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ABSTRACT: Background: Guillain-Barré syndrome (GBS) is an acute inflammatory disease of the peripheral nervous system with considerable morbidity and mortality. EAN is an experimental model of GBS. EAN is caused by T cell-mediated inflammation. Aim: The purpose of this study was exploring the mechanisms underlying the beneficial effect of G-CSF in EAN. Results: Here, we demonstrate that the in vivo administration of G-CSF to Lewis rats with EAN led to a significant reduction of the proliferative response of autoreactive T lymphocytes with a concomitant decrease of the proinflammatory response and an increase of anti-inflammatory cytokines, such as IL-10, TGFβ and BDNF. Adoptive transfer of neuritogenic T lymphocytes cultured in the presence of G-CSF resulted in a less severe disease than that found in the control group. These results may be explained by the increase of Foxp3 expression in CD4+ and CD8+ T lymphocytes following treatment. Moreover, the increased expression of BDNF suggests that G-CSF acts simultaneously as an anti-inflammatory and a neuroprotective agent in EAN. Conclusion: Our data suggest that G-CSF acts simultaneously as an anti-inflammatory and a neuroprotective cytokine in the EAN model.
CNS Neuroscience & Therapeutics 05/2013; · 4.44 Impact Factor
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Alessandro S Farias,
Gabriela S Spagnol,
Pedro Bordeaux-Rego,
Camila O F Oliveira,
Ana Gabriela M Fontana,
Rosemeire F O de Paula,
Mariana P A Santos,
Fernando Pradella,
Adriel S Moraes,
Elaine C Oliveira,
Ana Leda F Longhini,
Alexandre C S Rezende,
Mauro W Vaisberg, Leonilda M B Santos
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ABSTRACT: A growing body of evidence supports the hypothesis that vitamin D is an important environmental factor in the etiology of T-cell-mediated autoimmune diseases such as multiple sclerosis (MS).
The purpose of this study was exploring the mechanisms underlying the beneficial effect of vitamin D3 in encephalomyelitis (EAE).
We treated monophasic experimental autoimmune EAE, induced in Lewis rat, with vitamin D3 and adoptively transfer tolerogenic bone marrow-derived DCs generated in the presence of vitamin D3.
This study provides evidence that the in vivo administration of vitamin D3, as well as the adoptive transfer of vitamin D3 -induced IDO(+) immature/tolerogenic dendritic cells, leads to a significant increase in the percentage of CD4(+) CD25(+) Foxp3(+) regulatory T cells in the lymph nodes in a rat model of MS, experimental autoimmune EAE. Concomitant with the increase in this cell population, there is a significant decrease in the number of autoreactive T cells in the central nervous system. Bone marrow-derived DCs cultivated in the presence of vitamin D3 present a tolerogenic profile with high IL-10, TNFα, and IDO expression and decreased MHC-II and CD80 expression. The adoptive transfer of IDO (+) DCs induces a significant increase in the percentage of CD4(+) CD25(+) Foxp3(+) T cells in the lymph nodes, comparable with vitamin D3 treatment.
These mechanisms contribute actively to the generation of a microenvironment in the lymph nodes that suppresses the activation of encephalitogenic T cells, resulting in the downregulation of the inflammatory response in the central nervous system.
CNS Neuroscience & Therapeutics 04/2013; 19(4):269-77. · 4.44 Impact Factor
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ABSTRACT: The induction of autoimmune encephalomyelitis (EAE) in Lewis rats results in a period of exacerbation followed by complete recovery. Therefore, this model is widely used for studying the evolution of multiple sclerosis. In the present investigation, differentially expressed proteins in the spinal cord of Lewis rats during the evolution of EAE were assessed using the combination of 2DE and MALDI-TOF MS. The majority of the differentially expressed proteins were identified during the acute phase of EAE, in relation to naïve control animals. On the other hand, recovered rats presented a similar protein expression pattern in comparison with the naïve ones. This observation can be explained, at least in part, by the intense catabolism existent in acute phase due to nervous tissue damage. In recovered rats, we have described the upregulation of proteins that are apparently involved in the recovery of damaged tissue, such as light and medium neurofilaments, glial fibrillary acidic protein, tubulins subunits, and quaking protein. These proteins are involved mainly in cell growth, myelination, and remyelination as well as in astrocyte and oligodendrocyte maturation. The present study has demonstrated that the inflammatory response, characterized by an increase of the proliferative response and infiltration of autoreactive T lymphocytes in the central nervous system, occurs simultaneously with neurodegeneration.
