Understanding of the roles of CD4+CD25+ T cells and Tregs in development of anti-FVIII in hemophilia A: insights for inhibitor development prevention

Hemophilia A, characterized by factor VIII (FVIII) deficiency, can be managed with factor replacement therapy. However, FVIII-neutralizing antibodies developed in people with hemophilia A (PwH) can reduce treatment efficacy. This study investigated the impact of FVIII inhibitors on immunity in PwH. Twenty PwH (with the presence and absence of inhibitors) and 10 healthy individuals have participated. CD4 + , CD4 + CD25 + , Treg cell percentages, proliferation levels, and cytokine levels in cell-culture supernatants were evaluated. An increased CD4 + CD25 + T-cell subset was noted in PwH without inhibitors. CD4 + and CD4 + CD25 + T cells showed increased proliferation, while Treg cells had decreased proliferation in PwH without inhibitors compared to controls. With rFVIII added to cell culture, CD4 + CD25 + proliferation decreased and Treg proliferation increased in PwH with inhibitors, while it remained unchanged in other groups. IL-10 was reduced in both PwH groups. TGF-β was decreased in PwH with inhibitors compared to those without inhibitors. IL-10/TGF-β ratio was reduced in both PwH groups compared to controls. rFVIII in culture conditions significantly reduced TNF-α only in PwH with inhibitors, while TGF-β was decreased in PwH without inhibitors and healthy controls. Monitoring T-cell immunity in PwH before anti-FVIII antibody development may improve treatment success and help prevent antibodies and related complications.