myelin-basic-protein and Paralysis

Integrin alpha4beta1 plays an important role in inflammatory processes by regulating the migration of leukocytes into inflamed tissues. Previously, we identified BIO5192 [2(S)-{[1-(3,5-dichloro-benzenesulfonyl)-pyrrolidine-2(S)-carbonyl]-amino}-4-[4-methyl-2(S)-(methyl-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-pentanoylamino]-butyric acid], a highly selective and potent (K(D) of 9 pM) small molecule inhibitor of alpha4beta1. Although BIO5192 is efficacious in various animal models of inflammatory disease, high doses and daily treatment of the compound are needed to achieve a therapeutic effect because of its relatively short serum half-life. To address this issue, polyethylene glycol modification (PEGylation) was used as an approach to improve systemic exposure. BIO5192 was PEGylated by a targeted approach in which derivatizable amino groups were incorporated into the molecule. Two sites were identified that could be modified, and from these, five PEGylated compounds were synthesized and characterized. One compound, 2a-PEG (K(D) of 19 pM), was selected for in vivo studies. The pharmacokinetic and pharmacodynamic properties of 2a-PEG were dramatically improved relative to the unmodified compound. The PEGylated compound was efficacious in a rat model of experimental autoimmune encephalomyelitis at a 30-fold lower molar dose than the parent compound and required only a once-a-week dosing regimen compared with a daily treatment for BIO5192. Compound 2a-PEG was highly selective for alpha4beta1. These studies demonstrate the feasibility of PEGylation of alpha4beta1-targeted small molecules with retention of activity in vitro and in vivo. 2a-PEG, and related compounds, will be valuable reagents for assessing alpha4beta1 biology and may provide a new therapeutic approach to treatment of human inflammatory diseases.

Topics: Animals; Anti-Inflammatory Agents; Cell Adhesion; Drug Design; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Injections, Intravenous; Injections, Subcutaneous; Integrin alpha4beta1; Jurkat Cells; Luminescent Measurements; Lymphocyte Count; Myelin Basic Protein; Oligopeptides; Paralysis; Phenylurea Compounds; Polyethylene Glycols; Rats; Rats, Inbred Lew; Structure-Activity Relationship

Multiple sclerosis (MS) is thought to involve CD4 T cell recognition of self myelin, many studies focusing on a pathogenic role for anti-myelin, HLA-DR15-restricted T cells. In experimental allergic encephalomyelitis, it is known which epitopes trigger disease and that disease is associated with determinant spread of T cell reactivity. Characterization of these events in human MS is critical for the development of peptide immunotherapies, but it has been difficult to define the role of determinant spread or define which epitopes might be involved. In this study, we report humanized transgenic mice, strongly expressing HLA-DR15 with an MS-derived TCR; even on a RAG-2 wild-type background, mice spontaneously develop paralysis. Disease, involving demyelination and axonal degeneration, correlates with inter- and intramolecular spread of the T cell response to HLA-DR15-restricted epitopes of myelin basic protein, myelin oligodendrocyte glycoprotein, and alphaB-crystallin. Spread is reproducible and progressive, with two of the epitopes commonly described in responses of HLA-DR15 patients. The fact that this pattern is reiterated as a consequence of CNS tissue damage in mice demonstrates the value of the transgenic model in supplying an in vivo disease context for the human responses. This model, encompassing pathologically relevant, spontaneous disease with the presentation of myelin epitopes in the context of HLA-DR15, should offer new insights and predictions about T cell responses during MS as well as a more stringent test bed for immunotherapies.

