An imbalance in the expression of Th1 and Th2 type cytokine is implicated in the pathogenesis of rheumatoid arthritis. The correlation between the dominance of the Th1 type inflammatory cytokine, IFN-gamma, over the Th2-type anti-inflammatory cytokine, IL-4, and chronic arthritis suggests that the ration of Th1:Th2 cytokines is important in regulating inflammation. A critical question is whether the ration of Th1:Th2 cells can be changed and whether this alternation leads to long- term suppression of disease. It is important to understand how Th2 cytokines function to suppress arthritis and whether susceptibility and resistance to arthritis is regulated by the balance in Th1: Th2 type cells. In a murine model of inflammatory arthritis induced by immunization with cartilage proteoglycan (PG), susceptible BALB/c mice develop a higher IFN-gamma to IL-4 ratio, whereas resistant DBA/2 mice develop a higher IL-4 to IFN-gamma ration. This balance between Th1 and Th2 cytokines may regulate susceptibility and resistance to disease. Increasing the level of IL-4 by administering IL-4 protects BALB/c mice from the development of arthritis and suppresses the acute symptoms of established disease. Reducing the level of IFN-gamma by a deficient in the Stat4 gene results in a lower incidence and severity of arthritis. Based these observations we hypothesize that arthritis is a Th1 type disease and that shifting the balance to a Th2 type response will lead to long-term suppression of disease. To test this hypothesis we propose in aim one and two to confer either resistance or susceptibility to arthritis by manipulating cytokines. We will neutralize cytokines with mAbs, use mice with disruptions in cytokine genes IFN-gamma, IL-4 and IL-10 and transcription factors, Stat4 and Stat6, and reconstitute cytokine defects with exogenous cytokines.
In aim three, the mechanism of suppression by Th2 cytokines will be defined in disease transfer and cell migration studies. As a model to study intervention in humans, Th2 activity will be studied by engraftment of SCID mice with human synovial tissue.
In aim 4 as a model for prevention, we will examine study, site- specific delivery of cytokines to the joint by replication deficient adenoviral vectors encoding regulatory cytokines. The overall goal of this study is to advance the successful treatment of arthritis through understanding the role of Th1 and Th2 cytokines in the pathophysiology of arthritis.
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