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Results for “Neuritis, Autoimmune, Experimental”

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At least 19 recordsLinked to original sources

PubMed2002

CD4 and CD8 T cells, but not B cells, are critical to the control of murine experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is a T cell-mediated autoimmune disease of the peripheral nervous system that duplicates the clinical, pathological, and electrophysiological features of Guillain-Barré syndrome in humans. However, the molecular pathogenesis of EAN remains controversial. Therefore, for this study, we induced EAN with P0 protein peptide 180-199 in CD4(-/-), CD8(-/-), CD4(-)8(-), and B cell knockout (microMT) mice to further investigate the roles of these cells in EAN. Our results showed that the severity of clinical signs and histopathological manifestations of EAN and the T cell response to P0 peptide 180-199 in CD4(-/-) mice were significantly lower than those in their wild-type counterparts. CD8(-/-) mice also had a milder clinical course, less histopathological change, and a diminished T cell response to P0 peptide 180-199. However, more severe clinical and histopathological manifestations, a stronger T cell response to P0 peptide 180-199, and enhanced IFN-gamma production in the spleen were observed in the EAN of CD4(-)8(-) and microMT mice, but these were not obviously different from those of wild-type mice. Levels of IgG production were similar in sera from CD4(-/-), CD8(-/-), and CD4(-)8(-), and wild-type mice. These findings suggest that the induction and control of murine EAN are dependent on both CD4(+) and CD8(+) T cells and that B cells apparently do not perpetuate the related inflammatory demyelination.

Animals↗

PubMed1998

Treatment with P2 protein peptide 57-81 by nasal route is effective in Lewis rat experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is a CD4+ T cell-mediated autoimmune disorder of the peripheral nervous system (PNS) that can be actively induced in susceptible animal species and strains by active immunization with PNS myelin + Freund's complete adjuvant (FCA). EAN represents an animal model for studying the immunopathogenesis and treatment of Guillain-Barré syndrome (GBS), which is a major inflammatory demyelinating disease of the PNS in humans. Here, we report that treatment by nasal administration of the neuritogenic peptide 57-81 of the PNS myelin component, P2 protein, dose-dependently suppressed EAN severity and shortened clinical EAN. Clinical EAN relapse induced by rechallenge with BPM + FCA was also prevented in EAN rats receiving high dose P2 peptide. P2 peptide induced suppression of EAN was associated with PNS antigen specific T cell hyporesponsiveness reflected by lymphocyte proliferation, numbers of PNS antigen-reactive IFN-gamma secreting and IFN-gamma mRNA expressing lymph node cells, but elevated levels of PNS antigen reactive TGF-beta mRNA secreting cells. Reduced CD4+ T cell and macrophage infiltrations within the PNS were also observed. Based on these observations, nasal autoantigen administration should be further evaluated, considering its possible future use in GBS.

Administration, Intranasal↗

PubMed1995

Administration of nitric oxide synthase inhibitors in experimental autoimmune neuritis and experimental autoimmune encephalomyelitis.

The nitric oxide (NO) synthase pathway is activated during experimental autoimmune inflammation of the central nervous system, and administration of aminoguanidine, an inhibitor of the cytokine-inducible NO synthase (NOS), ameliorated the disease course of autoimmune encephalomyelitis in the SJL mouse. We studied the role of nitric oxide synthase (NOS) in the pathogenesis of experimental autoimmune neuritis (EAN) and experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. NG-L-monomethyl-arginine (L-NMMA), a competitive inhibitor of NOS, partially suppressed T cell line-mediated EAN, but not myelin-induced EAN, myelin basic protein (MBP)-induced EAE, or T cell line-mediated EAE. Aminoguanidine (AG), a selective inhibitor of the cytokine-inducible NOS, enhanced MBP-induced EAE, but had no significant effects on myelin-induced EAN. Two other NOS inhibitors, nitro-arginine methyl-ester and N-nitro arginine, had only little or no effects in EAN and EAE. The administration of NOS inhibitors showed some striking effects in EAN and EAE, but the observed diversity of actions points to a much more complex role of the NO pathway than previously suggested.

