Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To explore the mechanisms responsible for the development of tolerance to allografts after intrathymic (IT) injection of alloantigen, the well-defined model of experimental autoimmune encephalomyelitis (EAE), which mimics the human autoimmune disease multiple sclerosis, was used. This inflammatory neurologic syndrome is initiated by myelin basic protein (MBP)-reactive CD4+ T lymphocytes restricted to self-MHC class II molecules. Naive adult, EAE-susceptible Lewis (RT1(1) rats were treated IT, i.v., or i.p. with a single dose (100 micrograms) of guinea pig-myelin basic protein (GP-MBP 1-176) in PBS plus 1 ml rabbit anti-rat lymphocyte serum i.p. Twenty-one days later, all rats were challenged by intradermal hind footpad injections of 50 micrograms GP-MBP in PBS emulsified in CFA. Only IT, but not i.p. or i.v., administration of GP-MBP plus anti-lymphocyte serum conferred marked resistance to a subsequent systemic challenge of GP-MBP, as demonstrated by the prevention of weight loss and paralysis characteristic of EAE. The IT administration dramatically decreased the size and number of histologic perivascular infiltrates observed per visual field in spinal cord of the tolerant animals and decreased GP-MBP-specific T lymphocyte in vitro proliferation (p < 0.01), whereas proliferation to a nonspecific mitogen (Con A) was not altered. With the addition of rIL-2, the decreased Ag-specific proliferative responses of IT-treated animals increased to control levels. Adoptive transfer of 100 x 10(6) splenocytes from tolerant hosts i.v. to naive syngeneic Lewis rats challenge with 100 micrograms GP-MBP in CFA had no effect on clinical or histologic EAE. Exposure of MBP to maturing thymocytes results in functionally immunounresponsive lymphocytes and prevention of autoimmune EAE.
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PMID:Immunological tolerance to a defined myelin basic protein antigen administered intrathymically. 752 8

The effects of intracerebroventricular administration of mAbs against LFA-1 and ICAM-1 on both active and passive experimental allergic encephalomyelitis (EAE) in rats were examined. Lewis rats were immunized with guinea pig myelin basic protein (MBP) or MBP 68-86 peptide in complete Freund's adjuvant to induce active EAE, or they were injected with encephalitogenic MBP-reactive lymphocytes for adoptive transferred EAE. LFA-1-specific mAbs and/or ICAM-1-specific mAbs or a control mAb or PBS were injected into the lateral ventricles via implanted needles. Intracerebroventricular administration of the specific mAbs together on Days 0, 2, 4, and 6 or on Days 4, 6, 8, and 10 after immunization almost completely suppressed the clinical signs of the actively induced EAE with reduced numbers of the infiltrating cells and reduced percentages of W3/25(+) and IA-29(+) cells in the central nervous system (CNS) of the rats. Pretreatment with both specific mAbs from 14 to 11 days prior to immunization also exhibited a considerable protective effect. However, daily injection from Day 10 to 13 after immunization did not suppress the clinical signs. In rats with adoptive transferred EAE, daily treatment from Day 0 to Day 4 after cell transfer completely abolished clinical signs of EAE, although comparison of histological findings was not remarkable. In conclusion, intrathecal administration of antibodies against LFA-1 and ICAM-1 may be useful for the treatment of human demyelinating diseases, such as multiple sclerosis.
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PMID:Intrathecal administration of antibodies against LFA-1 and against ICAM-1 suppresses experimental allergic encephalomyelitis in rats. 880 96

This study explores nasal administration of myelin basic protein (MBP) as a potential means of inducing tolerance to relapsing experimental autoimmune encephalomyelitis (PR-EAE), an experimental multiple sclerosis (MS) model that was induced in DA rats by immunization with rat spinal cord homogenate and incomplete Freund's adjuvant. DA rats received a total dosage of 0, 6, 60, 600 micrograms/rat of bovine MBP on ten consecutive days prior to immunization. EAE with typical course was observed in control rats receiving only PBS nasally, and in rats receiving 6 micrograms/rat of MBP. Rats receiving 60 micrograms/rat of MBP developed acute EAE but no relapse during 60 days of observation post immunization (p.i.). Only one of eight rats receiving 600 micrograms/rat of MBP developed slight, transient EAE. This protection was confirmed at the histology level and was associated with decreased levels of MBP-reactive IFN-gamma secreting Th1-like spleen cells on day 13 and 60 p.i. Rats receiving 60 and 600 micrograms/rat of MBP showed decreased serum anti-MBP IgG2b antibody levels on day 60 p.i., and rats receiving 600 micrograms/rat of MBP had marginally increased anti-MBP IgG1 antibody levels in serum compared to control EAE rats. Cytokine mRNA profiles in central nervous system (CNS) and spleen mononuclear cells were evaluated. Dose-dependent reduction of TNF-alpha mRNA expression were observed both in CNS and in splenocytes. Increased IL-4 and TGF-beta mRNA expression were observed in CNS of low (6 micrograms/rat) and median (60 micrograms/rat) dose of MBP tolerized rats and in splenocytes of rats tolerized with 600 micrograms/rat of MBP. We conclude that nasal administration of MBP in DA rat prevents EAE induced by immunization with whole rat spinal cord homogenate that, besides MBP, contains multiple antigenic myelin proteins. A mechanism involving MBP-reactive regulatory cells expressing IL-4 and TGF-beta mRNA acts as part in the induction of this tolerance.
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PMID:Nasal administration of myelin basic protein prevents relapsing experimental autoimmune encephalomyelitis in DA rats by activating regulatory cells expressing IL-4 and TGF-beta mRNA. 941 60