Topics: Animals; Antigen Presentation; Cell Movement; Central Nervous System; Disease Models, Animal; Disease Progression; DNA-Binding Proteins; Epitopes, T-Lymphocyte; HLA-DR Antigens; HLA-DR Serological Subtypes; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Multiple Sclerosis; Myelin Basic Protein; Paralysis; Peptide Fragments; Receptors, Antigen, T-Cell, alpha-beta; T-Lymphocyte Subsets

Immunization with heat-shock protein (HSP) gp96 elicits protective immunity to the cancer or virus-infected cells from which it is derived. Low doses of gp96 generate immunity, while doses 10 times the immunizing dose do not. We show here that injection of high doses of gp96 generates CD4(+) T cells that down-regulate a variety of ongoing immune responses. Immunization with high doses of gp96 prevents myelin basic protein- or proteolipid protein-induced autoimmune encephalomyelitis in SJL mice and the onset of diabetes in non-obese diabetic mice. The suppression of immune response can be adoptively transferred with CD4(+) cells and does not partition with the CD25 phenotype. The immunomodulatory properties of gp96 (and possibly other HSP) may be used for antigen-specific activation or suppression of cellular immune responses. The latter may form the basis for novel immunotherapies for autoimmune diseases.

Topics: Adoptive Transfer; Animals; Antigens, Neoplasm; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Transplantation; Diabetes Mellitus, Type 1; Encephalomyelitis, Autoimmune, Experimental; Female; Fibrosarcoma; Glycosuria; Immune Tolerance; Immunohistochemistry; Immunologic Factors; Immunotherapy, Active; Insulin; Lipopolysaccharides; Lymphocyte Subsets; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Myelin Basic Protein; Myelin Proteolipid Protein; Pancreas; Paralysis; Peptide Fragments; Receptors, Interleukin-2; Spleen; Time Factors; Tumor Cells, Cultured; Vaccination

Lewis rats, on recovery from monophasic clinical experimental allergic encephalomyelitis (EAE), can be induced to develop repeated paralytic relapses with a graded reduction in clinical severity following intraperitoneal administration of IL-12. By the time of the third relapse, the number and size of inflammatory cuffs in the spinal cord were reduced with the makeup of the cellular infiltrate shifting to a significantly increased number of B cells. Serum levels of myelin basic protein (MBP)-specific IgG1 and IgG2b were found to rise over time while MBP and MBP peptide-positive macrophages and microglia became evident in perivascular cuffs and in spinal cord parenchyma, indicative of myelin phagocytosis. Axonal death was observed in semithin and EM sections of spinal cord in third relapse animals in association with iNOS and tPA immunostaining throughout gray and white matter. These neurotoxic or excitotoxic agents may contribute to axonal damage directly or indirectly by activated microglia and macrophages, leading to limited damage of the axonal-myelin unit.

Topics: Acute Disease; Animals; Autoantibodies; Axons; Encephalomyelitis, Autoimmune, Experimental; Female; Immunoglobulin G; Interleukin-12; Interleukins; Leukocyte Count; Macrophage Activation; Myelin Basic Protein; Myelin Sheath; Paralysis; Rats; Rats, Inbred Lew; Recurrence; Spinal Cord; Tissue Plasminogen Activator; Transforming Growth Factor beta; Transforming Growth Factor beta1

Experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), is useful for preclinical testing for agents to be considered for treatment for this human demyelinating disease. Microtubules in lymphocytes play an important role in the cascade of human T cell activation, and paclitaxel (PTX), a microtubule stabilizer, can inhibit T cell function. A new formulation of micellar PTX, free of Cremophor and ethanol, was tested for its effect on the induction of EAE in Lewis rats. Adoptive EAE was induced with an encephalitogenic T cell line activated with guinea pig myelin basic protein (GP MBP) peptide 68-88. PTX (10 mg/kg) was administered 24 and 72 h after cell transfer. The clinical signs, fulminating in controls, were completely blocked by PTX, but mild CNS inflammation remained unaltered. A similar dose of PTX, given on days 6 and 8 to animals developing active EAE after immunization with GP MBP peptide 68-88 in complete Freund's adjuvant, greatly reduced the severity of paralysis and delayed the onset of disease by 8-9 days. Marked weight loss and severe toxicity were noted with higher and more prolonged administration. In vitro micellar PTX inhibited activation of encephalitogenic T cells by both specific antigen and mitogen. Lower doses and longer treatment programs may provide effective treatment with acceptable adverse effects with this agent in the treatment of inflammatory demyelinating disease.

