Cytokines, in particular, an imbalance in the expression of Th1 and Th2 type cytokines is implicated in the pathophysiology of rheumatoid arthritis. The correlation between the presence of the Th1 type cytokine, IFN-gamma, and arthritis suggests that this cytokine may promote inflammation. Alternatively, the reduced levels of the inhibitory Th2 type cytokines, IL-4 and IL-10, may result in disease. Although individual aspects of Th1 and Th2 function have been studied in models of arthritis, no comprehensive examination of the critical role of Th1 and Th2 cytokines has been studied in the same model system. It is important to understand how cytokines function in arthritis, and how intervention might alter cytokine production, and how they affect cell migration and synovial inflammation ultimately leading to loss of joint function. In a model of arthritis induced by immunization of BALB/c mice with proteoglycan (PG), we have found that rIL-4 treatment protected mice from the development of arthritis and suppressed the acute symptoms of disease. The susceptibility to PG-induced arthritis is restricted to the BALB/c strain. After immunization with 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 ratio. We hypothesis that in this autoimmune disease the subordinate Th2 response permits an uncontrolled reaction to autoantigens. On the basis of this hypothesis, we predict that a dominate Th1 response results in arthritis as a result of a defect in Th2 responses. 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, reconstitute cytokine defects with exogenous cytokines and use mice with disruptions in cytokine genes IFN- gamma IL-4, and IL-10 and transcription factors, stat4 and stat6.
In aim three, to understand the mechanism of suppression by Th2 cytokines, disease transfer, cell migration, and engraftment of SCID mice with human synovial tissue will be studied.
In aim four we will study, as a model for delivery of cytokines directly to the joint, replication deficient adenoviral vectors encoding regulatory cytokines. The goal of this study is to elucidate the role of Th1/Th2 cytokines in the pathophysiology of arthritis.
