Cytokine-mediated immunity plays a crucial role in the pathogenesis of various diseases including autoimmunity. Recently, IL-27 was identified, which along with IL-12, 23 and 35 belongs to the IL-12 cytokine family. These family members play roles in regulation of Th cell differentiation. IL-27 is unique in that while it induces Th1 differentiation, the same cytokine suppresses immune responses. In the absence of IL-27-mediated immunosuppression, hyper-production of various pro-inflammatory cytokines concomitant with severe inflammation in affected organs was observed in IL-27 receptor α chain (WSX-1)-deficient mice infected with Trypanosoma cruzi. Experimental allergic or inflammatory responses were also enhanced in WSX-1-deficient mice. The immunosuppressive effects of IL-27 depend on inhibition of the development of Th 17 cells (a newly identified inflammatory T helper population), and induction of IL-10 production. Moreover, administration of IL-27 or augmentation of IL-27 signaling suppresses some diseases of autoimmune or allergic origin, including encephalitis, arthritis, and systemic lupus erythematosus, demonstrating its potential in therapy of diseases mediated by inflammatory cytokines.

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  Multiple sclerosis is an autoimmune disease affecting the central nervous system (CNS), in which Th17 and Th1 cells are involved. Comprehensive gene expression profiling analysis employing DNA microarray showed that NR4A2, an orphan nuclear receptor, is strongly upregulated in the peripheral blood T cells derived from MS patients. Further analysis revealed that NR4A2 plays a pivotal role for mediating production of inflammatory cytokines from pathogenic T cells. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, NR4A2 was selectively upregulated in the CNS-infiltrating T cells and the peripheral blood T cells. Intriguingly, a forced expression of NR4A2 augmented promoter activities of IL-17 and IFN-γ genes, leading to an excessive production of these cytokines by splenic T cells. In contrast, treatment with siRNA specific for NR4A2 resulted in a significant reduction in the production of IL-17 and IFN-γ. Furthermore, treatment with NR4A2-specific siRNA reduced the ability of encephalitogenic T cells to adoptively transfer EAE in recipient mice. These results imply that NR4A2 is an essential transcription factor for triggering the inflammatory cascade in MS/EAE and may serve as a novel therapeutic target of the diseases.

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  Recently, we have discovered a new type of regulatory T (Treg) cell, designated HOZOT, by co-culturing human umbilical cord blood cells with mouse stromal cell lines. There are three unique characteristics of HOZOT ; the first one is the induction method using the unfractionated cell population, the second is a phenotype of CD4⁺CD8⁺, the third is a multifunctional property of killer, suppressor, and helper activities. HOZOT can be defined as a new type of Treg cells because of its immunosuppressive activity in allogeneic MLR and of its phenotype and functions distinct from conventional Treg cells. HOZOT exerts cytotoxic activities against mouse stromal cells as well as human tumor cells such as colon carcinoma. Moreover, IL-10/RANTES/IL-8 are defined as signature cytokines of HOZOT due to the remarkably high production of them. Given the unique properties of HOZOT, especially anti-tumor and immunosuppressive activities, HOZOT should be utilized for clinical application for the treatment of cancer and immunological disorders.

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  Chronic myelogenous leukemia (CML) is associated with the Ph1 chromosome translocation, which produces a chimeric tyrosine-specific kinase gene, the product of the fusion of the BCR gene and the ABL gene. The immune system has long been implicated in the control of CML. We found oligoclonal T cell responses in treated patients with IFN-α or leukemic dendritic cells. Also other groups treated chronic phase CML (CP-CML) patients with various leukemic antigen peptides, resulted in apparent immune response and clinical response. Imatinib mesylate is currently used as the first line therapy for CP-CML patients. Although it selectively targets the ABL portion of BCR-ABL protein as a reversible tyrosine kinase inhibitor, it cannot kill the leukemic stem cells of CML. To find a possibility to enhance the immunity in imatinib-treated CML patients by combining it with immunotherapy, we summarized the immune response of innate and adaptive immunity in CML. Development of such immunotherapeutic strategies would be a promising approach to treat the imatinib-treated CML-CP patients.