One important therapeutic goal during CNS injury from trauma or demyelinating diseases such as multiple sclerosis is to develop methods to promote remyelination. We tested the hypothesis that spontaneous remyelination in the toxic nonimmune model of lysolecithin-induced demyelination can be enhanced by manipulating the inflammatory response. In PBS-treated SJL/J mice, the number of remyelinating axons per square millimeter of lesion area increased significantly 3 and 5 weeks after lysolecithin injection in the spinal cord. However, methylprednisolone or a monoclonal antibody (mAb), SCH94.03, developed for its ability to promote remyelination in the Theiler's virus murine model of demyelination, further increased the number of remyelinating axons per lesion area at 3 weeks by a factor of 2.6 and 1.9, respectively, but did not increase the ratio of myelin sheath thickness to axon diameter or the number of cells incorporating tritiated thymidine in the lesion. After 3 weeks, the number of remyelinating axons in the methylprednisolone or mAb SCH94.03 treatment groups was similar to the spontaneous remyelination in the 5 week PBS control-treated group, indicating that these treatments promoted remyelination by increasing its rate rather than its extent. To address a mechanism for promoting remyelination, through an effect on scavenger function, we assessed morphometrically the number of macrophages in lesions after methylprednisolone and mAb SCH94.03 treatment. Methylprednisolone reduced the number of macrophages, but SCH94.03 did not, although both enhanced remyelination. This study supports the hypothesis that even in toxic nonprimary immune demyelination, manipulating the inflammatory response is a benefit in myelin repair.
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PMID:Acceleration in the rate of CNS remyelination in lysolecithin-induced demyelination. 950 10

Infection of C57BL/6 mice with mouse hepatitis virus strain V5A13.1 (MHV-V5A13.1) results in an acute encephalitis followed by a chronic, progressive demyelinating disease with clinical and histological similarities to the human demyelinating disease Multiple Sclerosis (MS). Studies were undertaken to evaluate the contribution of NOS2 generated NO in demyelination in MHV-infected mice. MHV-infected animals were treated daily with either 8 mg of aminoguanidine (AG), a selective inhibitor of NOS2 activity, or PBS by intraperitoneal (i.p.) injection. MHV-infection of mice resulted in 20% mortality in both groups with surviving mice clearing virus below levels of detection, as measured by plaque assay, by day 12 postinfection (p.i.). A significant decrease in the severity of clinical disease was observed in AG-treated animals as compared to mice receiving PBS at days 7 and 12 p.i. (P< or =0.001 and 0.003, respectively) however, by day 21 p.i. AG-treated mice exhibited the same severity of clinical disease as control animals. Examination of brain and spinal cords from infected mice revealed a pronounced reduction in the severity of inflammation at day 7 p.i. in mice treated with AG as compared to control mice. By day 12 p.i. there was a significant decrease (P< or =0.02) in the severity of demyelination in AG-treated mice as compared to control animals yet both PBS and AG treated mice had a similar degree of demyelination by day 21 p.i. Analysis of chemokine mRNA transcripts by RNase protection assay revealed that AG-treated mice had significantly lower levels (P < or = 0.007) of transcripts for the C-C chemokine monocyte chemoattractant protein-1 (MCP-1) at day 7 p.i. as compared to control animals. By day 12 p.i., AG-treated mice and control mice had similar levels of chemokine transcripts. Together, these data suggest that inhibition of NOS2/NO slows the progression of MHV-induced demyelination. One potential mechanism by which this may occur is through controlling inflammation through modulation of chemokine expression in the CNS.
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PMID:Inhibition of nitric oxide synthase-2 reduces the severity of mouse hepatitis virus-induced demyelination: implications for NOS2/NO regulation of chemokine expression and inflammation. 1019 Jun 90

Cytokines have a crucial role in initiation and perturbation of EAE that represents an animal model of multiple sclerosis (MS). Administration of transforming growth factor-beta1 (TGF-beta1) to EAE mice improves clinical EAE and prevents relapses by unknown mechanisms. Administering low doses of TGF-beta1 nasally, we confirmed that TGF-beta1 inhibited development and relapse of protracted-relapsing EAE (PR-EAE) in DA rats. Infiltration of CD4+ T-cells and macrophages within the central nervous system was clearly reduced, while proliferation and IFN-gamma secretion of mononuclear cells (MNC) was augmented in TGF-beta1-treated EAE rats compared to PBS-treated control EAE rats. TGF-beta1 administered nasally also increased nitric oxide production and CD4+ T cell apoptosis. TGF-beta1 treated rats showed augmented proliferation of dendritic cells (DC) compared to MNC. These data imply that low doses of TGF-beta1 given by the nasal route prevent PR-EAE and upregulate DC functions that may be involved for disease prevention.
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PMID:Nasal administration of transforming growth factor-beta1 induces dendritic cells and inhibits protracted-relapsing experimental allergic encephalomyelitis. 1040 19

