Inflammation is a critical component of an immune response. However, acute or chronic inflammation is highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma, multiple autoimmune disorders and increased risk of cancer. Inflammation is also a major limiting factor in the successful utilization of genetically-modified NK or T cell-based immunotherapy. Thus, inflammation is a major health concern with high clinical relevance. Inflammation is caused by soluble mediators, including prostaglandins, histamine, lysosomal granules and cytokines or chemokines (IFN-?, GM-CSF, MIP-1?, MIP- and RANTES). NK cells that are the major lymphocyte population of the innate immunity, produce many of these factors and thereby play a central role in causing pathological conditions. Exclusive intracellular signaling molecules that are responsible for the production of inflammatory mediators in lymphocytes are largely unknown. Using NK cells, we have recently identified unique molecules that are exclusively responsible for the production of inflammatory cytokines or chemokines. Our findings identify signaling protein ADAP as a novel molecular target to successfully treat many inflammatory disorders. This will be achieved by exclusively blocking the production of inflammatory cytokines/chemokines without impairing other effector functions, including cytotoxicity. Using these findings, we propose to formulate an effective NK cell-mediated immunotherapy for cancer patients with augmented anti-tumor cytotoxicity without the associated inflammation ('cytokine-release syndrome'). Our long term goals are to formulate innovative therapeutic approaches to reduce inflammation in a variety of diseases. Here, we propose the following.
Aim -1: Evaluate tumor killing and inflammatory cytokine production in vivo, using ADAP-/- mice.
Aim -2: Formulate a molecular intervention to contain inflammatory cytokines from NK cells.
Aim -3: Determine the preclinical efficacy of ADAP-derived minimal 'decoy' peptide.
Inflammation is a critical component of an immune response. However, acute or chronic inflammation is highly destructive. Uncontrolled inflammation forms the basis for allergy, asthma, multiple and autoimmune disorders. We have identified unique signaling proteins that regulate the production of major inflammatory mediators in NK cells that are part of the innate immunity. In this application, we propose to employ novel intervention strategies to reduce and contain inflammation.
|Abel, Alex M; Tiwari, Aradhana A; Gerbec, Zachary J et al. (2018) IQ Domain-Containing GTPase-Activating Protein 1 Regulates Cytoskeletal Reorganization and Facilitates NKG2D-Mediated Mechanistic Target of Rapamycin Complex 1 Activation and Cytokine Gene Translation in Natural Killer Cells. Front Immunol 9:1168|
|Abel, Alex M; Yang, Chao; Thakar, Monica S et al. (2018) Natural Killer Cells: Development, Maturation, and Clinical Utilization. Front Immunol 9:1869|
|Jang, Youngsoon; Gerbec, Zachary J; Won, Taejoon et al. (2018) Cutting Edge: Check Your Mice-A Point Mutation in the Ncr1 Locus Identified in CD45.1 Congenic Mice with Consequences in Mouse Susceptibility to Infection. J Immunol 200:1982-1987|
|Xu, Wenwen; Hi?u, T?Minh; Malarkannan, Subramaniam et al. (2018) The structure, expression, and multifaceted role of immune-checkpoint protein VISTA as a critical regulator of anti-tumor immunity, autoimmunity, and inflammation. Cell Mol Immunol 15:438-446|
|Nanbakhsh, Arash; Best, Brad; Riese, Matthew et al. (2018) Dextran Enhances the Lentiviral Transduction Efficiency of Murine and Human Primary NK Cells. J Vis Exp :|
|Li, Na; Xu, Wenwen; Yuan, Ying et al. (2017) Immune-checkpoint protein VISTA critically regulates the IL-23/IL-17 inflammatory axis. Sci Rep 7:1485|
|Fisher, J B; Peterson, J; Reimer, M et al. (2017) The cohesin subunit Rad21 is a negative regulator of hematopoietic self-renewal through epigenetic repression of Hoxa7 and Hoxa9. Leukemia 31:712-719|
|Rajasekaran, Kamalakannan; Riese, Matthew J; Rao, Sridhar et al. (2016) Signaling in Effector Lymphocytes: Insights toward Safer Immunotherapy. Front Immunol 7:176|
|Abel, Alex M; Schuldt, Kristina M; Rajasekaran, Kamalakannan et al. (2015) IQGAP1: insights into the function of a molecular puppeteer. Mol Immunol 65:336-49|
|Gerbec, Zachary J; Thakar, Monica S; Malarkannan, Subramaniam (2015) The Fyn-ADAP Axis: Cytotoxicity Versus Cytokine Production in Killer Cells. Front Immunol 6:472|