Critical role of M. tuberculosis for dendritic cell maturation to induce collagen‐induced arthritis in H‐2b background of C57BL/6 mice

Abstract

Summary Collagen‐induced arthritis (CIA) can be induced even in CIA‐resistant H‐2b background of C57BL/6 mice when these mice are immunized with type II collagen (CII) emulsified in complete Freund's adjuvant (CFA) containing high, but not low, dose of Mycobacterium tuberculosis. Here, we investigated the pathogenesis of CIA in C57BL/6 mice induced by the immunizing protocol. We examined expressions of cytokines, costimulatory molecules and major histocompatibility complex (MHC) class II in draining lymph nodes (DLN) in CIA‐induced C57BL/6 mice by quantitative reverse transcription–polymerase chain reaction. We also examined an effect of M. tuberculosis on the expression of these molecules on dendritic cells (DC) in vitro by flow cytometry. We finally examined an effect of M. tuberculosis in CFA used for immunization with CII antigen on priming of CD4+ helper T cells specific to CII in DLN of CIA‐induced C57BL/6 mice. The expression of interferon‐γ (IFN‐γ), Interleukin‐12p40 (IL‐12p40), costimulatory molecules CD40, CD80 and CD86 and MHC class II were up‐regulated in DLN of CIA‐induced C57BL/6 mice. Expressions of these costimulatory molecules were also up‐regulated on DC after stimulation with high, but not low, dose of M. tuberculosis in vitro. Furthermore, priming of CD4+ helper T cells specific to CII antigen in DLN required immunization with CII using CFA containing high, but not low, dose of M. tuberculosis. These results suggested that high dose of M. tuberculosis were required for maturation of DC enough to prime CD4+ helper T cells specific to CII antigen in DLN of H‐2b background of C57BL/6 mice.

Characterization of relapsing–remitting and chronic forms of experimental autoimmune encephalomyelitis in C57BL/6 mice

“…The activation and proliferation of effector T cells in response to antigen has been shown to occur in dose-dependent fashion (Henrickson and von Andrian, 2007;Itoh and Germain, 1997;Rothoeft et al, 2006). It is therefore possible that the higher dose of MOG used to generate CH-EAE leads to a more efficient activation of na€ ıve myelin-reactive T cells, which in turn could promote a greater autoimmune (Billiau and Matthys, 2001;Chen et al, 2006;Kai et al, 2006). In addition to the increased lesion burden, the peak stage of CH-EAE also showed increased myelin loss compared with RR-EAE.…”

Collagen-induced arthritis

“…The susceptibility of B6 mice to CIA is presently controversial. Some investigators have reported little or no incidence of CIA in these mice [28][29][30] while others have clearly demonstrated that CIA can be established in this strain 31,32 .…”

Projection of Exposure and Efficacious Dose Prior to First-in-Human Studies: How Successful Have We Been?

“…In oncology, for example, nude mice transplanted with human xenografts are routinely used to assess the in vivo efficacy of anti-tumor agents (12,13). In immunology, rodents with arthritis, induced by agents such as collagen or adjuvant, are also common (14)(15)(16). Compounds acting on the central nervous system are evaluated similarly in various behavioral animal models, with a focus on brain penetration and target (e.g., receptor) occupancy (17,18).…”