Topics: Amino Acid Sequence; Animals; Antigens; Chemistry, Pharmaceutical; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Female; Freund's Adjuvant; Guinea Pigs; Immunization, Passive; Inflammation; Lymphocyte Activation; Micelles; Molecular Sequence Data; Multiple Sclerosis; Myelin Basic Protein; Paclitaxel; Paralysis; Peptide Fragments; Rats; Rats, Inbred Lew; T-Lymphocytes; Weight Loss

The Golli-MBP transcription unit contains three Golli-specific exons as well as the seven exons of the classical myelin basic protein (MBP) gene and encodes alternatively spliced proteins that share amino acid sequence with MBP. Unlike MBP, which is a late Ag expressed only in the nervous system, Golli exon-containing gene products are expressed both pre- and postnatally at many sites, including lymphoid tissue, as well as in the central nervous system. To investigate whether Golli-MBP peptides unique to Golli would result in neurological disease, we immunized rats and observed a novel neurological disease characterized by mild paralysis and the presence of groups of lymphocytes in the subarachnoid space but not in the parenchyma of the brain. Disease was induced by Th1-type T cells that displayed an unusual activation phenotype. Primary stimulation in vitro induced T cell proliferation with increased surface CD45RC that did not become down-regulated as it did in other Ag-stimulated cultures. Secondary stimulation of this CD45RChigh population with Ag, however, did not induce proliferation or IL-2 production, although an IFN-gamma-producing population resulted. Proliferation could be induced by secondary stimulation with IL-2 or PMA-ionomycin, suggesting an anergic T cell population. Cells could adoptively transfer disease after secondary stimulation with IL-2, but not with Ag alone. These responses are suggestive of a chronically stimulated, anergic population that can be transiently activated to cause disease, fall back into an anergic state, and reactivated to cause disease again. Such a scenario may be important in chronic human disease.

Topics: Adoptive Transfer; Amino Acid Sequence; Animals; Antibody Formation; Clonal Anergy; Cytokines; Flow Cytometry; Injections, Intradermal; Myelin Basic Protein; Paralysis; Peptide Fragments; Rats; Rats, Inbred Lew; T-Lymphocytes; Tail

We have previously shown that interferon-tau (IFN-tau) pretreatment inhibits the development of both acute and chronic mouse experimental allergic encephalomyelitis (EAE), an animal model for the human demyelinating disease multiple sclerosis (MS). IFN-tau is a type I IFN that has pregnancy recognition hormone activity in ruminants. Here we show that IFN-tau induced remission in SJL/J mice that had ongoing chronic active EAE disease and protected mice against secondary relapses. IFN-tau treatment reversed lymphocyte infiltration and microglial activation in the central nervous system. Mice that were treated with IFN-tau had lower levels of anti-MBP antibodies than untreated mice in both chronic and acute forms of EAE. MBP induced proliferation in B cells from EAE mice, but treatment with IFN-tau either in vivo or in vitro blocked activation. Furthermore, IFN-tau inhibited MBP activation of T cells from EAE mice. Thus, IFN-tau inhibits the humoral arm as well as the cellular arm of the autoimmune disease EAE. The data presented here show that IFN-tau inhibits both B cell and T cell responses in EAE as well as active, chronic EAE, and this may help explain the effectiveness of type I IFNs in treatment of MS.

Topics: Animals; Antibodies; Antibody Formation; B-Lymphocytes; Cattle; Cell Division; Cell Line; Encephalomyelitis, Autoimmune, Experimental; Immunity, Cellular; Interferon Type I; Mice; Microglia; Myelin Basic Protein; Paralysis; Pregnancy Proteins; Recurrence; Sheep; T-Lymphocytes

Experimental allergic encephalomyelitis (EAE) was induced in SJL/J mice by adoptive transfer of MBP-reactive T cells in order to investigate the role of astrocytes in pathology. GFAP protein and mRNA expression (analyzed using semiquantitative Western blot and RT-PCR techniques) were upregulated in the spinal cord of mice, which had developed a complete paralysis of hind- and fore-limbs and tail (grade 4 EAE), thus establishing that reactive gliosis occurred under these experimental conditions. Within the same samples and using similar techniques, we found that glutamine synthetase (GS) and glutamate dehydrogenase (GDH) expression were dramatically reduced. These two astrocytic enzymes are responsible for degradation of glutamate, the most abundant excitatory neurotransmitter in the brain. Since elevated levels of glutamate may be neurotoxic, we propose that the decreased capacity of astrocytes to metabolize glutamate may contribute to EAE pathology.

