The inability to selectively target undesirable T cell responses driving a myriad of immunopathologic conditions including autoimmunity, allergy, inborn disorders of immune regulation, and allogeneic rejection, is a fundamental clinical problem. While progress has been made with newer immunosuppressive drugs, the underlying strategy remains one of global suppression in order to inhibit a few detrimental effector T cells. This broad inhibitory approach is the equivalent of declaring martial law on the immune system;curtailing the normal and beneficial actions of most adaptive immune cells in order to stop the rare rogue T cell. Current strategies have three major drawbacks: (i) they lack specificity;(ii) they increase the risks of opportunistic infections and cancers;and (iii) they are associated with substantial agent-specific organ damage and toxicity. Thus, it is clear that we need to find novel and non-toxic means of controlling infrequent, yet injurious T cells, while maintaining beneficial memory and na?ve T cells to combat pathogens. We believe we have a novel approach to the specific targeting of unwanted T cells in vivo. As T cells transition between their developmental states - na?ve, activated effector, quiescent memory, and activated memory - we have found that they exhibit unique attributes that can be exploited to render their demise. First, we have observed that acutely-activated T cells display a strong DNA damage response (DDR) in vivo. Second, we found that etoposide, a chemotherapeutic agent in wide clinical use, ablates activated T cells while sparing na?ve and quiescent memory T cells. Mechanistically, we hypothesize that antigenic activation of T cells renders them uniquely susceptible toDDR-mediated apoptosis, which may be therapeutically triggered with either DNA- damaging and/or DDR-modulating agents, while affording survival of na?ve and pre-existing memory T cells. This hypothesis will be tested by (i) defining the parameters of successful in vivo targeting of effecto T cells using modulators of the DDR;(ii) defining downstream mechanisms of DDR-driven apoptosis in activated T cells;and (iii) determining the selectivity/efficacy of DDR manipulation for targeting human disease-associated T cells. Our long-term goal is to spare beneficial immunity, while purging undesirable T cells with minimal toxicity in a broad array of clinical contexts.

Public Health Relevance

White blood cells can be a double-edged sword. They are essential for protecting us from infectious diseases, but are also responsible for autoimmune diseases and are a major barrier for transplantation. Current therapies are immunosuppressive because they do not discriminate between protective and pathologic cells. We have developed a therapy that can target and kill acutely activated, pathologic T cells, whilst sparing beneficialT cells. Studies in this proposal will examine how this therapy can be improved, how it works, and if it can be translated to human cells.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
1R01AI109810-01A1
Application #
8780156
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Bourcier, Katarzyna
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
City
Cincinnati
State
OH
Country
United States
Zip Code
45229