; D005169:Factor VIII / Q000009:adverse effects / Q000276:immunology* / Q000627:therapeutic use; D015234:HLA-A Antigens / Q000276:immunology; D006684:HLA-DR Antigens / Q000276:immunology; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D008297:Male; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D013997:Time Factors
D000906:Antibodies; D019774:Blood Coagulation Factor Inhibitors; D015234:HLA-A Antigens; D006684:HLA-DR Antigens; D059805:HLA-DR alpha-Chains; D059811:HLA-DRB1 Chains; C487961:HLA-DRB1*01:01 antigen; D005169:Factor VIII