T cell regulation of collagen‐induced arthritis in mice. II. Immunomodulation of arthritis by cytotoxic T cell hybridomas specific for type II collagen

Abstract

Injection of native type II collagen (CII) to susceptible strains of mice (H-2q) induces a rheumatoid arthritis-like disease. To study the role of CD8+ T cells in the collagen-induced arthritis (CIA), we generated CII-specific T cell hybridomas by fusion of cells from arthritic C3H. Q mice and an AKR thymoma. Two hybrid clones (P3G8 and P2D9) were selected for their ability to lyse syngeneic CII-pulsed macrophages and recognize different antigenic epitopes in association with Kq molecules. When these T cell clones were irradiated and inoculated into (C3H.Q x AKR)F1 mice 21 days prior to priming with native CII/complete Freund's adjuvant, the incidence and the duration of CIA were significantly reduced in comparison to groups receiving saline or control T cell hybridoma. Furthermore, both anti-CII T cell hybridomas were able to attenuate CIA in highly susceptible inbred strains of mice and this suppression was antigen and disease specific. The protective activity seems to require intact cells as neither membrane fractions nor cytosolic preparations of the hybridoma T cells retained the vaccinating activity. Most importantly, one of the hybrid clones (P3G8) had a therapeutic effect on CIA since its administration to arthritic DBA/1 mice on day 30 after priming down-regulated the ongoing disease. Taken together, these findings suggest that anti-CII cytotoxic T cell clones can vaccinate against CIA and even reverse the disease.

Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

“…Interestingly, there is some evidence for a regulatory role of CD8ϩ T cells in arthritis. CD8-knockout mice are more susceptible to a second induction of arthritis after remission of disease (37), and type II collagen-specific CD8ϩ T cell hybridomas inhibited established disease in a CIA model (38). It has also been shown that CIA develops more readily in IFN␥ receptor-knockout mice, and that IFN␥ inhibits the development of Th17 cells from naive precursor T cells (39,40).…”

Auricular chondritis in NOD.DQ8.Aβo (Ag7–/–) transgenic mice resembles human relapsing polychondritis

“…Immunoreactive peptides of CIX have been identified in synovial fluid of RA patients (31). CD8 + clones generated from CII-immunized mice were shown to cross-react with CIX, thus suggesting an epitope shared between the two collagens (32). Both of our transgenic strains express DQ8; however, only NOD.DQ8 mice respond to CIX, suggesting that in NOD.DQ8 mice immunization with CII leads to stimulation of another subset of autoreactive T cells that might home to the ear, causing destruction.…”

Biphasic effect of interferon‐γ in murine collagen‐induced arthritis

“…Evidence has accumulated that CIA is dependent upon T cell activation, including the T cell proliferative response to mouse CII in immunized mice [8], the successful adoptive transfer of the disease with immune spleen cells [9], and the resistance of athymic nude animals to the induction of the pathology [lo]. In addition, CIA was reported to be efficiently suppressed either by drugs targeting the T cells [11-141 or by CD8+ Tcells specific for CII [15]. The mechanisms by which T cells participate in the articular pathology is not fully elucidated and may involve the cytokines released during the immune response to CII.…”