Proteomics 06/2012; 12(17):2656-62. · 4.43 Impact Factor
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ABSTRACT: The pathological hallmarks of multiple sclerosis (MS) lesions are inflammation, demyelination, axon loss and gliosis. The aim of this study was to verify the relation of brain lesion load and volume of the cerebral hemisphere determined by brain MRI with intrathecal antibody synthesis.
A longitudinal study of 54 Brazilian patients with the relapsing-remitting form of MS was undertaken after an average of 6.3 ± 2.7 years of treatment. MRI scans were performed, and cerebrospinal fluid samples were collected both during the diagnostic process and after treatment with β-interferon or glatiramer acetate.
A positive correlation between the IgG index and total lesion volume was identified. Intrathecal IgG against Epstein-Barr virus (EBV) was observed in 21 patients. The number of contrast-enhanced lesions observed in these patients was correlated with intrathecal IgM synthesis. Brain atrophy was observed early in the disease, with the number of relapses inversely correlated with brain volume.
The high intrathecal IgG synthesis observed in these relapsing-remitting MS patients is associated with the brain lesion burden and the presence of antibodies to EBV, whereas intrathecal IgM synthesis is associated with the activity of the disease, as revealed by MRI.
NeuroImmunoModulation 03/2012; 19(5):277-82. · 2.38 Impact Factor
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Felipe von Glehn,
Sven Jarius,
Augusto C Penalva de Oliveira,
Carlos Otávio Brandão,
Alessandro S Farias,
Alfredo Damasceno,
Jorge Casseb,
Adriel S Moraes,
Ana Leda F Longhini,
Klaus-Peter Wandinger,
Benito P Damasceno,
Brigitte Wildemann, Leonilda M B Santos
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ABSTRACT: The seroprevalence of human T-cell leukemia virus type 1 (HTLV-1) is very high among Brazilians (1:200). HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP) is the most common neurological complication of HTLV-1 infection. HAM/TSP can present with an acute/subacute form of longitudinally extensive myelitis, which can be confused with lesions seen in aquaporin-4 antibody (AQP4-Ab) positive neuromyelitis optica spectrum disorders (NMOSD) on MRI. Moreover, clinical attacks in patients with NMOSD have been shown to be preceded by viral infections in around 30% of cases.
To evaluate the frequency of AQP4-Ab in patients with HAM/TSP. To evaluate the frequency of HTLV-1 infection in patients with NMOSD.
23 Brazilian patients with HAM/TSP, 20 asymptomatic HTLV-1+ serostatus patients, and 34 with NMOSD were tested for AQP4-Ab using a standardized recombinant cell based assay. In addition, all patients were tested for HTLV-1 by ELISA and Western blotting.
20/34 NMOSD patients were positive for AQP4-Ab but none of the HAM/TSP patients and none of the asymptomatic HTLV-1 infected individuals. Conversely, all AQP4-Ab-positive NMOSD patients were negative for HTLV-1 antibodies. One patient with HAM/TSP developed optic neuritis in addition to subacute LETM; this patient was AQP4-Ab negative as well. Patients were found to be predominantly female and of African descent both in the NMOSD and in the HAM/TSP group; Osame scale and expanded disability status scale scores did not differ significantly between the two groups.
Our results argue both against a role of antibodies to AQP4 in the pathogenesis of HAM/TSP and against an association between HTLV-1 infection and the development of AQP4-Ab. Moreover, the absence of HTLV-1 in all patients with NMOSD suggests that HTLV-1 is not a common trigger of acute attacks in patients with AQP4-Ab positive NMOSD in populations with high HTLV-1 seroprevalence.
