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PubMed2000

Flow cytometric analysis of infiltrating cells in the peripheral nerves in experimental allergic neuritis.

Experimental autoimmune neuritis (EAN) is an animal model that shares clinical, pathological and electrophysiological features with the human disease Guillain-Barré syndrome (GBS). In this study, we isolated and characterized by fluorescent activated cell sorter (FACS) phenotype of the inflammatory cells infiltrating cauda equina (CE) of Lewis rats at the active stage of the disease. We found that at this stage of EAN macrophages (Mphi) and alphabeta T cells were two major populations isolated from CE. We also found that among total cell population isolated from CE, gammadelta T and NK cells composed two small but distinct populations, while B cells were negligible. We characterized phenotype of alphabeta T cells in CE as CD45RC(+)CD8(+) (activated cytotoxic lymphocytes) and CD45RC(-)CD4(+) (memory Th cells). The phenotype of gammadelta T cells was found to be consisted of only CD45RC(+)CD8(+) cells. Both alphabeta and gammadelta T cells in CE expressed a higher level of CD25, CD44 and CD54 activation markers compared to the other tissues. Immunohistochemistry demonstrated that gammadelta T cells existed apart from the intense cellular infiltrate. This is the first report on the isolation and FACS analysis of CE-infiltrating cells, contributing a new and alternative approach to study the inflammatory lesions in EAN. We conclude that both alphabeta and gammadelta T cells have a unique activation/inflammatory phenotype required to traffic through and be retained in the peripheral nerves during EAN.

Animals↗
PubMed2000

Sequential expression of chemokines in experimental autoimmune neuritis.

Recruitment of inflammatory cells is of critical importance in the pathogenesis of immune-mediated demyelinating diseases in the peripheral nervous system (PNS). Evidence is increasing that chemokines might play a key role in this process, since they promote leukocyte entry into the nervous system during immune-mediated inflammation. In the present study we report the expression pattern of the chemokines interferon-gamma-inducible protein (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and regulated upon activation normal T cell expressed and secreted (RANTES) in sciatic nerves from animals with myelin-induced experimental autoimmune neuritis, using a semiquantitative reverse transcriptase-PCR dot-blot hybridization assay. The mRNAs for MIP-1alpha and MIP-1beta were found to be upregulated with peak values at day 13 post-immunization (p.i.), preceding maximum disease severity. In contrast, mRNAs for MCP-1, RANTES, and IP-10 exhibited peak levels coincident with peak of the disease at day 15 p.i. Increased mRNA expression was associated with enhanced protein levels, as demonstrated by immunoblotting for each chemokine investigated. Immunohistochemistry for IP-10 protein revealed immunoreactivity associated with perineurial endothelial cells. RANTES protein was localized immunohistologically to invading T lymphocytes. Our findings suggest that chemokines, which act towards T cells and mononuclear phagocytes, are sequentially upregulated during the clinical course of EAN and thus may contribute to the pathogenesis of inflammatory demyelinating diseases of the PNS.

Animals↗
PubMed2000

Heme oxygenase-1 in lesions of rat experimental autoimmune encephalomyelitis and neuritis.

The enzyme heme oxygenase-1 (HO-1) is reducing heme to the gaseous mediator carbon monoxide, to iron and the antioxidant biliverdin. The inducible expression of HO-1 is considered a protective cellular mechanism against reactive oxygen intermediates. Further, carbon monoxide (CO) is a regulator of cGMP synthesis, of NO-synthetases and cyclooxygenases, thereby indirectly modulating reactive processes. Here we report expression of HO-1 in rat experimental autoimmune encephalomyelitis (EAE) and neuritis (EAN). With both models, similar results were obtained: HO-1 was localized predominantly to infiltrating, monocytic, but only rarely to ramified microglial cells or astrocytes surrounding the inflammatory lesions. Prominent expression by monocytic cells was seen from day 11 after immunization correlating with the development of neurologic disease. Further, local expression is persistent for long after cessation of neurologic signs. Thus, HO-1 could be considered a factor in the formation and resolution of inflammatory autoimmune lesions of the nervous system.

Animals↗
PubMed2001

CD28-B7 costimulation: a critical role for initiation and development of experimental autoimmune neuritis in C57BL/6 mice.