Topics: Adoptive Transfer; Animals; Astrocytes; Brain; Encephalomyelitis, Autoimmune, Experimental; Female; Glial Fibrillary Acidic Protein; Glutamate Dehydrogenase; Glutamate-Ammonia Ligase; Glutamic Acid; Mice; Mice, Inbred Strains; Myelin Basic Protein; Paralysis; Polymerase Chain Reaction; RNA, Messenger; Spinal Cord; T-Lymphocytes; Transcription, Genetic

A duplication of a 1.5-Megabase genomic region encompassing the gene for the peripheral myelin protein 22 (PMP22) is found on chromosome 17p11.2-12 in Charcot-Marie-Tooth disease type 1A (CMT1A), whereas the reciprocal deletion is associated with hereditary neuropathy with liability to pressure palsies (HNPP). Since most CMT1A patients harbor three copies of the PMP22 gene, and most HNPP patients carry only a single copy, a gene dosage effect has been proposed as a mechanism for both diseases. We have analyzed the steady-state expression of PMP22 protein in sural nerve biopsies from three CMT1A and four HNPP patients. Quantitative immunohistochemical determination showed that PMP22 protein expression relative to that of myelin protein zero and myelin basic protein was increased in all CMT1A patients and reduced in all HNPP patients, as compared with biopsy samples of patients with normal PMP22 gene expression. These data demonstrate that both neuropathies result from an imbalance of PMP22 protein expression.

Topics: Adolescent; Adult; Biopsy; Charcot-Marie-Tooth Disease; Child; Female; Gene Dosage; Genetic Predisposition to Disease; Genotype; Humans; Immunohistochemistry; Male; Middle Aged; Myelin Basic Protein; Myelin P0 Protein; Myelin Proteins; Nerve Compression Syndromes; Paralysis; Peripheral Nervous System Diseases; Sural Nerve

Following induction of experimental encephalomyelitis with a T-cell clone, L10C1, that is specific for the myelin basic protein epitope p87-99, the inflammatory infiltrate in the central nervous system contains a diverse collection of T cells with heterogeneous receptors. We show here that when clone L10C1 is tolerized in vivo with an analogue of p87-99, established paralysis is reversed, inflammatory infiltrates regress, and the heterogeneous T-cell infiltrate disappears from the brain, with only the T-cell clones that incited disease remaining in the original lesions. We found that antibody raised against interleukin-4 reversed the tolerance induced by the altered peptide ligand. Treatment with this altered peptide ligand selectively silences pathogenic T cells and actively signals for the efflux of other T cells recruited to the site of disease as a result of the production of interleukin-4 and the reduction of tumour-necrosis factor-alpha in the lesion.

Topics: Amino Acid Sequence; Animals; Base Sequence; Brain; Encephalomyelitis; Epitopes; Immune Tolerance; Interleukin-4; Mice; Molecular Sequence Data; Myelin Basic Protein; Paralysis; Peptide Fragments; T-Lymphocytes

Vacuolar myelopathy is a common neurological complication in AIDS patients. The pathogenesis of this spinal cord white matter disease remains unclear and it is still debated whether infection of spinal cord with the human immunodeficiency virus type 1 (HIV-1) is causing the disease. We have generated transgenic mice expressing the entire HIV-1 genome under the regulation of an oligodendrocyte-specific promoter. These mice develop spinal cord vacuolar lesions similar to those found in AIDS patients. This animal model provides in vivo evidence linking the expression of HIV-1 proteins in oligodendrocytes to the spinal cord damage found in vacuolar myelopathy.

