The long term objectives are to develop a novel treatment for human lupus that has fewer side effects than currently available immunosuppressive treatment and has improved efficacy. To this end, we have used a pre-clinical model of lupus and demonstrated that immunomodulation, i.e. skewing of the immune response away from antibody production and enhancing cell mediated immunity to include cytotoxic T lymphocytes is both feasible and beneficial in this model. The current proposal also demonstrates that lupus predisposition may relate to a pre-existing defect in interleukin-2 which promotes immune skewing. Using in vivo and vitro approaches combined with flow cytometry, genetic analysis and cellular immunology, this proposal has the following aims: 1) use pre-clinical models to determine whether defective T cell production of IL-2 predisposes to lupus, the mechanism by which this occurs, whether IL-2 replacement will be beneficial and adapt the murine approach to screen human lupus patients for similar abnormalities;2) develop non IL-2 based immunomodulatory approaches (e.g., TLR stimulants) and test their efficacy in several murine models;3) define the mechanism(s) that mediate sex differences in lupus severity in a murine model. These studies will provide novel insights into the role of IL-2 in lupus pathogenesis and identify new, non-immunosuppressive therapeutic approaches to lupus treatment.

Public Health Relevance

This proposal addresses a novel form of potential treatment for lupus and identifies a potential cause of lupus predisposition i.e. defective interleukin-2 production. Unlike current therapeutic approaches that involve immune suppression, this approach uses interleukin -2 and non- interleukin-2 based approaches to modulate the immune response and skew it away from autoantibody production and toward cell mediated immunity.

National Institute of Health (NIH)
High Priority, Short Term Project Award (R56)
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Arthritis, Connective Tissue and Skin Study Section (ACTS)
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Johnson, David R
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Henry M. Jackson Fdn for the Adv Mil/Med
United States
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