Acetates↗

PubMed2000

Augmented expression of daintain/allograft inflammatory factor-1 is associated with clinical disease: dynamics of daintain/allograft inflammatory factor-1 expression in spleen, peripheral nerves and sera during experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome, characterized by inflammation and demyelination of the peripheral nervous system (PNS). Daintain/allograft inflammatory factor-1 (daintain/AIF-1) is a novel interferon-gamma-inducible protein expressed by macrophages during organ specific autoimmune diseases. To study the involvement of daintain/AIF-1 in EAN we induced EAN in Lewis rats by immunizing with bovine PNS myelin (BPM) and complete Freund's adjuvant (CFA). The expression of daintain/AIF-1 was examined in the spleen, peripheral nerves and sera during the course of EAN by immunohistochemistry and radioimunoassay (RIA). The expression of daintain/AIF-1 in the spleen and in the sciatic nerves peaked at the preclinical stage (day 7 post immunization (p.i.)) and at the height (day 15 p.i.) of clinical EAN, consistent with a disease promoting role for daintain/AIF-1. Daintain/AIF-1 expressing cells represented a subset of ED1+ or CD11b/c+ mononuclear cells. A significant increase of daintain/AIF-1-like immunoreactivity in sera occurred at the preclinical stage of EAN. Taken together, these data indicate that daintain/AIF-1 may play a proinflammatory role in the pathogenesis of EAN.

Animals↗

PubMed1998

Matrix metalloproteinase expression during experimental autoimmune neuritis.

Experimental autoimmune neuritis (EAN) is an animal model of Guillain-Barré syndrome. We have shown recently that BB-1101, a broad-spectrum matrix metalloproteinase (MMP) inhibitor, prevents development of EAN when given from the day of immunization and, more important clinically, reduces disease severity when given from symptom onset. This suggests the involvement of MMP activity in the pathogenesis of EAN. However, the exact function and expression patterns of MMPs in acute inflammation of the PNS have not been investigated. MMP-like enzymes are also involved in the processing of tumour necrosis factor-alpha (TNF-alpha), which has been implicated previously in the pathology associated with EAN. In the present study we investigated the profile of MMP and TNF-alpha expression and their localization in sciatic nerve tissue during EAN, using a semiquantitative competitive reverse transcriptase-coupled polymerase chain reaction and immunohistochemistry. In the normal rat PNS, four of the 10 MMPs studied were constitutively expressed and four MMPs were differentially regulated during EAN. Expression of TNF-alpha was elevated at peak disease severity and localized to Schwann cells, macrophages and endoneurial blood vessels. Expression levels of 92 kDa gelatinase and stromelysin-1 were significantly increased early in the development of EAN and continued to rise, peaking at day 15 coincident with maximum disease severity. Schwann cells and endothelial cells were the main cellular source of these enzymes. Prominent infiltration of inflammatory cells into the sciatic nerve was concordant with a significant increase in the expression levels of matrilysin and macrophage metalloelastase. Both matrilysin and macrophage metalloelastase were detected in invading macrophages, T lymphocytes and resident Schwann cells. The selective upregulation of specific MMPs during EAN and their varied cellular localization suggests that MMPs play a multifactorial role in the aetiology of EAN. Activity of MMPs could participate in the disruption of the blood-nerve barrier, breakdown of the myelin sheath, the release of TNF-alpha, and facilitate leukocyte invasion into the PNS. These observations highlight MMPs as potential targets for therapeutic intervention in acute peripheral neuropathies, such as Guillain-Barré syndrome.

Animals↗

PubMed1997

T-cell receptor V beta-element expression in peripheral nerves of Lewis rats suffering from experimental autoimmune neuritis.

