T cell homeostasis can be defined as the capacity of the immune system to maintain normal T cell numbers throughout the lifetime of an organism, and to restore this number following T cell depletion or expansion. This process is controlled by various mechanisms and signals, particularly those mediated by T cell trophic cytokines, such as IL-7 and IL-15. We have previously posited that lupus is essentially a lymphocyte homeostasis disease characterized by the expedited accumulation of activation/apoptosis-resistant memory phenotype T cells. Our current preliminary evidence with MRL-Faslpr lupus mice indicates that the highly expanded double-negative (DN) CD4?CD8? T cells do not express IL- 7R (CD127) or IL-15R (CD122). This and other findings outlined herein have prompted us to formulate the hypothesis that T cells engaged in repeated stimulations by ever-present self- antigens reach an exhaustion stage accompanied by absence of receptors for trophic cytokines, thereby creating an excess of the corresponding ligands that support the survival and proliferation of newly emerging autoreactive T cells. To address this hypothesis, we propose the following: a) define abnormalities in T cell trophic cytokines and their receptors in lupus by assessing changes in IL-7R and IL-15R expression, IL-7 and IL-15 transcript levels, proliferation of transferred T cells into non- lymphopenic hosts, and inhibition of proliferation by IL-7R-blocking antibodies;b) define the mechanisms of cytokine receptor downregulation and their implications to autoimmunity by determining the dynamic regulation of CD127 and CD25, the downregulation of CD127 on chronically-activated transgenic CD4 T cells by the regulated expression of a specific neo-self antigen, and the consequences of cytokine excess on peripheral T cell tolerance;c) examine the disease-enhancing effects of cytokine excess by providing IL-7 with micro-osmotic pumps or superagonistic IL-7/antibody complexes;and d) develop non-viral vectors encoding CD127/Fc and chimeric mouse anti-CD127 antibodies and examine their prophylactic and therapeutic efficacies in lupus models. These studies are likely to reveal new mechanistic aspects of systemic autoimmunity and pathways for novel therapeutic interventions. PROJECT NARRATIVE Because survival and proliferation of autoreactive T cells depend on the availability of trophic cytokines, such as IL-7 and IL-15, excess of these cytokines might be responsible for the continuous activation and expansion of these cells in lupus. Aside from providing a new mechanistic concept, blockade of these mediators may constitute a novel therapeutic approach for lupus and other autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR031203-29
Application #
8242877
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Mancini, Marie
Project Start
1983-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
29
Fiscal Year
2012
Total Cost
$396,222
Indirect Cost
$187,134
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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