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  Triggering receptor expressed on myeloid cells (TREM)-1 is inducible on monocyte/macrophages and neutrophils and accelerates tissue destruction by propagating inflammatory responses in diseases related to bacterial infection. Its blockade suppressed fatal immune responses in mice models of sepsis without impairing the host defense. However, the influence of TREM-1 on non-bacterial diseases was not elucidated. We describe here that TREM-1 expression was up-regulated by prostaglandin (PG) E₂ as well as lipopolysaccharide. Activation of TREM-1 expressed on PGE₂-pretreated peripheral blood mononuclear cells by an agonistic TREM-1 mAb significantly enhanced the production of TNFα. Indeed, monosodium urate monohydrate (MSU) crystals induced TREM-1 expression in vitro and in vivo. MSU crystals and an anti-TREM-1 agonistic antibody synergistically increased the production of interleukin-1β compared with stimulation with the crystals alone. Furthermore, TREM-1 was expressed on CD14+ cells in rheumatoid synovial tissue and synovial macrophages from mice with collagen-induced arthritis (CIA). Blockade of TREM-1 ameliorated CIA without affecting T cell and B cell immune responses to the inducing antigen. These results provide evidence that TREM-1 may contribute the development of non-microbial inflammatory diseases through the enhancement of inflammatory responses.

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  Many autoimmune diseases, such as rheumatoid arthritis (RA), have been thought as Th1-mediated diseases. However, recent studies demonstrated critical roles of IL-17, which is produced by a newly identified subset of helper CD4T cells, Th17, in the development of murine models of autoimmune diseases. In addition, many biological functions of IL-17 fit very well with the pathology of RA joints. However, despite the presence of some reports detecting IL-17 in RA joints, the prevalence of Th17 cells in human RA had been largely unknown. Therefore, we analyzed Th17 cells in RA by intracellular staining methods. We found the frequency of IL-17-producing T cells was not increased in RA and was not correlated with disease activity of RA. Surprisingly, the frequency of CD4 T cells capable of IL-17 was decreased in the joints compared with PBL in each individual, whereas Th1 cells predominantly infiltrated in the joints. Taken together with the results of other reports measuring IL-17 production in RA, it seems premature to conclude that IL-17 is abundantly produced in RA joints. Further investigation on the involvement of Th17/IL-17 in human RA is required.

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  Twenty patients with collagen diseases complicated with Pneumocystis pneumonia (PCP) were retrospectively examined in reference to the criteria for its protective therapy provided by the Ministry of Health Labor and Welfare. The breakdown of 20 patients was rheumatoid arthritis (RA) in 5 cases, systemic lupus erythematosus (SLE) in 5, dermatomyositis (DM) in 2, systemic scleroderma (SSc) in 1, mixed connective tissue disease (MCTD) in 1, Sjögren syndrome (SjS) in 1, polyarteritis nodosa (PN) in 3, rapidly progressive glomerulonephritis (RPGN) in 1, Schönlein-Henoch purpura in 1. Patients having interstitial pneumonia (IP) or renal dysfunction before acquiring PCP showed poor prognosis. High level of β-D glucan was observed in all patients, and elevated levels of LDH and KL-6 were also characteristic of PCP. For the treatment of their own collagen diseases, high dose steroids had been given in 11 patients (55%), and immunosuppressive agents in 12 (60%), resulting in severe suppression of immune function in these patients. They were treated with Sulfamethoxazole/trimethoprim (ST) after Pneumocystis infection, however, 10 patients died and 8 of them died of respiratory failure in spite of high dose steroids. Nine patients fulfilled the criteria for PCP protective therapy provided by Ministry of Health Labor and Welfare, and 7 of them died of respiratory failure. The frequency of PCP remarkably decreased in our hospital after we had started the protective therapy with ST using the criteria, suggesting that it is effective for the protection of PCP. However, some patients who do not fulfill the criteria may acquire severe PCP.

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  Systemic lupus erythematosus (SLE) is usually treated with corticosteroids and immunosuppressive agents. However, some patients are refractory to these agents, others show adverse effects. Usefulness of mycophenolate mofetil (MMF) in SLE has been reported in several studies. In this study, we evaluated the clinical efficacy and adverse effects of MMF in SLE. Sixteen cases which were difficult to reduce the dose of corticosteroid, resistant to immunosuppressive agents or could not use them for adverse effects were treated with MMF. Thirteen cases were females and three were males. Mean age was 44.4±9.2 year-old. Mean duration of SLE was 12.5±6.9 years. Mean observational duration was 12.0±5.5 months. Mean maintenance dose of MMF was 1.95±0.61 g/day. Good clinical response was obtained in 69% of total cases. In laboratory data, serum IgG (p<0.05) decreased and the levels of serum albumin (p<0.01) and complement (p<0.05) increased significantly. Adverse effects, mainly infections, were observed, but severe infection was not experienced. This study suggests that MMF is effective and relatively safe for SLE.