In experimental autoimmune neuritis (EAN), peripheral nerves are infiltrated by T-lymphocytes and macrophages. By RT-PCR and sequence analysis we characterized TCR V beta-element usage in sciatic nerve tissue of Lewis rats suffering from EAN induced by immunization with peripheral myelin antigens. Several TCR V beta-chain sequences were detected, which did not show homology to sequences of P2-reactive T cells published so far. In EAN induced with peripheral nerve myelin, but not with P2-protein or P2 peptide aa 53-78, TCR V beta 8.2 sequences identical to sequences of encephalitogenic myelin basic protein (MBP) reactive T-cells were identified. These results provide further evidence for a contribution of MBP-directed T-cell reactivity to the pathogenesis of myelin induced EAN and may have implications for the pathogenesis of human demyelinating neuropathies.

Animals↗

PubMed1995

Soluble complement receptor type 1 inhibits experimental autoimmune neuritis in Lewis rats.

Experimental autoimmune neuritis (EAN) in Lewis rats induced by immunization with bovine peripheral nerve myelin in complete Freund's adjuvant is an animal model of the human Guillain-Barré syndrome. In this study myelin-induced EAN was treated with 30 mg/kg per day human soluble complement receptor type 1 (sCR1) beginning on day 8 post immunization (p.i.). Clinical signs of disease were markedly suppressed by application of sCR1 and none of eight treated animals but seven of nine control rats developed paraparesis. Electrophysiologic examination of sciatic nerve function 13 days p.i. revealed faster nerve conduction velocities and significantly higher compound muscle action potentials in sCR1-injected animals. In sections of sciatic nerves acquired 16 days p.i. extended demyelination and axonal degeneration was prevented by treatment with sCR1 in vivo. Our findings underscore the functional importance of complement during inflammatory demyelination in the peripheral nervous system and suggest sCR1 as a potential therapeutic approach in these diseases.

Animals↗

PubMed2001

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade enhances incidence and severity of experimental autoimmune neuritis in resistant mice.

Experimental autoimmune neuritis (EAN), an autoimmune inflammatory demyelinating disease of the peripheral nervous system, represents an animal model of the human Guillain-Barré syndrome. EAN can be induced by active immunization in several animals, including Lewis rats. In contrast, most strains of mice including the widely used C57BL/6 (B6) strain are reputedly resistant to the induction of EAN. In the present study, we demonstrate that in B6 mice, anti-CTLA-4 monoclonal antibody administration in conjunction with immunization with the P0 protein derived peptide 180-199 can induce clinical and pathological definite EAN. Upregulating effects of CTLA-4 blockade on initial and ongoing EAN are demonstrated. CTLA-4 blockade augmented cellular infiltration and enhanced demyelination in the target organ sciatic nerves as well as increased T cell proliferation in lymph node cells. Moreover, serum levels of IFN-gamma and IL-4 were increased. Thus, manipulation of CTLA-4/B7 costimulatory pathway by CTLA-4 blockade can promote autoreactivity and break the relative tolerance to peripheral autoantigen P0 in resistant B6 mice.

Abatacept↗

PubMed2003

Inflammation and proinflammatory cytokine production, but no demyelination of facial nerves, in experimental autoimmune neuritis in Lewis rats.

Experimental autoimmune neuritis (EAN) is a CD4(+) T cell-mediated, inflammatory demyelinating disease of the peripheral nervous system (PNS) that serves as a model for Guillain-Barré syndrome (GBS) in humans. The facial nerve paralysis is relatively commonly found in GBS patients. Here, EAN was established in Lewis rats by immunization with P2 peptide 57-81, a purified component of peripheral nerve myelin, and Freund's complete adjuvant (FCA). To study whether the facial nerves are involved in the pathogenic process during the EAN course, we observed the clinical and pathological changes as well as cytokine production in facial nerves on Day 14 postimmunization (p.i.), i.e. at height of clinical EAN. As a result, all rats immunized with P2 peptide 57-81 developed severe EAN on Day 14 p.i., but none of the rats manifested clinical signs of facial nerve paralysis. Additionally, only mild inflammatory cell infiltration and proinflammatory cytokine, interferon-gamma (IFN-gamma) and tumour necrosis factor (TNF-alpha) production as well as devoid demyelination were seen in facial nerves of the EAN rats. On the contrary, severe inflammation and demyelination as well as upregulated IFN-gamma and TNF-alpha production were observed in sciatic nerves of the same EAN rats. The underlying mechanism for the difference of the local manifestation of the disease process of EAN remains to be resolved.

