Therapeutic effect of anti-OX40L and anti-TNF-α MAbs in a murine model of chronic colitis

Abstract

Interaction of OX40 (CD134) on T cells with its ligand (OX40L) on antigen-presenting cells has been implicated in pathogenic T cell activation. This study was performed to explore the involvement of OX40/OX40L in the development of T cell-mediated chronic colitis. We evaluated both the preventive and therapeutic effects of neutralizing anti-OX40L MAb on the development of chronic colitis in SCID mice induced by adoptive transfer of CD4+CD45RBhigh T cells as an animal model of Crohn's disease. We also assessed the combination of anti-OX40L and anti-TNF-α MAbs to improve the therapeutic effect. Administration of anti-OX40L MAb markedly ameliorated the clinical and histopathological disease in preventive and therapeutic protocols. In vivo treatment with anti-OX40L MAb decreased CD4+ T cell infiltration in the colon and suppressed IFN-γ, IL-2, and TNF-α production by lamina propria CD4+ T cells. The combination with anti-TNF-α MAb further improved the therapeutic effect by abolishing IFN-γ, IL-2, and TNF-α production by lamina propria CD4+ T cells. Our present results suggested a pivotal role of OX40/OX40L in the pathogenesis of T cell-mediated chronic colitis. The OX40L blockade, especially in combination with the TNF-α blockade, may be a promising strategy for therapeutic intervention of Crohn's disease.

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

“…Furthermore, a strong downregulation by probiotic strains of T h 1 cytokines, such as IL-2, IFN-c and the proinflammatory IL-17, has been reported in other studies using different model systems (Lee et al 2009;Llopis et al 2009;Reiff et al 2009;Schultz et al 2002). Two other genes relevant to IBD that followed this pattern were TNFRSF9 (also referred to as 4-1BB) and TNFRSF4 (Ox-40) (Lee et al 2005;Stuber et al 2000;Totsuka et al 2003). They are members of the tumor necrosis factor receptor (TNFR) family that sustain T cell numbers and responses after initial CD28-dependent T cell activation (Croft 2009).…”

Costimulation and Autoimmune Diabetes in BB Rats

“…Consistent with this concept, anti-CD134L mAb ameliorates experimental autoimmune encephalitis in mice (62) and blocks it completely in CD28 knockout mice (63). Anti-CD134L mAb also reduces mortality in murine GVHD (64,65) and prevents chronic colitis induced in SCID mice by CD4 + CD45RB high T cells (66,67). An agonistic anti-CD134 mAb can also break preexisting tolerance in CD4 + T cells (11).…”

IL-18 Bridges Innate and Adaptive Immunity through IFN-γ and the CD134 Pathway

“…CD134 signaling impacts autoreactive T cell homing to the CNS (71,72) and gut (73), trafficking to B cell follicles (74), and induction of CXCR5 (75,76). Thus, it is possible that IL-18 directs migration of T cells via CD134 signaling.…”