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  Relapsing polychondritis (RP) is a rare multisystemic disease characterized by the recurrent inflammation of the cartilaginous structures of the external ear, nose, joint, larynx, and tracheobronchial tree, whose etiology might involve an immunological mechanism. Five patients with RP were analyzed. They consisted of 4 males and 1 female, with ages of onset ranging from 27 to 75. Duration from onset to diagnosis varied from 10 months to 5 years. All 5 patients had auricular chondritis and arthritis. Laringotracheal involvement was detected in 4 patients, scleritis in 2 patients, nasal chondritis, and costal chondritis in one patient. One patient was diagnosed to have MAGIC syndrome, complicated with oral and genital ulcers. Antibodies to type II collagen were detected in 4 patients, and the antibody titer correlated with the level of C-reactive protein. Corticosteroids were given to 5 patients. After treatment, the symptoms improved in 5 patients, but 3 patients had a recurrence as reducing corticosteroids. One of them received steroid pulse therapy, one received immunosuppressive drugs, and one patient received both treatments. To prevent an impairment of organs, an early diagnosis involving the use of antibodies to type II collagen and steroid therapy are important in this disease.

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  Polymyalgia rheumatica (PMR) is an inflammatory disease of unknown etiology affecting elderly patients and characterized by muscle pain and morning stiffness in proximal areas (pelvic and shoulder girdles and neck). It is sometimes difficult to distinguish PMR from rheumatoid arthritis (RA), or vasculitis. In the present study, we examined the clinical characteristics of the patients diagnosed with PMR in our hospital retrospectively. There were 44 patients with the median age of 71s. Eighty percent of the patients were in their 60s or 70s, and 3 patients (6.8%) were in there 50s or younger. There was no sex preponderance in frequency. Fifteen patients (34%) presented with both proximal and distal muscle pain. Arthritis occurred in 16 patients (36%), the half of which was monarthritis or oligoarthritis, and was more involved in wrist or knee joint. Only 3 patients had temporal arteritis (TA) complicated with PMR. Mean of maximum serum CRP was 8.18 mg/dl, and rheumatoid factor and anti-CCP antibodies were positive in 2 patients and a patient, respectively. There was no patient positive for ANCA. Serum MMP-3 levels tended to be higher in female patients. Median of maximum prednisolone (PSL) dose used for the treatment was 0.195 mg/kg of body weight daily. No patient needed any immunosuppressants. In the 26 patients we had a chance to follow, there were no patients who developed RA 6 months after the initial diagnosis. Progression from PMR to RA was reported, and mean period between the diagnosis of PMR and RA was one to 5 years.

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  A 63-year-old woman was admitted to our hospital because of auricular chondritis, conjunctivitis, polyarthralgia, productive cough and dyspnea. On admission, pulmonary function test demonstrated an obstructive pattern, and flow-volume curve (FVC) revealed a constrictive upper airway flow pattern. Chest CT showed a thickened tracheal wall and narrowing of the airway. The laboratory findings revealed an elevation of CRP and high titer of anti-type II collagen antibody. She was diagnosed as relapsing polychondritis (RP) according to Damiani's criteria. After the initiation of the therapy with 32 mg/day of methylprednisolone, her symptoms, pulmonary function, FVC and CT findings ameliorated promptly, and the titer of anti-type II collagen antibody became normalized. Moreover, we measured the airway wall thickness, percentage wall area (WA%) and percentage wall thickness (WT%), by CT and HRCT, and also evaluated the airway involvement quantitatively. Both WA% and WT% were inversely correlated with FEV1.0%. The airway inlolvement is most important prognostic factor in patients with RP, and sequential evaluation of airway manifestation are necessary. We suggest that a quantitative evaluation of bronchial structures by sequential CT is useful for the evaluation of RP as well as pulmonary function tests.

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