PLoS ONE 01/2012; 7(7):e39372. · 4.09 Impact Factor
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ABSTRACT: Exposure to silica dust has been examined as a possible risk factor for autoimmune diseases, including scleroderma, rheumatoid arthritis and systemic lupus erythematosus. Since CTLA-4 [CD152] and PD-1 [CD279] are important for the maintenance of peripheral tolerance by regulating T cell responsiveness, we evaluated the expression of these molecules on the surface of CD4 and CD8 T cells, as well as single nucleotide polymorphisms (SNP) in CTLA-4 and PDCD1 genes, of 70 silica-exposed workers and 30 non-exposed, age-, ethnically- and sex-matched controls. Expression of CTLA-4 was significantly (P<0.05) reduced in CD4 T cells of exposed individuals [median=0.1% and interquartile range, IQR 0.0-0.1% (exposed), median=0.20%, IQR 0.0-0.4% (control)]. Also the expression of PD-1 was significantly (P<0.0001) reduced in both CD4 [median=0.9%, IQR 0.4-2.3% (exposed), median=5.7%, IQR 1.4-13.3% (control)] and CD8 T cells [median=0.9%, IQR 0.3-1.9% (exposed), median=5.0%, IQR 3.4-8.9% (control)]. The study of polymorphisms demonstrated a lower frequency of the A allele in the analysis of the PD1.3 SNP in the exposed group, which might be associated with the lower expression of PD-1 on the surface of CD4 T cells. Our findings provide evidence for the association of silica exposure and the maintenance of self-tolerance, i.e., the susceptibility to autoimmune disorders.
International journal of hygiene and environmental health 12/2011; 215(6):562-9. · 2.64 Impact Factor
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Ana Carolina P Grecco,
Rosemeire F O Paula,
Erica Mizutani,
Juliana C Sartorelli,
Ana M Milani,
Ana Leda F Longhini,
Elaine C Oliveira,
Fernando Pradella,
Vania D R Silva,
Adriel S Moraes,
Alfredo C Peterlevitz,
Alessandro S Farias,
Helder J Ceragioli, Leonilda M B Santos,
Vitor Baranauskas
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ABSTRACT: Our data demonstrate that multi-walled carbon nanotubes (MWCNTs) are internalized by macrophages, subsequently activating them to produce interleukin (IL)-12 (IL-12). This cytokine induced the proliferative response of T lymphocytes to a nonspecific mitogen and to ovalbumin (OVA). This increase in the proliferative response was accompanied by an increase in the expression of pro-inflammatory cytokines, such as interferon-gamma (IFNγ), tumor necrosis factor-alpha (TNFα) and IL-6, in mice inoculated with MWCNTs, whether or not they had been immunized with OVA. A decrease in the expression of transforming growth factor-beta (TGFβ) was observed in the mice treated with MWCNTs, whereas the suppression of the expression of both TGFβ and IL-10 was observed in mice that had been both treated and immunized. The activation of the T lymphocyte response by the pro-inflammatory cytokines leads to an increase in antibody production to OVA, suggesting the important immunostimulatory effect of carbon nanotubes.
Nanotechnology 05/2011; 22(26):265103. · 3.98 Impact Factor
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ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is used as an animal model for human multiple sclerosis (MS), which is an inflammatory demyelinating autoimmune disease of the central nervous system characterized by activation of Th1 and/or Th17 cells. Human autoimmune diseases can be either exacerbated or suppressed by infectious agents. Recent studies have shown that regulatory T cells play a crucial role in the escape mechanism of Plasmodium spp. both in humans and in experimental models. These cells suppress the Th1 response against the parasite and prevent its elimination. Regulatory T cells have been largely associated with protection or amelioration in several autoimmune diseases, mainly by their capacity to suppress proinflammatory response.
In this study, we verified that CD4(+)CD25(+) regulatory T cells (T regs) generated during malaria infection (6 days after EAE induction) interfere with the evolution of EAE. We observed a positive correlation between the reduction of EAE clinical symptoms and an increase of parasitemia levels. Suppression of the disease was also accompanied by a decrease in the expression of IL-17 and IFN-γ and increases in the expression of IL-10 and TGF-β1 relative to EAE control mice. The adoptive transfer of CD4(+)CD25(+) cells from P. chabaudi-infected mice reduced the clinical evolution of EAE, confirming the role of these T regs.
These data corroborate previous findings showing that infections interfere with the prevalence and evolution of autoimmune diseases by inducing regulatory T cells, which regulate EAE in an apparently non-specific manner.