Cytokines play a crucial role in initiating and perpetuating EAE, an animal model of multiple sclerosis (MS). A low dose of IL-4, administered by the nasal route over 5 days (100 ng/rat per day) prior to immunization, improved clinical scores of EAE induced in Lewis rats with myelin basic protein (MBP) peptide 68-86 (MBP 68-86). We examined whether dendritic cells (DC) may have contributed to the amelioration of the disease process. These professional antigen-presenting cells (APC) not only activate T cells, but also tolerize T cells to antigens, thereby minimizing autoimmune reactions. We found that IL-4 administration enhanced proliferation of DC. In comparison with DC of PBS-treated rats, DC from IL-4-treated rats secreted high levels of interferon-gamma (IFN-gamma) and IL-10. Nitric oxide (NO) production by DC was also strongly augmented in IL-4-treated rats. In vitro studies showed that IL-4 stimulated DC expansion and that IFN-gamma enhanced NO production by DC. DC-derived NO promoted apoptosis of autoreactive T cells. These results indicate that nasal administration of IL-4 promotes activation of DC and induces production of IFN-gamma and IL-10 by DC. IL-10 suppresses antigen presentation by DC, while IFN-gamma induces NO production by DC which leads to apoptosis in autoreactive T cells. Such a DC-derived negative feedback loop might contribute to the clinical improvement observed in EAE.
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PMID:Dendritic cell-derived nitric oxide is involved in IL-4-induced suppression of experimental allergic encephalomyelitis (EAE) in Lewis rats. 1054 Jan 68

Mucosal myelin autoantigen administration effectively prevented EAE, but mostly failed to treat ongoing EAE. Patients with multiple sclerosis (MS), for which EAE is considered an animal model, did not benefit from oral treatment with bovine myelin. We anticipated that autoantigen, administered together with a cytokine that counteracts Th1 cell responses, might ameliorate Th1-driven autoimmune disease, and that nasal administration might considerably reduce the amounts of antigen + cytokine needed for treatment purposes. Lewis rats with EAE actively induced with myelin basic protein peptide (MBP 68-86) and Freund's complete adjuvant (FCA), received from day 7 post-immunization, i.e. after T cell priming had occurred, 120 microg MBP 68-86 + 100 ng IL-4 per rat per day for 5 consecutive days. These rats showed later onset, lower clinical scores, less body weight loss and shorter EAE duration compared with rats receiving MBP 68-86 or IL-4 only, or PBS. EAE amelioration was associated with decreased infiltration of ED1+ macrophages and CD4+ T cells within the central nervous system, and with decreased interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) and enhanced IL-4, IL-10 and transforming growth factor-beta (TGF-beta) responses by lymph node cells. Simultaneous administration of encephalitogenic peptide + IL-4 by the nasal route thus suppressed ongoing EAE and induced IL-4, IL-10 and TGF-beta-related regulatory elements.
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PMID:Suppression of ongoing experimental allergic encephalomyelitis (EAE) in Lewis rats: synergistic effects of myelin basic protein (MBP) peptide 68-86 and IL-4. 1084 33

We studied the effect of high-dose mouse IgG on TMEV-induced demyelinating disease (TMEV-IDD). We injected TMEV intracerebrally into susceptible SJL/J mice and induced TMEV-IDD. Mouse IgG were injected intraperitonealy, and clinical course and various immunological indicators were studied. The results show that TMEV-IDD was significantly suppressed both clinically and histologically (P<0.01) when IgG were administered in the effector phase. The delayed type hypersensitivity and T cell proliferative response specific for TMEV were decreased by this treatment. In an ELISPOT assay, the number of TNF-alpha producing lymphocytes in the spinal cords was low in high-dose IgG treated mice compared with PBS treated control mice. These data suggest that administration of IgG suppresses TMEV-IDD and may be promising treatment to prevent exacerbation of human multiple sclerosis.
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PMID:High-dose mouse immunoglobulin G administration suppresses Theiler's murine encephalomyelitis virus-induced demyelinating disease. 1090 Mar 33

We have evaluated the effect of the immunosuppressant sodium fusidate (fusidin) on the course of acute monophasic experimental encephalomyelitis (EAE) in male Lewis rats. Prophylactic treatment with fusidin, 80 or 120 mg/kg bd wt., markedly ameliorated the course of the disease in rats immunized with myelin basic proteins in complete Freund's adjuvant, entailing delayed onset of symptoms, lower clinical scores and more rapid recovery than PBS-treated control rats. The fusidin-treated, immunized rats exhibited milder mononuclear cell infiltration of brains and spinal cords than control animals. These data provide further evidence for the anti-inflammatory effect of fusidin and suggest that this drug may be valuable for the treatment of human multiple sclerosis.
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PMID:Sodium fusidate (fusidin) ameliorates the course of monophasic experimental allergic encephalomyelitis in the Lewis rat. 1142 29


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