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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Successful modulation of type 2 diabetes in db/db mice with intra-bone marrow--bone marrow transplantation plus concurrent thymic transplantation.

There is increasing evidence that both autoimmune and autoinflammatory mechanisms are involved in the development of not only type 1 diabetes mellitus (T1 DM), but also type 2 diabetes mellitus (T2 DM). Our laboratory has focused on this concept, and in earlier efforts replaced the bone marrow cells (BMCs) of leptin receptor-deficient (db/db) mice, an animal model of T2DM, with those of normal C57BL/6 (B6) mice by IBM-BMT. However, the outcome was poor due to incomplete recovery of T cell function. Therefore, we hypothesized that intra-bone marrow-bone marrow transplantation plus thymus transplantation (IBM-BMT + TT) could be used to treat T2 DM by normalizing the T cell imbalance. Hence we addressed this issue by using such dual transplantation and demonstrate herein that seven weeks later, recipient db/db mice manifested improved body weight, reduced levels of blood glucose, and a reduction of plasma IL-6 and IL-1ß. More importantly, this treatment regimen showed normal CD4/CD8 ratios, and increased plasma adiponectin levels, insulin sensitivity, and the number of insulin-producing cells. Furthermore, the expression of pancreatic pAKT, pLKB1, pAMPK and HO-1 was increased in the mice treated with IBM-BMT + TT. Our data show that IBM-BMT + TT treatment normalizes T cell subsets, cytokine imbalance and insulin sensitivity in the db/db mouse, suggesting that IBM-BMT + TT is a viable therapeutic option in the treatment of T2 DM.

The role of dendritic cell subsets in 2,4,6-trinitrobenzene sulfonic acid-induced ileitis.

Dendritic cells (DCs) are widely distributed throughout the lymphoid and nonlymphoid tissues, and are important initiators of acquired immunity and also serve as regulators by inducing self-tolerance. However, it has not been thoroughly clarified whether DCs are involved in the termination of immune responses. In this paper, we have examined the kinetical movement of dendritic cells (DCs) in the lamina propria using the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced ileitis model (an animal model for Crohn's disease). Increased numbers of DCs were recruited to the inflammatory sites from day 1 to day 3 at which time the inflammatory responses was clearly observed, then gradually decreased to a steady-state level on day 7 along with the cessation of responses. Three subsets of DCs, PIR-A/B(high), PIR-A/B(med), and PIR-A/B(-) DCs in the CD11c(+)/B220(-) conventional DCs (cDCs) were noted on day 3; the number of PIR-A/B(med) cDCs increased when the inflammatory responses ceased on day 7. The expression of costimulatory molecules such as CD86 and CD54 was lower in the PIR-A/B(med) DCs compared with the other two cDC subsets or splenic DCs. Furthermore, the stimulatory activity of PIR-A/B(med) cDCs was lower than those of PIR-A/B(high) or PIR-A/B(-) cDCs, and far lower than that of splenic DCs. In addition, an increase in the message level of IL-10 was clearly observed in the PIR-A/B(med) cDCs on day 7 while that of proinflammatory cytokines such as IL-6 and IL-12 was low. These data demonstrate that PIR-A/B(med) cDCs which increase at the final stage of inflammation may be involved in the termination of the TNBS-induced ileitis by the delivery of anergic signals to effector T cells due to the lower expressions of costimulatory molecules and the production of immunoregulatory cytokine.

Induction of parotitis by fine-needle aspiration in parotid Warthin's tumor.

OBJECTIVES: To estimate parotitis caused by fine-needle aspiration (FNA) in parotid Warthin tumor. STUDY DESIGN: Case series with chart review. SETTING: Hospital records were reviewed for 104 parotid tumors (103 patients) including 35 Warthin tumors, which underwent FNA within our department. RESULTS: Three patients with four Warthin tumors among them noticed parotid pain, swelling, and abscess formation as a consequence of acute parotitis after FNA. Examinations of the materials obtained from tumor puncture or drainage before the start of antibiotic therapy showed no bacterial association in any patient. Two of the patients with Warthin tumor underwent parotidectomy, and the surgical specimens indicated histopathological changes with necrosis, abscess, granuloma, and the infiltration of inflammatory cells including Langhans-type multinucleated giant cells. CONCLUSIONS: It is conceivable that Warthin tumor bears the characteristics of inflammation induced by the FNA procedure without any relation to infection. Therefore, it may be better to avoid routine FNA and give priority to diagnostic imagings over FNA in the diagnosis of tumors strongly suspected as Warthin tumor.

Parotid mucosa-associated lymphoid tissue lymphoma regression after Helicobacter pylori eradication.

A 60-year-old woman with Sjögren's syndrome showed recurrence of parotid mucosa-associated lymphoid tissue (MALT) lymphoma with a simultaneous increase of serum sIL-2R antigen levels 10 years after surgical treatment. Helicobacter pylori infection had been detected in the stomach since the beginning of the lymphoma. Although H. pylori was not detected in the recurrent parotid lymphoma, antibiotic therapy contributed not only to successful eradication of gastric H. pylori but also to disappearance of the recurrent lymphoma. Further studies on the mechanisms of occurrence of extragastric MALT lymphomas are needed to establish the treatment of extragastric MALT lymphomas.