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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI093881-02
Application #
8386557
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Esch, Thomas R
Project Start
2011-12-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2013
Total Cost
$364,250
Indirect Cost
$129,250
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Ng, Spencer; Deng, Jiusheng; Chinnadurai, Raghavan et al. (2016) Stimulation of Natural Killer Cell-Mediated Tumor Immunity by an IL15/TGFβ-Neutralizing Fusion Protein. Cancer Res 76:5683-5695
Deng, Jiusheng; Pennati, Andrea; Cohen, Jonathon B et al. (2016) GIFT4 fusokine converts leukemic B cells into immune helper cells. J Transl Med 14:106
Deng, Jiusheng; Park, Dongkyoo; Wang, Mengchang et al. (2016) BCL2-BH4 antagonist BDA-366 suppresses human myeloma growth. Oncotarget 7:27753-63
Feng, Hao; Zhang, Han; Deng, Jiusheng et al. (2015) Incorporation of a GPI-anchored engineered cytokine as a molecular adjuvant enhances the immunogenicity of HIV VLPs. Sci Rep 5:11856
Hsieh, Jeremy; Ng, Spencer; Bosinger, Steve et al. (2015) A GMCSF and IL7 fusion cytokine leads to functional thymic-dependent T-cell regeneration in age-associated immune deficiency. Clin Transl Immunology 4:e37
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
Habib, Jakob; Deng, Jiusheng; Lava, Neil et al. (2015) Blood B Cell and Regulatory Subset Content in Multiple Sclerosis Patients. J Mult Scler (Foster City) 2:
Pennati, Andrea; Deng, Jiusheng; Galipeau, Jacques (2014) Maltose-binding protein fusion allows for high level bacterial expression and purification of bioactive mammalian cytokine derivatives. PLoS One 9:e106724
Deng, Jiusheng; Galipeau, Jacques (2014) B cells for cancer immunotherapy. Oncoimmunology 3:e955702
Deng, Jiusheng; Yuan, Shala; Pennati, Andrea et al. (2014) Engineered fusokine GIFT4 licenses the ability of B cells to trigger a tumoricidal T-cell response. Cancer Res 74:4133-44

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