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Blood. 2015 Apr 9;125(15):2418-27. doi: 10.1182/blood-2014-08-597070. Epub 2015 Feb 19.

Plant-based oral tolerance to hemophilia therapy employs a complex immune regulatory response including LAP+CD4+ T cells.

Author information

1
Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL;
2
Departments of Biochemistry and Pathology, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA;
3
Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston MA; and.
4
Department of Biomedical Engineering, Columbia University, New York, NY.

Abstract

Coagulation factor replacement therapy for the X-linked bleeding disorder hemophilia is severely complicated by antibody ("inhibitor") formation. We previously found that oral delivery to hemophilic mice of cholera toxin B subunit-coagulation factor fusion proteins expressed in chloroplasts of transgenic plants suppressed inhibitor formation directed against factors VIII and IX and anaphylaxis against factor IX (FIX). This observation and the relatively high concentration of antigen in the chloroplasts prompted us to evaluate the underlying tolerance mechanisms. The combination of oral delivery of bioencapsulated FIX and intravenous replacement therapy induced a complex, interleukin-10 (IL-10)-dependent, antigen-specific systemic immune suppression of pathogenic antibody formation (immunoglobulin [Ig] 1/inhibitors, IgE) in hemophilia B mice. Tolerance induction was also successful in preimmune mice but required prolonged oral delivery once replacement therapy was resumed. Orally delivered antigen, initially targeted to epithelial cells, was taken up by dendritic cells throughout the small intestine and additionally by F4/80(+) cells in the duodenum. Consistent with the immunomodulatory responses, frequencies of tolerogenic CD103(+) and plasmacytoid dendritic cells were increased. Ultimately, latency-associated peptide expressing CD4(+) regulatory T cells (CD4(+)CD25(-)LAP(+) cells with upregulated IL-10 and transforming growth factor-β (TGF-β) expression) as well as conventional CD4(+)CD25(+) regulatory T cells systemically suppressed anti-FIX responses.

PMID:
25700434
PMCID:
PMC4392010
DOI:
10.1182/blood-2014-08-597070
[Indexed for MEDLINE]
Free PMC Article

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