title: Adjuvant facilitates tolerance induction to factor VIII in hemophilic mice through a Foxp3-independent mechanism that relies on IL-10.
abstract: Current treatment of hemophilia consists of the administration of recombinant clotting factors, such as factor VIII (FVIII). However, patients with severe hemophilia can mount immune responses targeting therapeutically administered FVIII through inhibitory immunoglobulins that limit treatment efficacy. Induction of immune tolerance to FVIII in hemophilia has been extensively studied but remains an unmet need. We found that nondepleting anti-CD4 monoclonal antibodies (mAbs) are effective in inducing long-term tolerance to FVIII in different strains of hemophilic mice. Tolerance induction was facilitated when anti-CD4 mAbs were administered together with FVIII adsorbed in an adjuvant (alum). The observed state of tolerance was antigen specific, with mice remaining immune competent to respond to different antigens. Importantly, we found that following immunization with FVIII, the primed cells remained susceptible to tolerance induction. Studies with Foxp3-deficient and interleukin 10 (IL-10)-deficient mice demonstrated that the underlying tolerance mechanism is Foxp3 independent but requires IL-10. Our data show that an adjuvant, when administered together with a tolerizing agent such as nondepleting anti-CD4, can facilitate the induction of long-term tolerance to recombinant proteins, possibly not only in hemophilia but also in other diseases that are treated with potentially immunogenic therapeutics.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Vanessa G
authors.initials: VG
authors.lastname: Oliveira
authors.forename: Ana
authors.initials: A
authors.lastname: Agua-Doce
authors.forename: Maria A
authors.initials: MA
authors.lastname: Curotto de Lafaille
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Lafaille
authors.forename: Luis
authors.initials: L
authors.lastname: Graca
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000534:Alum Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology; D015704:CD4 Antigens / Q000276:immunology; D004338:Drug Combinations; D004353:Drug Evaluation, Preclinical; D005169:Factor VIII / Q000008:administration & dosage / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006467:Hemophilia A / Q000188:drug therapy* / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000502:physiology
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D004338:Drug Combinations; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C556062:IL10 protein, mouse; D016753:Interleukin-10; C041524:aluminum sulfate; D005169:Factor VIII