Animals↗

PubMed1999

Antigen-specific immunosuppression: nasal tolerance to P0 protein peptides for the prevention and treatment of experimental autoimmune neuritis in Lewis rats.

Experimental autoimmune neuritis (EAN) is an autoimmune inflammatory demyelinating disease of the peripheral nervous system (PNS), and represents an animal model of the human Guillain-Barré syndrome (GBS). In this study, we report that nasal administration of the neuritogenic peptide 180-199 and of the cryptic peptide 56-71 of the rat neuritogenic P0 protein of peripheral nerve myelin prevents EAN and attenuates ongoing EAN. Both peptides effectively decreased the severity and shortened clinical EAN. Both a prophylactic and a therapeutic approach proved to be beneficial. These effects were associated with T and B cells hyporesponsiveness to the peptide antigens, reflected by downregulated Th1 cell responses (interferon-gamma secretion) and macrophage function, whereas Th2 cell responses (IL-4 secretion) and transforming growth factor-beta mRNA expression were upregulated.

Administration, Intranasal↗

PubMed1999

Dynamics of production of MIP-1alpha, MCP-1 and MIP-2 and potential role of neutralization of these chemokines in the regulation of immune responses during experimental autoimmune neuritis in Lewis rats.

Experimental autoimmune neuritis (EAN) is an inflammatory autoimmune demyelinating disease of the peripheral nervous system (PNS) and represents an animal model of Guillain-Barré syndrome (GBS), which is a major inflammatory demyelinating disease of the PNS in humans. In the present study, the dynamics of the expression of the chemokines macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-2 and monocyte chemotactic protein-1 (MCP-1) were determined in the sciatic nerves of EAN rats. Additionally, the effect of neutralizing antibodies against MIP-1alpha, MIP-2 and MCP-1 on the clinical course of EAN and the chemokine expression was investigated. The maximum of MIP-1alpha positive cells in the sciatic nerves was seen on day 14 post immunization (p.i.) correlating with the development of severe clinical signs. Administration of an anti-MIP-1alpha antibody suppressed the clinical signs of EAN and inhibited inflammation and demyelination in the sciatic nerve. Peak numbers of MCP-1 positive cells in the sciatic nerves were detected on day 7 p.i. Administration of an anti-MCP-1 antibody caused a delay of onset of EAN. However, 4 of the 6 EAN rats receiving the anti-MCP-antibody showed the same degree of inflammatory cell infiltration and demyelination in the sciatic nerves as sham-treated EAN rats, whereas only 2 EAN rats had less inflammation and demyelination. The numbers of MIP-2 positive cells reached a maximum on day 21 p.i. Anti-MIP-2 antibody failed to suppress the clinical signs of EAN and the inflammation and demyelination in the sciatic nerves. Only administration of the anti-MIP-1alpha antibody resulted in a significant reduction in the number of chemokine (MIP-1alpha)-positive cells and ED1-positive macrophages in the sciatic nerves. The present results demonstrate that MIP-1alpha and MCP-1 may play a role in the immunopathogenesis of EAN, and that MIP-1alpha induced trafficking of inflammatory cells can be inhibited by immunoneutralization. Further elucidation of the regulation and coordination of MIP-1alpha and MCP-1 production may lead to new therapeutic approaches to GBS in humans.

Animals↗

PubMed1998

Inhibition of experimental autoimmune neuritis by the immunomodulator linomide.

Experimental autoimmune neuritis (EAN) is an animal model that shares clinical, pathological and electrophysiological features with the human disease Guillain-Barre syndrome. The synthetic immunomodulatory substance linomide has been successfully used to prevent the development of several experimental autoimmune models in laboratory animals and has been proved to be beneficial in modulating the course of multiple sclerosis in humans. In the present study we demonstrate that oral administration of linomide prevents the development of clinical and histopathological signs of EAN in Lewis rats, inoculated with the P2 (60-70) synthetic peptide. The immunomodulatory effect of linomide on this experimental model of disease was associated with marked apoptosis of lymphocytes in thymus and spleen early after starting the treatment. Furthermore, a downregulation of the endothelial expression of the adhesion molecules ICAM-1 at the target site and LFA-1 on lymphocytes could also contribute to the absence of inflammatory cells in the neuraxis.