Topics: Acquired Immunodeficiency Syndrome; Animals; Central Nervous System; Gene Expression Regulation, Viral; HIV-1; Humans; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myelin Basic Protein; Oligodendroglia; Paralysis; Spinal Cord; Spinal Cord Diseases; Tissue Distribution; Vacuoles; Viral Proteins

The role of infection in the pathogenesis of clinical relapses that occur in most autoimmune diseases, including multiple sclerosis, remains to be established. Experimental autoimmune encephalomyelitis (EAE) serves as a model for multiple sclerosis, with episodes of relapsing paralysis. In certain strains of mice, T-lymphocytes expressing the V beta 8 T-cell receptor (TCR) engage the amino-terminal epitope Ac1-11 of myelin basic protein, leading to EAE. The bacterial superantigen staphylococcal enterotoxin B (SEB) activates V beta 8-expressing T cells. Here we show that after immunization with Ac1-11, or after transfer of encephalitogenic T-cell lines or clones reactive to Ac1-11, SEB induces exacerbation or relapses of paralytic disease in mice that are in clinical remission following an initial episode of paralysis, and triggers paralysis in mice with subclinical disease. Tumour necrosis factor has a critical role in the mechanism underlying SEB-induced exacerbation of disease, because anti-tumour necrosis factor antibody given in vivo delays the onset of paralysis triggered by SEB. On reactivation of autoaggressive cells through their T-cell receptor, superantigens may induce clinical relapses of autoimmune disease.

Topics: Amino Acid Sequence; Animals; Cell Line; Encephalomyelitis, Autoimmune, Experimental; Enterotoxins; Mice; Molecular Sequence Data; Myelin Basic Protein; Paralysis; Staphylococcus aureus; Superantigens; T-Lymphocytes; Tumor Necrosis Factor-alpha

The aim of this study was to investigate the pathological and cellular basis for radiation-induced myelopathy in guinea pigs by monitoring biochemical alterations in levels of myelin basic protein and 2',3'-cyclic nucleotide phosphohydrolase. Guinea pigs were irradiated to the lumbar region with various doses of neutrons or cobalt gamma irradiation. The ED50s for paralysis were 17.2 Gy and 67.5 Gy for neutron and cobalt irradiation, respectively, and was histologically associated with demyelination. In spinal cords taken from animals at the onset of paralysis myelin basic protein levels were decreased in direct relationship to the radiation dose. The lowest doses to cause paralysis led to a 25% decrease in MBP levels. In a separate experiment, alterations in MBP were measured in the spinal cords over the time period leading up to paralysis. Surprisingly, decreases in MBP were found immediately after the end of the 4 week irradiation period. These early changes in MBP were not markedly dose dependent and occurred with nonparalyzing doses. Dose-dependent decreases were found only just before the onset of paralysis. CNPase activity measured in the same specimens showed changes that were essentially similar to those for MBP. In the CSF, MBP levels were essentially constant until onset of paralysis. This study showed that demyelination, as assessed by the levels of the myelin-associated proteins MBP and CNPase, can occur soon after spinal cord irradiation but that profound dose-dependent changes are seen only immediately preceding the onset of paralysis. Although increases in MBP in the CSF were associated with the onset of radiation-induced myelopathy, its assay is unlikely to predict this complication of irradiation.

Topics: 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase; 2',3'-Cyclic-Nucleotide Phosphodiesterases; Animals; Dose-Response Relationship, Radiation; Female; Guinea Pigs; Myelin Basic Protein; Paralysis; Phosphoric Diester Hydrolases; Spinal Cord; Time Factors

Experimental allergic encephalomyelitis (EAE) is a model system for T cell-mediated autoimmune disease. Symptoms of EAE are similar to those of multiple sclerosis (MS) in humans. EAE is induced in susceptible animal strains by immunization with myelin basic protein (MBP) and potent adjuvant. The major T cell response to MBP in B10.PL mice is directed towards an NH2-terminal epitope and involves T cells expressing either V beta 8.2 or V beta 13 gene segments. Animals treated with a TCR V beta 8-specific mAb have a reduced incidence of EAE. We report here that the in vivo administration of a combination of anti-V beta 8.2 and anti-V beta 13 mAbs results in a long-term elimination of T cells involved in the response to MBP. When given before MBP immunization, anti-TCR antibody treatment leads to nearly complete protection against EAE. Antibody treatment also results in a dramatic reversal of paralysis in diseased animals. Thus, treatment with a combination of V beta-specific antibodies is a very effective therapy for the prevention and treatment of EAE. It is hoped that the future characterization of TCR V gene usage in human autoimmune diseases may lead to similar strategies of immune intervention.

