Reprogramming of B cells into regulatory cells with engineered fusokines

• Type of Material: Article
• Authors: Jiusheng Deng, Emory University; Jacques Galipeau, Emory University
• Language: English
• Date: 2012-06
• Publisher: Bentham Science Publishers
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © Bentham Science Publisher
• Final Published Version (URL): http://www.eurekaselect.com/98013/article
• Title of Journal or Parent Work: Infectious Disorders - Drug Targets
• ISSN: 1871-5265
• Volume: 12
• Issue: 3
• Start Page: 248
• End Page: 254
• Grant/Funding Information: This work is supported by National Institutes of Health (1R01AI093881-01A1) and Georgia Cancer Coalition, USA.
• Keywords: IL-10; Fusokine; inflammation; IL-15; GM-CSF; multiple sclerosis; Bregs
• Research Categories: Biology, Cell; Health Sciences, Oncology

Abstract

B cells play a pivotal role in host adaptive immunity against pathogenic microorganisms, but may also maladaptively contribute to the pathogenesis of autoimmune diseases. In contrast, distinct B cell subsets have the capacity to regulate host immune response, and suppress inflammation. B regulatory cells are a rare population of endogenous B-lymphocytes defined in part by production of the anti-inflammatory cytokine IL-10. Although “natural” B regulatory cells exist in vivo, the low frequency of B regulatory cells may be a limiting factor on their impact in autoimmune ailments. In answer to this unmet need, we have developed a novel strategy for alternate lymphoid activation: fusokines. These wholly engineered chimeric leukines fuse two functionally unrelated cytokines for the purpose of alternate immune modulation. The GM-CSF- and IL-15-derived fusokine: GIFT15, possesses entirely novel and unheralded immune modulating properties mediated through the IL15 receptor which reprograms naïve B cells into B regulatory cells (Bregs). In this article, we review the current approaches to generate Bregs in vitro, and highlight gain-of-function mechanisms by which GIFT15-induced Bregs abrogate pathogenic autoimmunity in mice. We also demonstrate that the human equivalent of inducible Bregs may also serve as a new potent therapeutic tool for treatment of autoimmune disease.