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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA179363-03
Application #
9005843
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Welch, Anthony R
Project Start
2014-03-10
Project End
2019-02-28
Budget Start
2016-03-01
Budget End
2017-02-28
Support Year
3
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Medical College of Wisconsin
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937639060
City
Milwaukee
State
WI
Country
United States
Zip Code
53226
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