Coinhibitory signals attenuate T cell receptor signaling and inhibit T cell responses. PD-1 is the prototype coinhibitory receptor and has been shown to be highly expressed on exhausted hepatitis C virus (HCV)- specific T cells that have lost effector functions. Blockade of PD-1 with monoclonal antibodies (mAb) enhances HCV-specific CDS T cells responses in vitro. Our hypothesis is that coinhibitory pathways contribute to exhaustion of HCV-specific T cells, regulating progression to chronic infection, and that blockade of coinhibitory pathways will enhance effective anti-HCV immune responses. Recent work shows that additional coinhibitory pathways contribute to T cell exhaustion and that blockade of multiple coinhibitory pathways optimally enhances T cell responses. Core C will focus on the PD-1, CD160, LAG-3, CTLA4, and CD161 coinhibitory pathways identified by this work. Core C will generate and produce mAbs that will facilitate analysis of the function and expression of the PD-1/PD-1 Ligand pathway as well as other coinhibitory pathways including CD160, LAG-3, CTLA4, and CD161 pathways. Core C will generate novel dimeric and multimeric Ig fusion proteins of these coinhibitory pathway proteins in order to either block or transduce signals via cross-linking receptors. The capacity of these blocking mAbs to enhance HCV-specific T cell responses will be tested. These mAbs and Ig fusion proteins will be used in high throughput assays by Technology Development Project 1 to identify small molecule antagonists of coinhibitory pathways. Core C provides a critical means by which the U19 will achieve its goals of understanding how to manipulate the coinhibitory signals provided by PD-1, CD160, LAG-3, CTLA4, CD161 and their ligands as well as the mechanism of these inhibitory signals. Core C will work closely with project investigators, providing them mAbs and Ig fusion proteins as needed.

Public Health Relevance

Core C will generate the necessary antibodies and proteins that will facilitate analysis of the immune regulatory pathways leading to chronic HCV infection. The production of these critical reagents by a centralized core not only will be time and cost efficient, but also provide standardization that will facilitate comparison of data by investigators in this U19. Core C will work closely with project investigators, providing them mAbs and Ig fusion proteins as needed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082630-04
Application #
8376125
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
2012-06-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$324,242
Indirect Cost
$87,971
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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