Relationship between Th1/Th2 cytokine patterns and the arthritogenic response in collagen‐induced arthritis

Abstract

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.

Influence of heme oxygenase 1 modulation on the progression of murine collagen‐induced arthritis

“…A growing body of evidence suggests that Th1 responses are predominant in the development of murine CIA (2). It has been reported that IL-2 can play an antiinflammatory role during early phases of CIA induction, but is proinflammatory in established disease (32).…”

“…Some experimental models of autoimmune disease can be induced in animals by immunization with type II collagen. Collagen-induced arthritis (CIA) is an example of an autoimmune disease with a predominant Th1 response at the time of arthritis onset (2). This model of rheumatoid arthritis exhibits clinical and histopathologic features similar to those of the human disease (3).…”

The application of gene therapy in autoimmune diseases

“…[8][9][10] This may represent restoration of a more balanced immune response to auto-antigen stimulation and result in disease amelioration. Although alteration of effector function of a differentiated CD4 + T cell appears to be unlikely, 11,12 it appears to be possible to modulate the effector function and differentiation of undifferentiated Th0 T cells and CD4 + T cells that are not completely differentiated.…”

Collagen Type II and a Thermo-Responsive Polymer of N-Isopropylacrylamide Induce Arthritis Independent of Toll-Like Receptors

“…11,12 On the other hand, incomplete Freund's adjuvant (IFA), without any mycobacterium, deviates the immune response toward Th2 type. 13,14 However, use of strong adjuvants precludes our understanding of the actual immune responses to the self-protein, CII and associated pathological pathways.…”