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The Effect of IL-1 on Differentiation and Development of Treg Cells

Author: LongYao
Tutor: ChenGuoYou
School: Second Military Medical University
Course: Immunology
Keywords: Interleukin -1β IL-1 receptor antagonist Collagen-induced arthritis Regulatory T cells
CLC: R392
Type: Master's thesis
Year: 2010
Downloads: 111
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Abstract


Recent studies show that an immunosuppressive Treg cells are cells, primarily by inhibiting the secretion of a number of other cytokines and the expression of inhibitory molecules to inhibit irritation autoreactive T cell immune response plays in the maintenance of immune tolerance an important role, the number of deficiency or dysfunction can cause a variety of autoimmune diseases. Rheumatoid arthritis (RA) is a clinically-prone chronic autoimmune disease characterized by multiple joint, symmetry inflammation and progressive cartilage and bone destruction as the main feature, mainly involving the joints, especially common in the hands, feet small joints, the lesion can invade adjacent synovium, cartilage and bone, if not timely diagnosis and treatment of disease, may develop irreversible joint deformities, eventually leading to disability. IL-1 is important in the pathogenesis of RA cytokines. In the pathogenesis of rheumatoid, multiple cell-derived IL-1 may be part of the arthritis stimulated monocytes and macrophages, and T, B lymphocyte activation, promoting fibroblast proliferation and activation of osteoclasts, resulting in cartilage degradation increases, play an important role in tissue injury. IL-1 receptor antagonist can compete with IL-1RI not participate in signal transduction, thus blocking IL-1a and IL-1β biological effects. There are many reports have IL-1 receptor antagonist (IL-1ra) used in clinical treatment of patients with rheumatoid arthritis, can reduce the patient's symptoms and signs. However, there are a number of clinical data suggest that IL-1 receptor antagonist treatment of rheumatoid arthritis patients, the emergence of many new problems, the majority of patients with more severe local reactions, more studies show that long-term use of the drug after treatment disease occurs when repeated exacerbations. In the present study the in vivo experiments, we successfully established collagen-induced mouse model of rheumatoid observed the rhIL-1ra treatment on CIA mice. In in vitro experiments, we investigated the rmIL-1β and rhIL-1ra the DC vitro CD4 CD25 T cell proliferation and Public L-1β on TGF-β-induced CD4 CD25 Foxp3 regulatory T cell differentiation and development impact. The first part of the IL-1ra in vivo studies on the treatment of CIA mice in this part of the study, we first established according to the literature method successfully in mouse CIA model. In short, our chicken collagen type Ⅱ as an antigen, on day 0, first dissolved in glacial acetic acid 4mg/ml Ⅱ collagen and complete Freund's adjuvant emulsified in a 1:1 ratio, at each DBA / 1 mice were immunized subcutaneously 100μl tail root 2mg/ml good emulsifying type Ⅱ collagen, and then in the first 21 days for booster immunization, the above collagen solution with incomplete Freund's adjuvant emulsified in a 1:1 ratio, again in small cm at the base of the tail mice were injected subcutaneously 100μl 2mg/ml good emulsifying type Ⅱ collagen. According to the CIA clinical criteria score: 0: joint normal; 1 min: mild joint swelling; 2 points: joint swelling and severe, involving the entire joint; 3: paw or joint dysfunction, joint stiffness. Each mouse overall rating of arthritis limbs sum of the highest score of each mouse 12 minutes, the total score is greater than 1 joint mice successful modeling. According to the experimental purpose, the CIA mice were randomly divided into 3 groups, provided IL-Ira treatment group, PBS treated control group and the control group treated BSA protein. IL-1ra treatment group after the first immunization the first 33 days from 20 days to CIA mice were injected subcutaneously IL-1ra100μg / only in the control group in order to inject the same amount of PBS or BSA proteins. The established CIA mice 27 days after the first immunization from disease, 33 days and reached peak incidence. CIA mice incidence rate of 80%, the average joint index for 6 points. Articular manifestations of chronic progressive polyarthritis, acute manifestations of the first toe slight skin redness, and involving the paws and ankle, severe swelling of the skin hyperemia, late lead to joint deformity, activity was limited. Pathological manifestations of proliferative synovitis, pannus formation, cell fibrosis, articular cartilage and bone destruction. Joint score and clinical pathology results can be seen, IL-1ra treatment reduced the CIA's early joint swelling, inhibit inflammatory cell infiltration, pannus formation, reduce joint cartilage and bone destruction. But the latter joint swelling was intensified histopathological examination found that the articular cartilage and bone tissue damage. Acute phase of the CIA, IL-1ra treatment, CD4 CD25 Foxp3 regulatory T cells in the proportion of CD4 T cells did not increase. The results showed that IL-1ra treatment late symptoms repeated exacerbations, and Treg cell differentiation and is closely related to impaired development. The second part of the in vitro IL-1 对 CD4 CD25 Foxp3 regulatory T cell proliferation effect of regulatory T cell differentiation and function of developmental disorders that cause autoimmune disorders of the main mechanisms of disease. According to their developmental origin, regulatory T cells from the thymus into the natural regulatory T cells and the thymus Outer persistent antigen such as IL-10.TGF-β cytokine stimulation induced under conditions induced regulatory T cells. As a full-DC antigen presenting cells, not only involved in the initial activation of T cells of the immune process, but also control their differentiation into different cell subsets. Recent findings suggest, DC involved in the induction of Treg natural homeostatic proliferation. In this study, we found that both mature and immature DC and DC in vitro co-culture system, can stimulate CD4 CD25 Treg cell proliferation, and mature DC to stimulate the proliferation of Treg cells stronger. When after irradiation of mature DC, may partially inhibit the proliferation of its stimulating effect of Treg cells. The experimental results show that, DC to stimulate the proliferation of Treg cells on the one hand dependent on the cell - direct contact between cells. The other hand, also secrete a variety of mature DC closely related cytokines. Of mature DC to secrete high levels of proinflammatory cytokines, such as IL-1β, IL-6.IL-2 and TGF-β. In vitro culture system, we discovered that adding a low concentration of IL-1β, after, imDC promote CD4 CD25 T cell proliferation enhanced ability; added after 10μg/mlIL-1ra, IL-1ra inhibits mDC promoting CD4 CD25 T cells proliferative capacity. Show that low concentrations of IL-1 may be used as a Treg cell growth factors involved in DC on Treg cells proliferation effect process. In addition, in this experiment, we have established an in vitro TGF-β-induced CD4 CD25T cells into CD4 CD25 Foxp3 regulatory T cell-free system. TGF-β-induced regulatory T cells can these high expression of FoxP3, and can significantly inhibit the reactivity of CD4 T cell proliferation. When we add in this system IL-1β, and found that synergistic induction of TGF-β to promote regulatory T cell differentiation and development. In short, our previous experimental results show that the CIA acute phase, IL-1ra treatment of early CD4 CD25 Foxp3 regulatory T cells in reducing the proportion of CD4 T cells may be related to the late repeated exacerbations related joint symptoms. The results suggest that IL-1 as an important in vivo T-cell growth factor involved in the differentiation and development of Treg cells.

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