T lymphocytes known as type 1 or invariant NKT cells (iNKT cells) recognize specific lipid ligands presented by the CD1d protein, and this component of the CD1-dependent immune response is highly conserved between humans and mice. Many detailed studies in mouse models have shown that iNKT cells contribute to immune responses against pathogens, elimination of malignant tumors, maintenance of immunological tolerance and prevention of autoimmune diseases. Great progress in understanding and potentially harnessing the many immunological activities of iNKT cells has been made in recent years as a result of the identification of various forms of synthetic a-galactosylceramide (aGalCer) that specifically activate these cells. The current proposal is focused on the identification of modified forms of aGalCer that activate different cytokine patterns when used to stimulate mouse or human iNKT cells. Numerous Th2-cytokine biasing forms of aGalCer have been identified in our ongoing studies, and we propose new synthetic approaches to create additional aGalCer analogues that will include examples with tolerogenic or proinflammatory activities based on cytokine production or other effects. These compounds will be characterized in detail using assay systems to analyze both mouse and human iNKT cell responses to identify those that are most suitable to carry forward into translational studies. Using new monoclonal antibody reagents specific for CD1d/aGalCer complexes, and soluble iNKT cell antigen receptors, we will carry out a range of studies to determine the mechanisms that lead to the stimulation of markedly different patterns of cytokines by various aGalCer analogues. Studies to optimize the adjuvant properties of selected aGalCer analogues in model systems of vaccination are also proposed. These studies will increase our understanding of the mechanisms governing the regulation of the many potential activities of iNKT cells, and will contribute to development of therapeutic applications for glycolipid activators of this T cell subset.

Public Health Relevance

This project will develop chemical compounds that specifically activate a specialized subset of T lymphocytes known as iNKT cells. These T cells have the ability to either stimulate or suppress immune responses, depending on how they are activated. The studies put forth in this proposal will identify compounds that selectively activate either the stimulatory or suppressive functions of iNKT cells, which will lead to the ability to more precisely control the functions of these cells for the prevention or treatment of human disease. The potential range of applications for iNKT cell activators is very broad and includes their use as drugs for prevention of autoimmune diseases such as type 1 diabetes or multiple sclerosis, as well as their incorporation into new vaccines for infections and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI045889-15
Application #
8295005
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Rothermel, Annette L
Project Start
1999-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
15
Fiscal Year
2012
Total Cost
$406,742
Indirect Cost
$161,717
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Venkataswamy, Manjunatha M; Ng, Tony W; Kharkwal, Shalu S et al. (2014) Improving Mycobacterium bovis bacillus Calmette-Guèrin as a vaccine delivery vector for viral antigens by incorporation of glycolipid activators of NKT cells. PLoS One 9:e108383
Arora, Pooja; Baena, Andres; Yu, Karl O A et al. (2014) A single subset of dendritic cells controls the cytokine bias of natural killer T cell responses to diverse glycolipid antigens. Immunity 40:105-16
Singh, M; Quispe-Tintaya, W; Chandra, D et al. (2014) Direct incorporation of the NKT-cell activator ?-galactosylceramide into a recombinant Listeria monocytogenes improves breast cancer vaccine efficacy. Br J Cancer 111:1945-54
Carreño, Leandro J; Kharkwal, Shalu Sharma; Porcelli, Steven A (2014) Optimizing NKT cell ligands as vaccine adjuvants. Immunotherapy 6:309-20
Anantha, R V; Mazzuca, D M; Xu, S X et al. (2014) T helper type 2-polarized invariant natural killer T cells reduce disease severity in acute intra-abdominal sepsis. Clin Exp Immunol 178:292-309
Ly, Dalam; Kasmar, Anne G; Cheng, Tan-Yun et al. (2013) CD1c tetramers detect ex vivo T cell responses to processed phosphomycoketide antigens. J Exp Med 210:729-41
Arora, Pooja; Foster, Erin L; Porcelli, Steven A (2013) CD1d and natural killer T cells in immunity to Mycobacterium tuberculosis. Adv Exp Med Biol 783:199-223
Wen, Xiangshu; Rao, Ping; Carreno, Leandro J et al. (2013) Human CD1d knock-in mouse model demonstrates potent antitumor potential of human CD1d-restricted invariant natural killer T cells. Proc Natl Acad Sci U S A 110:2963-8
Yu, Esther Dawen; Girardi, Enrico; Wang, Jing et al. (2012) Structural basis for the recognition of C20:2-ýýGalCer by the invariant natural killer T cell receptor-like antibody L363. J Biol Chem 287:1269-78
Patel, Onisha; Pellicci, Daniel G; Uldrich, Adam P et al. (2011) Výý2 natural killer T cell antigen receptor-mediated recognition of CD1d-glycolipid antigen. Proc Natl Acad Sci U S A 108:19007-12

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