RELATIONSHIP BETWEEN TH1 TH2 CYTOKINE PATTERNS AND THE ARTHRITOGENIC RESPONSE IN COLLAGEN-INDUCED ARTHRITIS/

It is hypothesized that the balance of cytokines produced by Th1/Th2 s ubsets of T helper cells plays an important role in the development of autoimmune diseases. Murine collagen-induced arthritis (CIA) is an ex ample of an autoimmune disease in which immunization with cartilage-de rived type II collagen induces, firstly, a T cell response to type II collagen and, secondly, the manifestation of a destructive inflammator y response in affected joints. We have investigated the role of Th1/Th 2 responses in the development of CIA by monitoring levels of interfer on (IFN)-gamma (a Th1 cytokine) and interleukin (IL)-4 and IL-10 (Th2 cytokines), and IL-1 beta and tumor necrosis factor (TNF) (pro-inflamm atory cytokines) produced by cultured draining lymph node cells (LNC) from collagen-immunized DBA/1 mice during the induction phase of arthr itis and throughout the time of clinical manifestation and subsequent remission of the disease. Although a transient increase in IL-10 was d etected 3 days after immunization, Th2 cytokine production was found t o be almost completely suppressed 6 days after immunization. In contra st, IFN-gamma was detected in LNC cultures as early as 6 days after im munization and the addition of type II collagen to the culture medium resulted in an approximately 10-fold increase in IFN-gamma production, indicating that a predominantly Th1 response had become established b y this time. IFN-gamma production by LNC was found to be further incre ased at the time of clinical manifestation of arthritis and could be u p-regulated by co-culture with type II collagen. IL-10 was not detecte d in LNC cultures at the onset of arthritis and IL-4, although present , was found to be markedly suppressed in LNC cultures containing type II collagen. These findings indicate that Th1 responses are pre domina nt at the time of onset of arthritis and that the activation of collag en-specific Th1 cells may result in suppression of Th2 activity. IFN-g amma production declined progressively during the progression and subs equent remission of arthritis whereas levels of IL-10 increased and lo w, though persistent, levels of IL-4 were detected throughout this per iod. High levels of IL-1 beta and TNF-alpha production were detected a t the onset of the disease. The role of Th1 responses in the developme nt of CIA was further emphasized by the observation that immunization of mice with type II collagen in incomplete Freund's adjuvant, which n ormally fails to induce arthritis, resulted in a predominantly Th2 cyt okine profile.