PLoS ONE 01/2011; 6(3):e17849. · 4.09 Impact Factor
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Ana Leda F Longhini,
Felipe von Glehn,
Carlos Otávio Brandão,
Rosemeire F O de Paula,
Fernando Pradella,
Adriel S Moraes,
Alessandro S Farias,
Elaine C Oliveira,
Juan G Quispe-Cabanillas,
Cassiana Horta Abreu,
Alfredo Damasceno,
Benito P Damasceno,
Konstantin E Balashov, Leonilda M B Santos
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ABSTRACT: The plasmacytoid dendritic cells (pDCs) express a high level of Toll-like receptor 9 (TLR-9), which recognizes viral DNA. Activated via TLR-9, pDCs also secrete large amounts of type I interferon which are involved either in stimulation or down regulation of immune response in multiple sclerosis (MS). In the present study, we determinate pDCs levels by flow cytometry in Cerebrospinal Fluid (CSF) and Peripheral Blood from MS patients in relapsing and in remitting phases of the disease, comparing with other non-inflammatory diseases (OND). We provide evidence that MS patients in relapse without any treatment have a significantly (p < 0.01) higher percentage of pDCs in CSF than do patients in remission or those with OND. No change in the percentage of pDCs was observed in the peripheral blood of any of these patients. The increase of pDCs in central nervous system during relapse may be explained either by a virus infection or a down regulatory process.
Journal of Neuroinflammation 01/2011; 8(1):2. · 3.83 Impact Factor
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ABSTRACT: Inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) are pleiotropic molecules with widespread action in autoimmune diseases.
This study characterizes the distribution of iNOS and TNF-alpha in the spinal nerve roots, dorsal root ganglia and sciatic nerve of Lewis rats during experimental autoimmune neuritis (EAN).
Macrophages and neutrophils were identified by immunofluorescence as cellular sources of iNOS and TNF-alpha at various stages of EAN induced by synthetic peptide 26.
As the disease progressed, iNOS- and TNF-alpha-bearing cells gradually infiltrated the cauda equina, dorsal root ganglia, Th12-L3 spinal roots, and the sciatic nerve. A severer EAN profile developed when more iNOS- and TNF-alpha-bearing cells were present, and the recovery from EAN was related to the disappearance of these cells and the regeneration of nerve fibers.
This is the first report to show iNOS- and TNF-alpha-immunoreactive cells in dorsal root ganglia during EAN, suggesting an underlying pathology for the neuropathic pain behavior in EAN. Our results suggest that the cells bearing iNOS and TNF-alpha in the different parts of the peripheral nervous system are involved in the development of the clinical signs observed at each stage of EAN.
NeuroImmunoModulation 10/2009; 17(1):56-66. · 2.38 Impact Factor
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ABSTRACT: Immunotherapy with Interferon-beta (IFNbeta) results in remarkably beneficial effects in patients with relapsing-remitting multiple sclerosis (MS), although the mechanisms by which it exerts these beneficial effects remain poorly understood. An investigation was made of the effects of IFNbeta on pro-inflammatory and anti-inflammatory cytokine production in peripheral blood cells in MS patients, both untreated and those undergoing immunotherapy, as well as in healthy controls. Results show a significant increase in the production of pro-inflammatory cytokines such as TNFalpha, IFNgamma and IL-12 in the plasma and in the supernatant of leukocyte cultures from MS patients with the untreated disease; IFNbeta administration significantly reduced the levels of TNFalpha and IFNgamma, with no changes in the level of IL-12. The Interferon-beta therapy also led to a significant increase in the production of IL-10, as well as a slight increase in that of TGFbeta. The reduction in pro-inflammatory cytokine production in the treated MS patient group, accompanied by a simultaneous increase in the production of anti-inflammatory cytokines and the reduction of relapse rates suggests that the beneficial effects of IFNbeta immunotherapy result, at least in part, from the modulation of cytokine patterns.
