Clinical immunology and immunopathology最新文献

To clarify the role of CD4⁺intestinal mucosal lymphocytes in chronic intestinal inflammation, we developed a new rat colitis model by immunization with 2,4,6-trinitrobenzenesulfonic acid (TNB) in an emulsion with an adjuvant followed by transrectal administration of a low dose of TNB. Moreover, we assessed the therapeutic effect of anti-CD4 monoclonal antibody (mAb) on this model. In concert with the development ofserum anti-TNB Abs, transmural and segmental colitis that mimics some characteristics of human Crohn's disease was induced in the immunized rats. Immunohistochemical analysis showed the increase of infiltrating lamina propria CD4⁺T cells. Flow-cytometric analysis of isolated cells from inflamed mucosa revealed that CD45RC^highCD4⁺T cells were significantly increased. Interestingly, intraperitoneal administration of anti-CD4 mAbs could suppress severe inflammation in the model with decrease of anti-TNB Ab titer. After the treatment with anti-CD4 mAbs, CD45RC^highCD4⁺T cells in the lamina propria and interferon-γ mRNA expression in the colonic lamina propria CD4⁺T cells were decreased. These results indicated that Th1 CD4⁺intestinal mucosal T cells have a role in the progress of inflamed lesions in chronic enteritis. They implicate that a therapy targeting mucosal T cells expressing CD4 may be feasible in the treatment of human Crohn's disease.

To determine if soluble CD16 (sCD16) could alter the expression of lupus-like disease, groups of 10 female NZB/NZW mice (age 16–20 weeks) were given sCD16 three times a week for 5 weeks (control; 100 μg; 200 μg/dose) after onset of proteinuria. Results of this study indicate that the administration of sCD16 after onset of disease lowered anti-DNA levels, delayed the development of proteinuria, and significantly prolonged survival while the mice were on treatment. These results indicate that sCD16 alters the expression of autoantibodies and the progression of renal disease in NZB/NZW mice, suggesting that therapies directed at Fc receptors may be useful in the treatment of SLE.

We compared the state of activation and proliferation of T cells in synovial tissue (ST) from rheumatoid arthritis (RA) patients in early and late stages of the disease to find out whether T-cell-driven immune responses vary during the course of the disease. ST was obtained from 12 patients with early RA (< 1 year) and 12 patients with longstanding RA (> 5 years). T cells and interferon-γ (IFN-γ)-positive cells were detected in ST using immunohistologic methods. To determine the percentage of T cells expressing the interleukin-2 receptor, IFN-γ, or the proliferation associated antigen Ki-67, immunofluorescence double-staining techniques were used. The scores for the number of T cells and for the expression of IFN-γ as well as the percentages of T cells expressing CD25, IFN-γ, or Ki-67 in rheumatoid synovium were not dependent on disease duration. These results do not support the assumption that the responsiveness of T cells in ST of RA patients differs between early and late stages of the disease. The data indicate that at present no arguments exist that the effect of T-cell-directed interventions on synovial inflammation might vary in different stages of the disease.

A family was identified with 5 of 6 siblings and 3 other immediate family members who had developed chronic fatigue syndrome (CFS) as adults. All 8 met criteria for the CFS case definition as recommended by the Centers for Disease Control and Prevention. Sixty-eight blood samples were obtained over a period of 2 years from 20 family members (8 affected, 12 unaffected) and 8 normal controls. All blood samples were tested for NK activity in 4-h⁵¹Cr-release assays and for the number of circulating CD3–CD56⁺and CD3–CD16⁺by flow cytometry. NK activity of the affected immediate family members (cases,n= 8) was significantly lower (P= 0.006, two-sided) than that of the concurrently tested normal controls. The results for unaffected family members were intermediate between these two groups, and the pairwise comparison of unaffected family members to either cases or controls showed no statistically significant difference (P= 0.29, two-sided). No differences were seen between the groups in the absolute number of CD3–CD56⁺or CD3–CD16⁺lymphocytes in the peripheral blood. Familial CFS was associated withpersistentlylow NK activity, which was documented in 6/8 cases and in 4/12 unaffected family members. In the family with 5 of 6 siblings who had documented CFS, 2 of their offspring had pediatric malignancies. Low NK activity in this family may be a result of a genetically determined immunologic abnormality predisposing to CFS and cancer.

Multiple sclerosis (MS) is a presumed cell-mediated Th1-type autoimmune disease. Thus therapies which decrease T cells secreting IFN-γ production or increase IL-4 production would be expected to have an ameliorating effect on MS. We have previously reported increased anti-CD3-induced IL-4 secretion by T cells in progressive MS patients treated with cyclophosphamide plus methylprednisolone (CY/MP) which was associated with eosinophilia. To investigate whether the increased IL-4 secretion was myelin antigen specific, we generated 3990 short-term T cell lines to myelin basic protein (MBP), proteolipid protein (PLP), or tetanus toxoid (TT) from 31 progressive MS patients: 11 MS patients treated with CY/MP, 10 MS patients treated with MP alone, and 10 untreated MS patients. We found increased frequencies of both MBP- and PLP-specific IL-4-secreting T cell lines in CY/MP-treated patients compared to untreated MS patients. However, no change in the frequency of TT-specific IL-4-secreting T cells was observed. MP treatment alone did not increase the frequency of antigen-specific IL-4-secreting T cell lines. These results demonstrate immune deviation favoring Th2-type responses specific to autoantigens following pulse cyclophosphamide therapy in MS patients.

Regeneration is generally considered to be a phenomenon restricted to amphibians in which amputated limbs reform and regrow. We have recently noted a strain of mouse, the MRL, which displays a remarkable capacity for cartilagenous wound closure and provides an example of a phenomenon previously considered to be a form of regeneration. Specifically, through-and-through ear punches rapidly attain full closure with normal tissue architecture reminiscent of regeneration seen in amphibians as opposed to scarring, as usually seen in mammals. Histologically, we have demonstrated normal cell growth and microanatomy, including angiogenesis and chondrogenesis, as opposed to control C57BL/6 mice which have ear holes that contract minimally but do not close. Finally, this phenomenon is a genetically definable quantitative trait.

Deficient expression of the counterregulatory cytokine IL-10 by lung inflammatory cells may facilitate chronic inflammation and the pathogenesis of hyaline membrane disease (HMD), in premature infants. To determine if pathways which regulate proinflammatory cytokines in response to human recombinant IL-10 (rIL-10) were functional in the lungs of these neonates, bronchoalveolar lavage (BAL)-derived lung inflammatory cells (predominantly macrophages and neutrophils) from infants with HMD were cultured in the presence of lipopolysaccharide (LPS) and increasing concentrations of (rIL-10). The expression of IL-1β and IL-8 protein was assessed 24 h later. IL-10 protein was also measured from the BAL aspirates of these newborns at 4-day intervals over the first month of life. In cell culture IL-1β expression was inhibited by rIL-10 in a dose-dependent fashion while IL-8 expression was inhibited by higher concentrations of rIL-10. IL-10 protein was undetectable from BAL fluid of the premature infants sampled over 28 days. The results demonstrate that lung inflammatory cells, which do not express IL-10in vivo,are capable of responding to rIL-10 in cell culture with reduction of IL-1β and IL-8 expression. These data support the rationale for the development of rIL-10 as a potential anti-inflammatory agent in the treatment of HMD.