Neonatal Fc receptor-mediated tolerance induction in alloimmune and autoimmune conditions – Immunotolerins

Several pathological situations result from a break in immunological tolerance towards endogenous molecules, as seen in autoimmune diseases, or from the inability to mount tolerance towards exogenously administered molecules, as observed in alloimmune responses to protein therapeutics. In this project, we propose to develop a novel strategy to induce specific tolerance towards a given antigen (Ag), so as to prevent the development of pathological autoimmune manifestations or of iatrogenic alloimmune responses during replacement therapy. Our approach consists in introducing the Ag of interest during the fetal life and during the early life in the circulation of an individual, in order to shape its immune repertoire and to let the immune system develop tolerance throughout its ontogeny. To this end, the Ag coupled to the Fc portion of an immunoglobulin G1 (IgG1) is injected into the blood of pregnant and lactating mothers. The antigen-Fc chimeric protein is thus targeted to the offspring upon binding to the neonatal Fc receptor (FcRn) expressed on the syncytiotrophoblast and on the digestive epithelium and transfer into the newborn’s circulation. To validate our therapeutic strategy, we shall concentrate on two mouse models of human diseases: alloimmunization against therapeutic factor VIII (FVIII) in hemophilia A, and spontaneous autoimmune destruction of insulin-producing ß-cells in type 1 diabetes (T1D).

Hemophilia A is a rare X-linked recessive life-threatening, crippling hemorrhagic disorder consecutive to the absence of endogenous pro-coagulant FVIII. Treatment of bleeding episodes by administration of exogenous FVIII results, in up to 30% of cases, in the emergence of anti-FVIII IgG, that neutralize the pro-coagulant activity of therapeutic FVIII. FVIII inhibitors represent a major medical hurdle and a critical societal concern as the treatment of inhibitor-positive patients reaches more than 0.2 million euros/patient/year in developed countries. If successful in hemophilic mice, our preventive approach could be transferred into clinical trials. Interestingly, hemophilia in human may be anticipated based on the familial history of the disease in 2/3 of the cases, and may be diagnosed during pregnancy. In addition, the risks for a patient-to-be-born to develop FVIII inhibitors after initiation of replacement therapy can also be estimated before birth, according to the type of mutation in the F8 gene, on the history of an inhibitor among hemophiliac brothers or uncles, and on polymorphisms in the IL-10, TNF-a and CTLA-4 encoding genes.

T1D is one of the most common autoimmune diseases, characterized by the destruction of insulin-producing islet ß-cells. T1D mainly affects children and young adults below the age of 20 in 50% of cases, leading to lifelong treatments and frequent long-term complications (cardiovascular diseases, end-stage renal failure, blindness). Its incidence is steadily increasing, with up to 15 new diagnoses/100,000/year in France. It is thus a highly debilitating disease, and an important voice of public health expense. Success of our preventative therapy in experimental T1D would be groundbreaking. Early re-shaping of the autoimmune repertoire of susceptible individuals according to their risk profile would allow to intervene before epitope spreading and ß-cell destruction ensue, thus potentially offering disease cure.

In the case of both disorders, positive results in our study would have dramatic repercussions for the quality of life of the patients and, in the long range, reduce societal costs. At the same time, this selective Ag-specific approach would avoid generalized immunosuppression, which frequently carries unacceptable risk/benefit ratios.