International immunopharmacology 04/2009; 9(7-8):824-30. · 2.21 Impact Factor
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Elaine C Oliveira,
Márcia M Fujisawa,
Dannie E M Hallal Longo,
Alessandro S Farias,
Juliana Contin Moraes,
Maria Elena Guariento,
Eros Antônio de Almeida,
Mario José A Saad,
Francesco Langone,
Marcos H Toyama,
Nelson A Andreollo, Leonilda M B Santos
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ABSTRACT: Most reports of autoimmune response during infection with the parasite Trypanosoma cruzi have dealt with the cardiomyopathic form of Chagas' disease, but little is known about the mechanisms of tissue damage involved in the gastrointestinal form, which was studied here. Chronically infected patients with a severe gastrointestinal form of Chagas' disease present increased antibody production and proliferative responses to peripheral myelin components, such as myelin basic protein (MBP), which is homologous to the P1 protein fraction of peripheral myelin. T lymphocytes preferentially recognize a region on the MBP molecule (1-30), which suggests that the MBP is a potential target on the peripheral nerve for autoimmune reactions in patients with gastrointestinal lesions resulting from Chagas' disease.
NeuroImmunoModulation 01/2009; 16(1):54-62. · 2.38 Impact Factor
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Yara C Blanco,
Alessandro S Farias,
Uta Goelnitz,
Stefanie C P Lopes,
Wagner W Arrais-Silva,
Bruna O Carvalho,
Rogério Amino,
Gerhard Wunderlich, Leonilda M B Santos,
Selma Giorgio,
Fabio T M Costa
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ABSTRACT: Cerebral malaria (CM) is a syndrome characterized by neurological signs, seizures and coma. Despite the fact that CM presents similarities with cerebral stroke, few studies have focused on new supportive therapies for the disease. Hyperbaric oxygen (HBO) therapy has been successfully used in patients with numerous brain disorders such as stroke, migraine and atherosclerosis.
C57BL/6 mice infected with Plasmodium berghei ANKA (PbA) were exposed to daily doses of HBO (100% O(2), 3.0 ATA, 1-2 h per day) in conditions well-tolerated by humans and animals, before or after parasite establishment. Cumulative survival analyses demonstrated that HBO therapy protected 50% of PbA-infected mice and delayed CM-specific neurological signs when administrated after patent parasitemia. Pressurized oxygen therapy reduced peripheral parasitemia, expression of TNF-alpha, IFN-gamma and IL-10 mRNA levels and percentage of gammadelta and alphabeta CD4(+) and CD8(+) T lymphocytes sequestered in mice brains, thus resulting in a reduction of blood-brain barrier (BBB) dysfunction and hypothermia.
The data presented here is the first indication that HBO treatment could be used as supportive therapy, perhaps in association with neuroprotective drugs, to prevent CM clinical outcomes, including death.
PLoS ONE 02/2008; 3(9):e3126. · 4.09 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory disease of the white matter of the central nervous system (CNS) characterized by focal areas of demyelination. Interferon-beta (IFN-beta) provides an effective treatment that lessens the frequency and severity of exacerbations in relapsing-remitting multiple sclerosis (RRMS), but the mechanisms by which IFN-beta is efficient remain uncertain. The data presented here demonstrate that IFN-beta impairs the proliferative response to myelin basic protein (MBP) and myelin, as well as increasing the expression of the CTLA4 intracellular molecule. Moreover, this treatment increases the expression of surface Fas molecules and of the soluble form of these molecules. Our hypothesis is that the increase in Fas and CTLA4 molecules in MS patients may lead to lymphocyte apoptosis, which suggests possible mechanisms underlying the therapeutic response to IFN-beta.
Journal of Interferon & Cytokine Research 11/2007; 27(10):865-73. · 3.06 Impact Factor
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ABSTRACT: Biomedical research in which venom components are being investigated for their potential as novel therapeutic agents has emerged as an interesting option. Crotapotin, which is purified from the venom of the rattlesnake Crotalus durissus terrificus, has been described as an anti-inflammatory agent that acts on the innate arm of the immune response. Here we have demonstrated that intraperitoneal administration of crotapotin significantly reduces the severity of experimental autoimmune neuritis (EAN), an experimental model for Guillain-Barré syndrome. The reduction of the severity of the disease is associated with a reduction in the mononuclear cells infiltrating the sciatic nerve and a significant decrease in the lymphocyte proliferative response to neuritogenic peptide.
