Erratum to: Amelioration of 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice by immunoregulatory dendritic cells

Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Moriguchi, Osaka, Japan.
Journal of Gastroenterology (Impact Factor: 4.52). 09/2011; 46(12):1368-81. DOI: 10.1007/s00535-011-0460-4
Source: PubMed


Dendritic cells (DCs) are widely distributed throughout the lymphoid and nonlymphoid tissues, and are important initiators of acquired immunity. They also serve as regulators by inducing self-tolerance. However, it has not been thoroughly clarified whether DCs are somehow involved in the regulation or treatment of inflammatory bowel diseases.
We established an ileitis model by transmurally injecting 2,4,6-trinitrobenzene sulfonic acid (TNBS) into the lumen of the ileocolonic junction. The kinetic movement of DCs at the inflammatory sites was analyzed histologically and by flow cytometry, and DCs obtained from the small intestine were analyzed in order to determine the expression of paired immunoglobulin-like receptor-A/B (PIR-A/B) by flow cytometry and quantitative RT-PCR. Furthermore, the regulatory role of DCs was directly determined by a transfer experiment using TNBS-induced colitis model mice.
We observed three DC subsets (PIR-A/B(high), PIR-A/B(med), and PIR-A/B(-) DCs) in the conventional DCs (cDCs) from day 3, and the number of PIR-A/B(med) cDCs increased from the time the inflammatory responses ceased (day 7). PIR-A/B(med) cDCs actually migrated to the inflamed colon, and ameliorated the colitis induced by TNBS when transferred to colitis-induced recipients. The colitis was greatly exacerbated when mice had been treated with the indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor 1-methyltryptophan (1-mT) at the time PIR-A/B(med) cDCs were transferred, indicating that the therapeutic ability of PIR-A/B(med) cDCs is partially dependent on IDO.
The PIR-A/B(med) cDCs, which increase in number during the final stages of inflammation, can be used to treat colitis via an IDO-dependent mechanism.

Download full-text


Available from: Takashi Yokoi
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and aim: Crohn's disease treatments available today are not quite satisfactory. N-(3', 4'-dimethoxycinnamonyl) anthranilic acid (3, 4-DAA) has been proved to be effective in many autoimmune diseases. Therefore, we investigated the immunologic function of 3, 4-DAA on trinitrobenzene sulfonic acid (TNBS) colitis and human Crohn's disease. Methods: Mice with TNBS-induced colitis were treated with 3, 4-DAA or 1-methyl-tryptophan (1-MT). Colitis severity was assessed with clinical and histological scores. Cell proliferation, cytokine expression, and the percentage of CD4(+) CD25(+) T cells were measured in both mice and human samples. Results: In mice treated with 3, 4-DAA, the clinical and histological scores were decreased (P < 0.05); the proliferation of mesenteric lymph nodes (MLNs) cells and lamina propria mononuclear cells (LPMCs) were inhibited (P < 0.05); Th1 cytokine expressions were decreased (P < 0.05), and Th2 cytokine levels were increased (P < 0.05). 3, 4-DAA also induced CD4(+) CD25(+) T cells expression (5.88 ± 2.1 vs 11.03 ± 2.93, P < 0.05) in mice MLNs. Transfer of these cells into TNBS colitis mice resulted in the reduction of the disease activity index (DAI) and histological scores. In LPMCs isolated from human Crohn's disease, 3, 4-DAA had the same effect. It can inhibit the cell proliferation, decrease Th1 cytokine expressions (P < 0.05), and increase Th2 cytokine levels (P < 0.05). The percentage of CD4(+) CD25(+) T cells were also increased (1.60 ± 0.14 vs 2.45 ± 0.50, P < 0.05). 1-MT treatment led to opposite outcomes. Conclusion: 3, 4-DAA can alleviate the severity of colitis through inhibiting Th1 cells response, promoting Th2 cytokines expression and inducing CD4(+) CD25(+) T cells expression.
    No preview · Article · May 2013 · Journal of Gastroenterology and Hepatology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dendritic cells (DCs) may play an important role in forms of inflammatory bowel disease (IBD), such as Crohn's disease and ulcerative colitis. DCs are generally recognized as initiators of acquired immunity and also serve as regulators of both innate and acquired immunity. We used the animal model of colitis induced by dextran sodium sulfate (DSS), and examined whether DCs prepared from the colon show immunoregulatory roles in the termination of DSS-induced colitis. C57BL/6 mice exposed to DSS for 5 days developed acute colitis. DCs were isolated from the large intestinal lamina propria, and then analyzed for phenotypical, functional, and genetic data. Only PIR-A/B(low) conventional DCs (cDCs) were detected in the steady state. However, after the treatment of DSS, PIR-A/B(high) cDCs appeared and gradually increased from day 5 to day 7, at which time the DSS-induced colitis was terminated. Then, allogeneic mixed leukocyte reaction (MLR) was performed. The stimulatory activity of PIR-A/B(high) cDCs obtained on day 7 was very low, and the addition of PIR-A/B(high) cDCs suppressed the T cell proliferation in MLR, indicating the immunoregulatory role of PIR-A/B(high) cDCs. The immunoregulatory role of PIR-A/B(high) cDCs was confirmed by the in vivo transfer experiment, showing their therapeutic effect on DSS-induced colitis. The message level of TGFβi was significantly higher in PIR-A/B(high) cDCs, while that of IFN-γ was highly upregulated in PIR-A/B(low) cDCs, being well in accordance with the fact that PIR-A/B(high) cDCs showed a suppressive function against activated T cells. PIR-A/B(high) cDCs showed a suppressive function against activated T cells by producing inhibitory cytokines.
    No preview · Article · Sep 2013 · Journal of Gastroenterology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Patients with type 1 autoimmune pancreatitis (AIP) have several immunologic and histologic abnormalities. It is known that depletion of B cells by rituximab is effective for treatment of IgG4-related disease (IgG4-RD) such as type 1 AIP, suggesting that B cells may be a key player in IgG4-RD. However, the role of regulatory B cells (Bregs) in type 1 AIP is unclear, and the objective of this paper is to clarify the role of Bregs in the pathophysiology of type 1 AIP by analyzing circulating Bregs. Method: We recruited 21 patients with type 1 AIP as determined by the International Consensus Diagnostic Criteria for AIP (ICDC). No patients received corticosteroid treatments. For comparison, we recruited 14 patients with chronic pancreatitis (CP), 20 patients with pancreatic cancer, and 25 healthy subjects as controls. We analyzed Bregs as CD19+ CD24high CD38high and CD19+ CD24high CD27+ from peripheral blood by flow cytometry. Results: In peripheral blood, CD19+ CD24high CD38high Bregs were significantly increased in type 1 AIP patients compared with CP, pancreatic cancer, and healthy controls. Although not significant different, CD19+ CD24high CD27+ Bregs of type 1 AIP were decreased compared to those of other groups. IL-10(+) B cells were not significantly different from type 1 AIP patients and healthy controls. In untreated type 1 AIP patients, the number of CD19+ CD24high CD38high Bregs and IgG4 were not correlated. Conclusions: Our data suggested that CD19+ CD24high CD38high Bregs seemed to increase reactively to suppress the disease activity, and are consistent with the hypothesis that CD19+ CD24high CD27+ Bregs might be involved in the development of type 1 AIP, although it still remains unclear whether the decrease of CD19+ CD24high CD27+ cells is cause or effect of AIP.
    No preview · Article · May 2014 · Pancreatology
Show more