title: In vivo expansion of regulatory T cells with IL-2/IL-2 mAb complexes prevents anti-factor VIII immune responses in hemophilia A mice treated with factor VIII plasmid-mediated gene therapy.
abstract: Generation of transgene-specific immune responses can constitute a major complication following gene therapy treatment. An in vivo approach to inducing selective expansion of Regulatory T (Treg) cells by injecting interleukin-2 (IL-2) mixed with a specific IL-2 monoclonal antibody (JES6-1) was adopted to modulate anti-factor VIII (anti-FVIII) immune responses. Three consecutive IL-2 complexes treatments combined with FVIII plasmid injection prevented anti-FVIII formation and achieved persistent, therapeutic-level of FVIII expression in hemophilia A (HemA) mice. The IL-2 complexes treatment expanded CD4(+)CD25(+)Foxp3(+) Treg cells five- to sevenfold on peak day, and they gradually returned to normal levels within 7-14 days without changing other lymphocyte populations. The transiently expanded Treg cells are highly activated and display suppressive function in vitro. Adoptive transfer of the expanded Treg cells protected recipient mice from generation of high-titer antibodies following FVIII plasmid challenge. Repeated plasmid transfer is applicable in tolerized mice without eliciting immune responses. Mice treated with IL-2 complexes mounted immune responses against both T-dependent and T-independent neoantigens, indicating that IL-2 complexes did not hamper the immune system for long. These results demonstrate the important role of Treg cells in suppressing anti-FVIII immune responses and the potential of developing Treg cell expansion therapies that induce long-term tolerance to FVIII.
authors.affiliation: Center for Immunity and Immunotherapies, Seattle Children's Research Institute, Seattle, Washington, USA.
authors.forename: Chao-Lien
authors.initials: CL
authors.lastname: Liu
authors.forename: Peiqing
authors.initials: P
authors.lastname: Ye
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Yen
authors.forename: Carol H
authors.initials: CH
authors.lastname: Miao
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D005169:Factor VIII / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods; D006467:Hemophilia A / Q000276:immunology* / Q000628:therapy; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010957:Plasmids / Q000235:genetics / Q000627:therapeutic use; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000097:blood; D019076:Transgenes / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D016212:Transforming Growth Factor beta; D005169:Factor VIII