Akira Sugihara

Effects of Administration of Monoclonal Antibodies (anti-CD4 or anti-CD8) on the Development of Autoimmune Diseases in (NZW × BXSB)F1 Mice

(NZW x BXSB)F1 (W/BF1) mice spontaneously develop autoimmune diseases, characterized by lymphadenopathy, lupus nephritis, and immune thrombocytopenia associated with various autoantibodies such as anti-DNA, anti-platelet and anti-cardiolipin antibodies (Abs). In the present study, we investigate the effects of administration of monoclonal Abs (anti-CD4 or anti-CD8 mAb) on the development of autoimmune diseases in W/BF1 mice. MAb was administered from the age of 7 weeks. Prolongation of survival rate and reduction of severity of autoimmune diseases were observed after treatment with anti-CD4 mAb. However, anti-CD8 mAb treatment accelerated the diseases. Serum levels of IFN-gamma and IL-10 in old W/BF1 mice were significantly high, whereas IL-4 levels were low in comparison with those of young W/BF1 mice; the expression of mRNA of IFN-gamma, IL-4 or IL-10 in CD4+ T cells of old W/BF1 mice was parallel to the serum levels of each cytokine. These observations suggest that CD4+ cells are involved in the development of autoimmune diseases in W/BF1 mice, and that CD8+ cells have a suppressive effect on the development of autoimmune diseases in W/BF1 mice.

Immunosuppressive effects of photodynamic therapy by topical aminolevulinic acid

Photodynamic therapy (PDT) has been used for inflammatory skin disorders as well as superficial skin cancers such as solar keratosis and Bowens disease. Whether PDT with topical application of aminolevulinic acid (ALA) and exposure to visible light has a similar immunosuppressive action to ultraviolet phototherapy was investigated using a murine contact hypersensitivity (CHS) model. The number of epidermal Langerhans cells (LC) was decreased with their morphological changes 1 day after PDT with the minimal level at 5 days and gradual recovery thereafter. Conversely, the number of CD11c+ I‐A+ cells was significantly increased in the draining lymph nodes after PDT. This suggests that LC moved from PDT‐treated skin, resulting in the decrement of epidermal LC and migration to lymph nodes. CHS response to DNFB applied on the PDT‐treated skin with 20% ALA and 40 J/cm2 visible light was significantly suppressed (local immunosuppression). When mice were treated with 80 J/cm2 of PDT, CHS response to the antigen applied on untreated distant skin was also significantly suppressed (systemic immunosuppression). The locally or systemically immunosuppressed mice by PDT were attempted to sensitize again with DNFB on non‐treated skin, but elicitation responses were significantly suppressed. However, these mice were able to be sensitized with another hapten, oxasolone. Thus, a hapten‐specific immunological unresponsiveness (tolerance) was induced in mice by topical ALA‐PDT. These findings suggest that PDT has a potential immunological contribution to clinical efficacy for inflammatory diseases identical to ultraviolet phototherapies.

Ultraviolet B radiation suppresses Langerhans cell migration in the dermis by down-regulation of α4 integrin

Background/Purpose: Ultraviolet B (UVB) radiation affects the migration and function of epidermal Langerhans cells (LC) and causes immunosuppression of contact hypersensitivity. It is known that LC leaves the epidermis after exposure to UVB. To know the behavior of LC in the dermis after UVB radiation, we studied the effect of UVB radiation on the expression of integrin families on freshly isolated or cultured murine LC. We also examined whether UVB radiation affects the migration of LC to secondary lymphoid tissue chemokine (SLC/6Ckine).

Therapeutic and prophylactic effects of PUVA photochemotherapy on atopic dermatitis‐like lesions in NC/Nga mice

Background: Psoralens and ultraviolet A radiation (PUVA) photochemotherapy has been used for severe cases of atopic dermatitis (AD). To understand the mechanisms of action is important for the choice of treatments. AD‐like lesions can be induced experimentally in NC/Nga mice.

Differentiation from thymic B cell progenitors to mature B cells in vitro.

The role of the thymic microenvironment in the development of murine thymic B cells has yet to be fully clarified. We therefore investigate the microenvironment that supports the development of mature thymic B cells (sIg+/B220+/CD43-B cells) from thymic B cell progenitors with immunophenotypes of sIg-/B220med/CD43+ cells. As we have previously reported, thymic B cells generated from these progenitors in the thymus are CD5+ B cells. We next study the in vitro condition that supports the differentiation of thymic B cell progenitors. Stromal cells (from the bone marrow or thymus), thymus-derived cell lines with the character of thymic nurse cells (TNCs) or thymic epithelial cells (TECs), or the bone marrow-derived cell line (MS-5) are tested for their ability to support B-lymphopoiesis from thymic B cell progenitors. Interestingly, thymic stromal cells (but neither stromal cells from the bone marrow nor stromal cell lines) support the differentiation of thymic B cell progenitors into thymic B cells in the presence of IL-7. Cortical epithelia (but not medullary epithelia, thymic macrophages or dendritic cells) are found to contribute to thymic B cell differentiation. Surface phenotype and Ig rearrangement analyses reveal that mature B cells generated in this condition are primarily CD5+ B cells, indicating that the thymic microenvironment (particularly cortical epithelia) determines the differentiation of thymic B cells.

An autopsy case of fetal Gaucher disease

Abstract Background: A case of fetal form of Gaucher disease in a Japanese fetus is presented.

Age-Dependent Abnormalities of Hematopoietic Stem Cells in (NZW × BXSB)F1 Mice

The (NZW × BXSB)F1 (W/BF1) mouse is known as an autoimmune‐prone strain which develops lupus nephritis, thrombocytopenia due to platelet‐specific autoantibodies, leukocytosis, and myocardial infarction. In this experiment, we investigated the age‐dependent abnormalities of the hematopoietic stem cells (HSCs) and hematopoiesis in this mouse. White blood cell counts (especially Mac‐1‐ or Gr‐1‐positive cells) in the peripheral blood of 12‐week‐old W/BF1 mice increased in comparison with those of four‐week‐old W/BF1 or normal mice. To investigate whether the abnormal hematopoiesis can be attributed to the HSCs of W/BF1 mice, colony‐forming unit in spleen (CFU‐S) and colony‐forming unit in culture (CFU‐C) assays were performed. Day 12 CFU‐S counts of 12‐week‐old W/BF1 mice significantly increased in comparison with those of four‐week‐old W/BF1 mice or normal mice. In the CFU‐C assay, CFU‐GEMM and CFU‐GM counts in 12‐week‐old W/BF1 mice increased in comparison with those of four‐week‐old W/BF1 or control mice. The bone marrow cells (BMCs) from 12‐week‐old W/BF1 mice showed a high level of G‐CSF and a low level of GM‐CSF in mRNA expression. To examine the effect of HSCs from 12‐week‐old W/BF1 mice on the onset of autoimmune diseases and the abnormal hematopoiesis, T‐ and B‐cell‐depleted BMCs of four‐week‐old or 12‐week‐old W/BF1 mice were transplanted to C3H mice. Recipient C3H mice that had received the BMCs from 12‐week‐old W/BF1 mice showed an earlier onset of autoimmune diseases and a shorter survival rate than those that had received the BMCs from four‐week‐old W/BF1 mice. These data suggest that the HSCs from 12‐week‐old W/BF1 mice showing the symptoms of autoimmune diseases have the capacity to induce autoimmune diseases earlier than the HSCs from four‐week‐old W/BF1 mice.

Lupus pernio with 2 years of preceding symptomatic gastric sarcoidosis

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