CD28 provides a critical costimulatory signal for antigen-specific T cell activation. Because CD28 is an important factor in the development of autoimmune diseases, we investigated its role in T cell-mediated experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome in humans. CD28-deficient mutant (CD28-/-) C57BL/6 mice and corresponding wild-type mice were immunized with P0 peptide 180-199, a purified component of peripheral nerve myelin, and Freund's complete adjuvant. As a result, all wild-type mice developed severe EAN, in contrast, none of the CD28-/- mice manifested clinical signs of disease. Additionally, CD28-/- mice had fewer IL-12 producing cells in sciatic nerve sections and fewer IFN-gamma secreting splenic cells than wild-type mice on day 24 post immunization, i.e., at the peak of clinical EAN. At that time point, CD28-/- mice had milder infiltration of such inflammatory cells as macrophages, CD4+ T cells and monocytes into sciatic nerve tissues and less demyelination than wild-type mice. Moreover, the CD28-deficiency led to reduced production of specific anti-P0 peptide 180-199 antibodies compared with wild-type mice. Evidently, CD28 is required for interaction with B7 to regulate the activation of T and B cells that initiates development of EAN.

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↗
PubMed2001

Oral tolerance in experimental autoimmune neuritis (EAN) of the Lewis rat. II. Adjuvant effects and bystander suppression in P2 peptide-induced EAN.

Experimental autoimmune neuritis (EAN) in Lewis rats serves as an animal model of human inflammatory demyelinating neuropathies. We previously demonstrated that EAN actively induced by immunization with bovine PNS-myelin can be suppressed by feeding of myelin. This myelin-specific oral tolerance (OT) was enhanced by coapplication of cholera toxin (CT).In the present study, EAN induced by immunization with a neuritogenic P2 peptide was completely prevented by precedent feeding of the peptide. Oral application of the P2 peptide mediated tolerance as efficient as did nasal administration. In contrast to OT by myelin, addition of CT completely prevented oral induction of tolerance to peptide-induced EAN, while adjuvant feeding alone did not modulate disease. As a possible immunological basis to explain the prevention of OT induction by CT, we identified a highly enhanced protein-specific in vitro proliferation of splenocytes from antigen/CT-fed animals compared to those of rats fed with the antigen only. The opposite effects of oral CT in combination with proteins versus myelin confirm our former assumption that CT augments myelin-induced tolerance by its binding to gangliosides present in the myelin but not in the P2 peptide solution, while free CT prevents the induction of OT. It is suggested that CT is a useful adjuvant for OT if coadministered with myelin, but requires chemical linkage to proteins to exert this function. Regulatory lymphocytes orally induced by feeding the protein keyhole limpet hemocyanine (KLH) slightly ameliorated peptide-induced EAN via bystander mechanisms, but injection of KLH in close proximity to the site of peptide-immunization was essential. The restriction of bystander suppression to that site in the lymphoid system where neuritogenic T cells are activated may limit the impact of OT as a bonafide treatment strategy in human autoimmune diseases and underscores the necessity to identify the autoantigens involved.

Administration, Intranasal↗
PubMed2001

Guillain-Barré syndrome serum and anti-Campylobacter antibody do not exacerbate experimental autoimmune neuritis.

To investigate whether antibodies are pathogenic in Guillain-Barré syndrome (GBS), we injected pre-treatment serum from 11 GBS patients intraperitoneally into rats in which the blood-nerve barrier had been opened by induction of mild adoptive transfer experimental autoimmune neuritis. There was no significant clinical, neurophysiological or pathological difference between rats receiving GBS serum compared with those receiving control serum, except that GBS serum caused minor excess weight loss. Murine monoclonal antibody to Campylobacter jejuni and gangliosides also did not exacerbate disease. This experiment failed to show antibody-mediated disease exacerbation and so does not support an antibody-mediated mechanism in GBS.

Animals↗
PubMed2002

Brain-derived neurotrophic factor in experimental autoimmune neuritis.

Long-term disability in Guillain-Barré syndrome (GBS) is associated with axonal, and some neuronal, degeneration. Brain-derived neurotrophic factor (BDNF) can prevent neuronal death following damage to motor axons and we have therefore examined the ability of BDNF to ameliorate the effects of experimental autoimmune neuritis (EAN), a model of GBS. Treatment of Lewis rats with BDNF (10 mg/kg/day) did not significantly affect the neurological deficit, nor significantly improve survival, motor function or motor innervation. The weight of the urinary bladder was significantly increased in control animals with EAN, but remained similar to normal in animals treated with BDNF. With the exception of a possibly protective effect indicated by bladder weight, this study suggests that BDNF may not provide an effective therapy for GBS, at least in the acute phase of the disease.

