We have generated a completely new class of immune suppressive agents based on a GMCSF and IL15 synthetic protein we called GIFT15. We've validated its use in mice and have further demonstrated that this compound promotes development of inducible B-regulatory cells (aka as iBregs) which leads to remission of EAE in mice. Therefore, the funding of this study will enable us to better understand the mechanism of action of iBregs and GIFT15 in the treatment of EAE. We will also define the safest and most efficient use of iBregs and recombinant GIFT15. In addition, we have generated the human version of GIFT15 and demonstrated its suppressive potential on human immune cells. As an additional step, validation of the mouse cell therapy approach will be achieved using human immune cells collected from MS patients, ex vivo treated with the human GIFT15. Assuming that iBregs or GIFT15 protein therapy leads to clinical benefit with an acceptable toxicity profile in EAE mice, the translational use of the human ortholog of GIFT15 in phase I/II clinical studies could be rapidly initiated based on this pre-clinical work. Indeed, the use of rGIFT15 in the context of MS as part of a therapeutic treatment will serve as the basis for the adoption and validation of this approach for a variety of diseases such as inflammatory bowel disease (IBD), graft-versus-host disease (GVHD), rheumatoid arthritis (RA) or even in the context of cell and organ transplantations. Thus, the utility of the GIFT15 compound as a way to generate suppressive cells in vitro and likely in vivo represents an approach with a wide array of clinical applications for catastrophic illnesses with unmet medical needs, especially MS. In sum, this study will enable us to pursue the characterization of iBregs and GIFT15 protein pharmacological product and will serve as rational for human clinical studies.

Public Health Relevance

The development of innovative biopharmaceutical therapies suppressing the immune response seen in neuroinflammatroy disorders such as multiple sclerosis addresses an important clinical problem with unmet medical needs and serves as the preamble to first-in-man clinical trials. Knowledge gained from the proposed research will lead to improved outcome for patients suffering from autoimmune disorders at large.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
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Esch, Thomas R
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Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
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Pennati, Andrea; Asress, Seneshaw; Glass, Jonathan D et al. (2018) Adoptive transfer of IL-10+ regulatory B cells decreases myeloid-derived macrophages in the central nervous system in a transgenic amyotrophic lateral sclerosis model. Cell Mol Immunol 15:727-730
Deng, Jiusheng; Li, Yanqiu; Pennati, Andrea et al. (2017) GM-CSF and IL-4 Fusion Cytokine Induces B Cell-Dependent Hematopoietic Regeneration. Mol Ther 25:416-426
Pennati, Andrea; Ng, Spencer; Wu, Yuanqiang et al. (2016) Regulatory B Cells Induce Formation of IL-10-Expressing T Cells in Mice with Autoimmune Neuroinflammation. J Neurosci 36:12598-12610
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Ng, Spencer; Galipeau, Jacques (2015) Concise review: engineering the fusion of cytokines for the modulation of immune cellular responses in cancer and autoimmune disorders. Stem Cells Transl Med 4:66-73
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