Adjuvants, Immunologic↗

PubMed1997

Failure of intravenous immunoglobulin (IVIg) therapy in experimental autoimmune neuritis (EAN) of the Lewis rat.

Experimental autoimmune neuritis (EAN) is an animal model for Guillain-Barré syndrome (GBS). Intravenous immunoglobulins (IVIg) are an effective treatment for GBS, but their mechanism of action is not well understood. Here we tested whether IVIg treatment, a potent modulator of proinflammatory assaults, reduces inflammation in EAN. The evaluation of IVIg treatment failed to demonstrate a salutary effect in different models of EAN. IVIg appears not to suppress the acute inflammatory insult on the peripheral nerve, but may have beneficial long-term effects not looked for in the present investigation.

Animals↗

PubMed1999

Heterogeneity of T-cell receptor usage in experimental autoimmune neuritis in the Lewis rat.

In experimental autoimmune neuritis (EAN), T-cell receptor (TCR) variable (V)-region gene usage by neuritogenic T cells has been reported to be clonally restricted at the RNA level. This study was designed to verify TCR usage by neuritogenic T cells at the protein level. We generated two monoclonal antibodies (mAbs) 7H4 and 8G8 specific for a Vbeta4/Valpha11 associated idiotype expressed by the majority of neuritogenic cells of P2-specific T-cell lines. The remaining neuritogenic P2-specific T cells either exhibited a dominant usage of the TCR Vbeta13 chain recognized by the recently generated mAbs 17D5 and 18B1 or showed diverse Vbeta usage. Treatment of adoptive-transfer (AT)-EAN or of EAN actively induced with the neuritogenic P2 peptide by mAbs 7H4 and 8G8 led to a partial, but significant, reduction of clinical disease. Treatment with Vbeta13-specific mAb 17D5 had no clear effect on active EAN. Our data show that at least three different TCR are used by P2-specific pathogenic T cells in EAN, an animal model for human inflammatory neuropathies.

Adoptive Transfer↗

PubMed1998

Matrix metalloproteinases MMP-9 and MMP-7 are expressed in experimental autoimmune neuritis and the Guillain-Barré syndrome.

Matrix metalloproteinases (MMPs) are a family of enzymes that may be implicated in the pathogenesis of inflammatory demyelinating disorders such as multiple sclerosis. The present study investigated the expression of 92-kd gelatinase (MMP-9) and five other MMPs in sciatic nerve from Lewis rats with autoimmune experimental neuritis (EAN), an experimental model of the Guillain-Barré syndrome (GBS). Quantitative polymerase chain reaction analysis revealed an up-regulation of MMP-9 mRNA with peak levels concurrent with maximal disease severity. Increased mRNA expression was associated with enhanced enzyme activity, as detected by gelatin zymography. Immunohistochemically, MMP-9 could be localized primarily around blood vessels within the epineurium and endoneurium in diseased but not normal sciatic nerve. Among all other MMPs investigated, mRNA levels of matrilysin (MMP-7) were found to be up-regulated at the peak of the disorder, remaining at high levels throughout the clinical recovery phase of the disease. To apply these findings to human disease, sural nerve biopsies from GBS patients were examined. By using immunohistochemistry, positive immunoreactivity against MMP-9 and MMP-7 was noted and corroborated by demonstrating augmented mRNA expression in comparison with noninflammatory neuropathies. Furthermore, increased MMP-9 activity was detected by zymography. These findings indicate that 92-kd gelatinase and matrilysin are selectively up-regulated during EAN and expressed in nerves of GBS patients and thus may contribute to the pathogenesis of inflammatory demyelination of the peripheral nervous system.

Animals↗

PubMed1999

Suppression of chronic experimental autoimmune neuritis by nasally administered recombinant rat interleukin-6.