Toxicon 04/2007; 49(3):299-305. · 2.51 Impact Factor
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ABSTRACT: The involvement of inducible nitric oxide synthase (iNOS), which plays various roles in the progression of autoimmune diseases, was studied in iNOS knockout (KO) mice and wild-type (WT) controls with respect to experimental autoimmune encephalomyelitis (EAE). The iNOS (KO) mice presented a less severe form of the disease than the WT control mice. Although the levels of TNFalpha decreased in the periphery in both groups, an increase in the number of TNFalpha-positive cells was detected in the central nervous system during the acute phase of EAE in the WT mice, but not in the KO mice. These findings suggest that NO and TNFalpha contribute to the pathogenesis of acute EAE.
NeuroImmunoModulation 02/2007; 14(1):32-8. · 2.38 Impact Factor
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ABSTRACT: It was the aim of this study to evaluate if the quantitative intrathecal immunoglobulin G (IgG) synthesis correlates with the brain atrophy and the total lesion volume (TLV) in brain magnetic resonance imaging (MRI) of multiple sclerosis (MS) patients.
A total of 50 patients with relapsing-remitting MS were included in this study. MRIs were performed and cerebrospinal fluid samples were collected during the diagnostic determination when patients were in remission without treatment.
At study baseline, IgG index values were elevated in 36 patients (72%), and oligoclonal IgG bands were positive in 42 of 50 patients (84%). Brain MRI was abnormal in 94% of patients, and, compared with healthy controls, brain atrophy was observed in MS patients. A positive correlation among IgG index, cerebrospinal fluid leukocyte count and TLV was observed; the Expanded Disability Status Scale correlated positively with TLV and the number of lesions, although a significant relationship between disability and brain atrophy was not demonstrated.
Although new parameters will be necessary in longitudinal studies to characterize the axonal injury in various stages of the disease, the data suggest that the high intrathecal IgG synthesis may predict a greater brain lesion burden.
NeuroImmunoModulation 02/2006; 13(2):89-95. · 2.38 Impact Factor
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ABSTRACT: The aim of the present study was to determine the immune response profile that differentiates patients with newly diagnosed (non-treated) pulmonary tuberculosis from multidrug-resistant (MDR) ones, as well as from healthy, tuberculin positive individuals.
Lymphocytes proliferative response to non-specific mitogen (PHA) and PPD were evaluated by 3H thymidine incorporation and cytokines were quantified using an ELISA assay.
Patients with active disease showed a diminished proliferative response to PHA and PPD, while multidrug-resistant patients showed a diminished proliferative response to PHA, but a normal response to PPD. The cytokine production of newly diagnosed patients was characterized by a diminished production of IFNgamma and normal production of transforming growth factor (TGFbeta), while MDR patients revealed a normal production of IFNgamma accompanied by an increase in TGFbeta.
The production of significant amounts of TGFbeta in MDR patients leads to a poor immune response and may contribute to the resistance of tuberculosis patients to drugs.
The Journal of infection 12/2005; 51(4):318-24. · 4.13 Impact Factor
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ABSTRACT: The immunosuppressive property has been demonstrated for the venom of the Crotalus durissus terrificus. Using a simple, novel method for obtaining crotapotin and phospholipase A2 isoforms from venom, it was possible to demonstrate that the addition of crotapotin to cultures of isolated lymphocytes resulted in a significant inhibition of the cellular proliferative response to Concanavalin A. This reduction in blastogenic response of lymphocytes is accompanied by a significant increase in the production of PGE2 by macrophages. This effect on the innate immune response suggests that this compound may modify the subsequent adaptative immune response.
Toxicon 10/2003; 42(4):433-7. · 2.51 Impact Factor
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ABSTRACT: Interferon-beta (IFN-beta) is of benefit in the treatment of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), but the mechanisms by which it exerts this beneficial effect remain uncertain. The present data demonstrate that IFN-beta therapy impairs the proliferative response to concanavalin A (ConA) and myelin basic protein (MBP), decreases expression of the CD80 molecule on leukocytes of treated mice, and may thereby impede the Th1 cell activation-promoting anergy in EAE. Moreover, IFN-beta therapy increases expression of the CTLA4 molecule, which induces a counterregulatory Th2 response. The reduction of CD80 expression with concomitant increase of CTLA4 expression alters the course of EAE and may be useful as a monitor in therapy with IFN-beta.
Journal of Interferon & Cytokine Research 07/2003; 23(6):293-8. · 3.06 Impact Factor
