Naturally occurring CD4+ CD25+ cells in modulating immune response to administered coagulation factor VIII in factor VIII‐deficient mice

CD4+ CD25+ T regulatory (Treg) cells are critical mediators of peripheral self-tolerance and immune homeostasis. In this study, we characterized the ability of naturally occurring CD4+ CD25+ cells from the wild-type mice to modulate the immune response to administered coagulation factor VIII (FVIII) in FVIII-deficient mice. For the cell therapy, CD4+ CD25+ cells and CD4+ CD25- cells were purified from the spleens of wild-type normal mice and administered to FVIII-deficient mice prior to four injections of recombinant FVIII (rFVIII). The titre of FVIII antibodies and antibodies with inhibitory activity against FVIII was lower in the mice treated with natural CD4+ CD25+ cells or CD4+ CD25- cells compared with the mice treated only with rFVIII. We also demonstrated that CD4+ CD25- cells could differentiate to acquire the Treg phenotype expressing CD25 and FoxP3 if stimulated in vitro. These observations provide evidence that Treg cells can be used for designing cell therapy for controlling the immune response to FVIII.