Experimental autoimmune neuritis (EAN) is a CD4+ T-cell-mediated demyelinating disease of the peripheral nervous system (PNS) and serves as experimental model for human immune-demyelinating neurophathies, especially the Guillain-Barré syndrome. In this study, we examined the effect of recombinant rat interleukin-6 (rrIL-6) on chronic EAN in Lewis rats induced by immunization with P2 peptide 57-81 and Freund's complete adjuvant (FCA). Nasal administration of rat rIL-6 (1 microg/rat/day) beginning in the initial phase of EAN as a therapeutic agent, decreased the severity and the duration of clinical EAN. Low-grade inflammation and suppression of regional demyelination within the sciatic nerves were seen in rrIL-6-treated rats. Hyporesponsiveness of lymph node T cells, down-regulation of serum tumour necrosis factor-alpha (TNF-alpha) and increased levels of P2-specific immunoglobulin G1 (IgG1) antibodies document that nasal administration of rrIL-6 was effective systemically. However, because of the non-specific nature of the treatment and multiple effects of IL-6, more experience and great caution are needed, before nasal administration of IL-6 can be considered as a treatment of human autoimmune demyelinating neurophathies.

Administration, Intranasal↗

PubMed1990

Macrophages but not Schwann cells express Ia antigen in experimental autoimmune neuritis.

This study was designed to identify which cells express major histocompatibility complex class II (Ia) antigen in experimental autoimmune neuritis and may therefore be antigen presenters. Serial 1-micron-thick cryosections of ventral roots of animals with experimental autoimmune neuritis were labeled with Ox6 antibody against rat Ia, the ED1 antibody to identify monocytes/macrophages and an antiserum against S100, a marker for Schwann cells. Ia-positive cells were predominantly present before overt clinical signs and demyelination (day 12). At later stages when many axons were demyelinated, their number was markedly reduced. Few Ia-positive cells that had extending long processes, which over some distance were in immediate contact with several myelin sheaths, were scattered in normal-appearing nerve roots at these later time points. Most of the Ia-positive cells could be identified as ED1-positive lean monocytes/macrophages, but in contrast most phagocytic macrophages in advanced stages of myelin degradation no longer expressed Ia. Ia-positive structures were invariably negative for S100 at early and late stages of experimental autoimmune neuritis, indicating that Schwann cells did not express identifiable Ia antigen. These findings contrast with reports of expression of major histocompatibility complex class II antigens by Schwann cells in human neuropathies. Furthermore they do not support the notion that aberrant Ia expression by Schwann cells plays a major pathogenic role in experimental autoimmune disease of the peripheral nervous system.

Animals↗

PubMed1994

Regulation of experimental autoimmune neuritis by transforming growth factor-beta 1.

Experimental autoimmune neuritis (EAN) is a T-cell-mediated autoimmune disease characterized by demyelination and mononuclear cell infiltration of the peripheral nervous system. It is induced in Lewis rats by administration of myelin P2 protein or a synthetic peptide (SP-26) corresponding to amino acid residues 53-78 of bovine P2 protein. The effects of transforming growth factor-beta 1 (TGF-beta 1) on the clinical signs, histological changes, cell-mediated immune responses, and secretion of interferon-gamma (IFN-gamma) by lymphoid cells of rats with EAN were examined. Systemic administration of TGF-beta 1 markedly inhibited the clinical signs and histological changes of EAN when given intraperitoneally every other day for Days 0 through 18. In addition, it decreased proliferative responses and reduced the delayed-type hypersensitivity (DTH) response to SP-26 compared to control rats. The reduction in clinical severity correlated with skin test unresponsiveness (DTH) to the disease-inducing agent (SP-26) as well to decreased cellular responsiveness to the antigen in vitro. The decrease in cellular responsiveness extended to a decrease in at least one T cell lymphokine, IFN-gamma. The profound effect of TGF-beta on disease progression in EAN, a T-cell-mediated process, is consistent with a direct effect of this growth factor on T lymphocytes.

Amino Acid Sequence↗