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Background: A number of recent studies have demonstrated a protective effect of renin-angiotensin system (RAS) antagonism against immune mediated diseases such as myocarditis, chronic allograft rejection, and antiglomerular basement membrane nephritis. To our knowledge, there has been no report on the immunological contribution of the RAS in colonic tissue. Aims: We evaluated the direct effect of angiotensin II (AII) on the pathogenesis of immune mediated colitis using angiotensinogen deficient homozygous (Atg2/2) mice. Subjects: 2,4,6-Trinitrobenzene sulphonic acid (TNBS) colitis was induced in Atg2/2 and wild-type (Atg+/+) mice. Methods: Levels of proinflammatory cytokines in the colon were determined by enzyme linked immunosorbent assay. Histological analysis was performed simultaneously. Results: Although Atg2/2 mice developed colitis, the degree was much milder than that in Atg+/+ mice (p,0.05). Colonic cytokine analysis showed that the production of proinflammatory cytokines (interleukin (IL)-1b, interferon c (IFN-c)) was impaired in Atg2/2 mice. Furthermore, expression of cytokines such as IL-4 and IL-10 in the colon was predominant in Atg2/2 compared with Atg+/+ mice after TNBS instillation (p,0.005, p,0.01, respectively). Similarly, subcutaneous infusion of losartan suppressed colitis (p,0.05) and the production of proinflammatory cytokines (IL-1b, IFN-c). These results indicate that the RAS is directly involved in the pathogenesis of TNBS colitis through regulation of proinflammatory and anti-inflammatory cytokines in the colon. Conclusions: This study revealed that the RAS is involved in the immune system in the colon. Antagonism of the RAS is a potential prophylactic strategy for the treatment of human inflammatory bowel disease.

During active UC, all 4 cytokine mRNA levels were high; only IL-6 and IL-8 mRNAs decreased to normal levels during remission. IL-8 mRNA was high even at sites of endoscopically quiescent UC during active disease. Steroid naïve patients respond well to granulocytapheresis.

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We have defined a peptide K2 (ADKDVVVLTSSRTGGV) that corresponds to residues 201–216 of bovine interphotoreceptor retinoid-binding protein and induces experimental autoimmune uveoretinitis (EAU)4 in H-2Ak-carrying mice (H-2Ak mice). In this study, we attempted to ameliorate EAU in the H-2Ak mice without nonspecific suppression of T cell responses. Preceding s.c. administration of liposomes including K2 (liposomal K2) specifically inhibited subsequent generation of T cell response to K2. The same result was obtained with a combination of OVA323–339 peptide and the OVA-specific TCR-transgenic T cells. It was suggested that the inhibition was mainly attributed to peripheral anergy induction of T cells specific for the peptide Ag, although specific cell death might also be involved in the inhibition. Pretreatment with liposomal K2 also considerably abolished IFN-γ production but not IL-4 production. The specific inhibitory effect of the pretreatment with liposomal peptide was augmented by a simultaneous administration of anti-CD40 ligand (anti-CD40L) mAb. Moreover, it was shown that the pretreatment with liposomal K2 reduced both the incidence and severity of the subsequent K2-induced EAU, and the simultaneous administration of anti-CD40L mAb augmented this preventive effect by liposomal K2. Our findings demonstrate that the s.c. administration of liposomal pathogenic peptide and anti-CD40L mAb can be applied to preventing autoimmune diseases without detrimental nonspecific suppression of T cell responses.