It is hypothesized that the balance of
cytokines produced by Th1/Th2 subsets of T helper cells plays an important role in the development of
autoimmune diseases. Murine
collagen-induced arthritis (CIA) is an example of an
autoimmune disease in which immunization with cartilage-derived
type II collagen induces, firstly, a T cell response to
type II collagen and, secondly, the manifestation of a destructive inflammatory response in affected joints. We have investigated the role of Th1/Th2 responses in the development of CIA by monitoring levels of
interferon (IFN)-
gamma (a Th1
cytokine) and
interleukin (IL)-4 and
IL-10 (Th2
cytokines), and
IL-1 beta and
tumor necrosis factor (TNF) (pro-inflammatory
cytokines) produced by cultured draining lymph node cells (LNC) from
collagen-immunized DBA/1 mice during the induction phase of
arthritis and throughout the time of clinical manifestation and subsequent remission of the disease. Although a transient increase in
IL-10 was detected 3 days after immunization, Th2
cytokine production was found to be almost completely suppressed 6 days after immunization. In contrast, IFN-gamma was detected in LNC cultures as early
as 6 days after immunization 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 by this time. IFN-gamma production by LNC was found to be further increased at the time of clinical manifestation of
arthritis and could be up-regulated by co-culture with
type II collagen.
IL-10 was not detected 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 predominant at the time of onset of
arthritis and that the activation of
collagen-specific Th1 cells may result in suppression of Th2 activity. IFN-gamma production declined progressively during the progression and subsequent remission of
arthritis whereas levels of
IL-10 increased and low, though persistent, levels of
IL-4 were detected throughout this period. High levels of
IL-1 beta and
TNF-alpha production were detected at the onset of the disease. The role of Th1 responses in the development of CIA was further emphasized by the observation that immunization of mice with
type II collagen in
incomplete Freund's adjuvant, which normally fails to induce
arthritis, resulted in a predominantly Th2
cytokine profile.