title: T lymphocyte proliferative responses induced by recombinant factor VIII in hemophilia A patients with inhibitors.
abstract: In this study we sought to determine whether factor VIII-reactive T lymphocytes were present in hemophilia A patients with inhibitor antibodies. Peripheral blood mononuclear cells (MNC) were obtained from 12 severe hemophilia A patients having high titer inhibitors, 4 severe hemophilia A patients without inhibitors and 5 normal male subjects. B cell-depleted MNC were cultured in serum-free medium in the absence or presence of 2 micrograms of recombinant human factor VIII (rFVIII) per ml, and cellular proliferation was assessed after 5 days of culture by measuring 3H-thymidine incorporation. rFVIII induced marked cellular proliferation in cultures of 4 of 12 inhibitor-positive hemophilia patients: fold increase over background (stimulation index, SI) of 7.8 to 23.3. The remaining 8 inhibitor-positive patients, the 4 hemophilia patients without inhibitors and the 5 normal subjects, all had lower proliferative responses to rFVIII, SI range = 1.6 to 6.0. As a group, the inhibitor-positive subjects had significantly higher proliferative responses to rFVIII than did the inhibitor-negative and normal subjects (p < 0.05 by t-test). Cell fractionation experiments showed that T lymphocytes were the rFVIII-responsive cell type, and that monocytes were required for T cell proliferation. Thus, rFVIII-reactive T lymphocytes are present in the peripheral circulation of some inhibitor-positive hemophilia A patients. These T cells may recognize FVIII in an antigen-specific manner and play a central role in the regulation of inhibitor antibody production.
authors.affiliation: Hematology-Oncology Department, Children's Hospital Oakland, CA 94609, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Singer
authors.forename: J E
authors.initials: JE
authors.lastname: Addiego
authors.forename: D C
authors.initials: DC
authors.lastname: Reason
authors.forename: A H
authors.initials: AH
authors.lastname: Lucas
mesh_terms: D000293:Adolescent; D000328:Adult; D000906:Antibodies / Q000097:blood*; D001667:Binding, Competitive; D002648:Child; D002675:Child, Preschool; D005169:Factor VIII / Q000276:immunology / Q000627:therapeutic use*; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000906:Antibodies; D011994:Recombinant Proteins; D005169:Factor VIII