Animals↗
PubMed2002

Expression of constitutive endothelial and inducible nitric oxide synthase in the sciatic nerve of Lewis rats with experimental autoimmune neuritis.

This study examined the expression of constitutive endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) in the sciatic nerve of Lewis rats with experimental autoimmune neuritis (EAN). Western blot analysis showed that both eNOS and iNOS expressions in the sciatic nerves of rats increased significantly during the peak stage of EAN, but declined thereafter. Only minimal amounts of these enzymes were identified in normal rat sciatic nerves. Immunohistochemical studies showed that eNOS was increased in vascular endothelial cells and Schwann cells, but not in inflammatory cells, during the peak stage of EAN. However, iNOS was found mainly in inflammatory macrophages in sciatic nerve EAN lesions.These findings suggest that, depending on the stage of peripheral nervous system autoimmune disease, the increased expressions of both eNOS and iNOS might be involved in either the production of detrimental effects during the induction stage of EAN or in the recovery from EAN paralysis.

Animals↗
PubMed2002

Efficacy of leukemia inhibitory factor in experimental autoimmune neuritis.

Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that exerts neurotrophic and myotrophic actions. We have investigated the effect of LIF in experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome (GBS). Treatment with LIF at the onset of the disease showed a slight, but not significant, improvement in the clinical course but no effect on nerve histology.

Animals↗
PubMed2003

Monocyte chemoattractant protein 1 and chemokine receptor CCR2 productions in Guillain-Barré syndrome and experimental autoimmune neuritis.

Infiltration of activated lymphocytes and monocytes is a key phenomenon in the pathogenesis of Guillain-Barré syndrome (GBS) and experimental autoimmune neuritis (EAN). To investigate the role of chemokines, we determined the blood and nerve tissue expression of monocyte chemoattractant protein 1 (MCP-1), a major chemoattractant of monocytes and activated lymphocytes, and its receptor CCR2 in GBS and EAN. MCP-1 circulating levels (ng/ml) in GBS were increased at the time of progression, peaked at the time of plateau and normalized with recovery. MCP-1 circulating levels were the highest in the most disabled patients. The number of circulating CCR2 positive cells was lower in patients with GBS than in healthy subjects (p<0.004). In GBS, MCP-1 expression was observed in epineurial and endoneurial vessels, on infiltrating cells, Schwann cells and in the endoneurial extracellular matrix. Some CCR2 positive cells were observed in nerve biopsies of GBS patients. In EAN, a slight positivity for MCP-1 was observed in the sciatic nerve. There was no circulating CCR2 positive cells. However, at the time of plateau, a conspicuous infiltration of CCR2 positive cells was observed in the sciatic nerve that was no longer observed at the time of recovery. These results suggest that MCP-1 and CCR2 may participate to the recruitment of circulating mononuclear cells in nerve tissue in EAN and GBS.

Animals↗
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↗
PubMed2003

Treatment and prevention of experimental autoimmune neuritis with superagonistic CD28-specific monoclonal antibodies.

Two distinct CD28-specific mAb were used in treatment of active or adoptive transfer (AT)-experimental autoimmune neuritis (EAN): "superagonistic" JJ316 activates T cells without T cell receptor (TCR) occupancy, and conventional JJ319 activates T cells only in the presence of TCR-stimulation. Treatment with JJ316 during induction phase of active and adoptive-transfer experimental autoimmune encephalomyelitis (AT-EAN) dramatically reduced disease severity and improved nerve function as revealed by electrophysiology. JJ316 given 1 week before immunization had a preventive effect. By immunohistology, JJ316 markedly reduced TC infiltration of the sciatic nerve in active and AT-EAN. JJ319 was less effective. Ex vivo, JJ316 therapy reduced P2-specific proliferation and interferon-gamma (IFN-gamma) production of lymph node cells. We demonstrate preventive and therapeutic effects of a "superagonistic" mAb-mediated, TCR-independent CD28 stimulation in EAN, possibly with implications for therapy of autoimmune-inflammatory disorders.

Adoptive Transfer↗
PubMed1985

Experimental allergic neuritis induced in SJL mice by bovine P2.

Bovine myelin or bovine myelin-derived P2 protein was injected into 4 inbred mouse strains. SJL mice developed neurological deficit, and histological lesions characteristic of experimental allergic neuritis. BALB/C, CBA and C57.B1/6 mice were relatively resistant to disease induction by this method.

Animals↗
PubMed1996

The antibody repertoire in experimental allergic neuritis: evidence for PMP-22 as a novel neuritogen.

