Hemophilia A (HA) is an inherited bleeding disorder caused by congenital factor VIII (FVIII) deficiency. Around 30% of HA patients treated with recombinant human FVIII develop antibodies neutralizing the therapeutic protein. Surprisingly, these anti-FVIII antibodies are also found in around 20% of healthy donors, who express normal levels of FVIII. In 2017, the research team had measured significant quantities of FVIII-specific conventional T lymphocytes (Tconvs) in the peripheral blood of these donors, explaining the existence of circulating anti-FVIII auto-antibodies.
Since tolerance to "self" proteins requires the suppression of Tconvs lymphocytes in the thymus and the recruitment of Tregs lymphocytes, which contribute to reducing potentially deleterious auto-immune responses, the team looked for the presence of FVIII-specific Tregs in the blood of healthy donors. To achieve this, an innovative approach based on the weekly stimulation of polyclonal Tregs by recombinant FVIII and the evaluation of their specificity by analyzing membrane expression of an activation marker, has been developed. The results show that FVIII-specific Tregs are present at a frequency 10 times lower than that of specific Tconvs in 11 healthy donors, and their characterization strongly suggests their thymic origin.
By demonstrating for the first time the presence of human FVIII-specific Tregs in the blood of healthy donors, this study highlights the existence of a mechanism of tolerance to FVIII, and also shows that it is not "ignored" by the immune system, even in normal subjects. Further studies in HA patients should clarify the mechanisms of peripheral tolerance to FVIII and the role of Tregs in reducing the immunogenicity of recombinant FVIII.
Contact : Catherine Menier (catherine.menier@cea.fr)
T lymphocytes are a category of white blood cells that play a crucial role in the immune response (T is short for thymus, the organ in which their development is completed).