title: Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses.
abstract: Expansion of human regulatory T cells (Tregs) for clinical applications offers great promise for the treatment of undesirable immune responses in autoimmunity, transplantation, allergy, and antidrug antibody responses, including inhibitor responses in hemophilia A patients. However, polyclonal Tregs are nonspecific and therefore could potentially cause global immunosuppression. To avoid this undesirable outcome, the generation of antigen-specific Tregs would be advantageous. Herein, we report the production and properties of engineered antigen-specific Tregs, created by transduction of a recombinant T-cell receptor obtained from a hemophilia A subject's T-cell clone, into expanded human FoxP3(+) Tregs. Such engineered factor VIII (FVIII)-specific Tregs efficiently suppressed the proliferation and cytokine production of FVIII-specific T-effector cells. Moreover, studies with an HLA-transgenic, FVIII-deficient mouse model demonstrated that antibody production from FVIII-primed spleen cells in vitro were profoundly inhibited in the presence of these FVIII-specific Tregs, suggesting potential utility to treat anti-FVIII inhibitory antibody formation in hemophilia A patients.
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD;
authors.forename: Yong Chan
authors.initials: YC
authors.lastname: Kim
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD;
authors.forename: Ai-Hong
authors.initials: AH
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD;
authors.forename: Yan
authors.initials: Y
authors.lastname: Su
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD; and.
authors.forename: Sadiye Amcaoglu
authors.initials: SA
authors.lastname: Rieder
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Rossi
authors.affiliation: Puget Sound Blood Center Research Institute, Seattle, WA.
authors.forename: Ruth A
authors.initials: RA
authors.lastname: Ettinger
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD;
authors.forename: Kathleen P
authors.initials: KP
authors.lastname: Pratt
authors.affiliation: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD; and.
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Shevach
authors.affiliation: Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD;
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D060846:Cell Engineering / Q000379:methods; D002478:Cells, Cultured; D005169:Factor VIII / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005818:Genetic Engineering; D015316:Genetic Therapy; D006467:Hemophilia A / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D008297:Male; D051379:Mice; D008875:Middle Aged; D037182:T-Cell Antigen Receptor Specificity / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: C078147:F8 protein, human; D005169:Factor VIII