Experimental allergic neuritis (EAN) is an autoimmune disease that serves as an animal model for the Guillain-Barré syndrome (GBS). In both disorders there is still great uncertainty as to the significance and diversity of autoantibodies involved. We focused on the characterization of serum antibody production in response to various peripheral nervous system (PNS) myelin proteins during the course of actively induced EAN in Lewis rats. These data were compared with EAN induced by adoptive transfer of P2-specific CD4+ T cells (AT-EAN) and with inoculation with complete Freund's adjuvant (CFA) alone. Semiquantitative Western blotting was applied to measure serum IgM and IgG titers against specific myelin proteins, including P2, P0, myelin basic protein (MBP), myelin-associated glycoprotein (MAG) and PMP-22. Considerable differences in the dynamics of antibody titers against individual myelin proteins were observed in active EAN and after inoculation with CFA alone. Our data suggest a pathogenic role of IgM antibodies against HNK adhesion carbohydrate epitope expressing PNS proteins P0, MAG and PMP-22. Among these, PMP-22, a novel candidate neuritogen may be of particular relevance. Thus, we provide evidence for the involvement of antibody-mediated immune response in actively induced EAN and a basis for similar studies on related human disorders such as GBS or other demyelinating neuropathies.

Animals↗
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↗
PubMed1997

Linomide-induced suppression of experimental autoimmune neuritis is associated with down-regulated macrophage functions.

Experimental autoimmune neuritis (EAN) is a T-cell mediated autoimmune disease of the peripheral nervous system, in which macrophages and T-cells feature prominently in nerve lesions. EAN represents a counterpart to Guillain-Barré syndrome in humans. In the present study, we investigated the in vitro and in vivo effects of Linomide (LS-2616, quinoline-3-carboxamide), a synthetic immunomodulatory compound, on macrophages in relation to EAN. Linomide strongly suppressed IFN-gamma and lipopolysaccharide (LPS)-induced IL-1 beta, TNF-alpha and IL-6 mRNA expression in macrophages in vitro as demonstrated by in situ hybridisation. Linomide administered daily subcutaneously from the day of inoculation completely prevented the development of clinical symptoms of EAN. Linomide administered from day 9 post immunisation (p.i.) significantly suppressed clinical EAN. Macrophages from Linomide-treated EAN rats showed decreased IL-1 beta, TNF-alpha and IL-6 mRNA expression in response to IFN-gamma and LPS. LPS-induced nitric oxide production by macrophages was also suppressed by Linomide in vitro. Linomide, however, does not affect macrophage death and release of lactate dehydrogenase. We conclude that Linomide may exert its actions in EAN and perhaps also in other autoimmune disease models, by suppressing macrophage functions.

Adjuvants, Immunologic↗
PubMed1997

Experimental allergic neuritis: cytolysin mRNA expression is upregulated in lymph node cells during convalescence.

Experimental allergic neuritis (EAN) is a T cell mediated animal model of Guillain-Barré syndrome, characterized by inflammation and demyelination of the peripheral nervous system (PNS). To study the involvement of immunoregulatory cytokines, we induced EAN in Lewis rats by immunizing with bovine PNS myelin (BPM) and Freund's complete adjuvant. mRNA expression of the cytokines IL-1beta, IL-6, IL-10, IL-12, TNF-alpha and TNF-beta, and the cytolytic effector molecule cytolysin was examined in lymph node mononuclear cells (MNC) over the course of EAN by in situ hybridization after culture without antigen and in the presence of BPM, the myelin P2 protein, the control antigen acetylcholine receptor, or the mitogen PHA. Three patterns of cytokine mRNA expressing MNC in relation to clinical EAN could be distinguished: (i) IL-1beta mRNA expressing cells peaked already on day 3 post immunization (p.i.), and BPM- and P2-reactive TNF-alpha, and BPM-reactive IL-6 mRNA expressing cells were also detected already on day 7 p.i., i.e., before onset of clinical EAN; (ii) BPM- and P2-reactive TNF-alpha peaked together with P2-reactive TNF-beta, IL-6 and IL-12 mRNA expressing cells at height of clinical EAN, consistent with a disease-promoting role for these four cytokines; (iii) high levels of BPM- and P2-reactive IL-10 and cytolysin mRNA expressing cells were observed only during recovery (day 28 p.i.), consistent with a disease down-regulating role of IL-10 and cytolysin. The results suggest a major proinflammatory role for IL-1beta, TNF-alpha, TNF-beta, IL-6 and IL-12 and a disease down-regulating function of IL-10 as well as cytolysin in EAN.

Animals↗