Topics: Animals; Antibodies, Monoclonal; Autoimmune Diseases; Cell Separation; Encephalomyelitis, Autoimmune, Experimental; Flow Cytometry; Lymph Nodes; Lymphocyte Activation; Mice; Mice, Inbred Strains; Myelin Basic Protein; Paralysis; Receptors, Antigen, T-Cell; Receptors, Antigen, T-Cell, alpha-beta

The pathologic role of the specific immune and inflammatory responses to viral infections of the CNS was investigated by using mice which are susceptible (SJL/J) and resistant (C57Bl6 and BALB/c) to the development of experimental autoimmune encephalomyelitis (EAE). Intracerebral inoculation of 10(4) PFU of Sindbis virus (SV) into 6- to 8-wk-old SJL/J mice resulted in a severe and sometimes fatal encephalomyelitis. A mild to severe hind leg paralysis was observed around days 6 to 7 postinfection (pi) which closely resembled EAE stages and persisted for up to 8 wk pi. Immunosuppression with cyclophosphamide on day 4 alleviated the severity of this disease. Significant perivascular and parenchymal infiltration was present in the brains and spinal cords of SV-infected SJL/J mice for up to 1 mo. This apparent immunopathologic reaction was found to be a characteristic of SJL/J mice, because infection of 6- to 8-wk-old BALB/c and C57Bl6 mice with SV did not cause paralytic disease. These mice also exhibited a significantly milder cellular infiltrate which was mostly resolved on day 12 to 14 pi. Titers of virus in the brain and spinal cords of mice were comparable with clearance by day 7 pi. SV-specific lymphoproliferation and serum antibody responses were also comparable in all mice. SV-infected SJL/J mice developed antibodies to myelin components as demonstrated in Western blots and responded to myelin basic protein by lymphoproliferation. Lymph node cells from these mice, after in vitro challenge with myelin basic protein, transferred a mild EAE-like disease to naive recipients and potentiated subclinical EAE into a severe disease.

Topics: Animals; Autoantibodies; Encephalomyelitis, Autoimmune, Experimental; Female; Immunization, Passive; Mice; Mice, Inbred Strains; Myelin Basic Protein; Paralysis; Sindbis Virus; Togaviridae Infections

Lymphocyte proliferation tests to rabies antigen and myelin basic protein were performed on peripheral blood lymphocytes from nine patients with the encephalitic form and on seven with the paralytic form of human rabies. Six of the nine patients with encephalitis had proliferative responses to rabies antigen, whereas all of the patients with paralysis had no response. Two patients in each group also had a proliferative response to myelin basic protein. The myelin basic protein-reactive patients had a more rapidly fatal disease than the non-reactive patients. This preliminary study suggests that host immune responses may influence the clinical manifestations and course in human rabies.

Topics: Adolescent; Adult; Aged; Antibodies, Viral; Child; Encephalitis; Female; Humans; Lymphocyte Activation; Male; Middle Aged; Myelin Basic Protein; Paralysis; Rabies; Rabies virus

Class II-restricted T cell clones specific for myelin basic protein (MBP) have been generated from PL/J and (PL/J X SJL/J)F1 [((PLSJ)F1] mice following sensitization to rat MBP. Of 17 T cell clones generated from (PLSJ)F1 mice, 5 are I-Au(A alpha uA beta u) restricted, one is restricted to I-As(A alpha sA beta s), 10 are restricted to hybrid I-A(u X s)F1 (A alpha sA beta u) determinants, and one clone is restricted to hybrid I-E(u X s) (E alpha uE beta s) molecules. Thus, of 16 I-A-restricted T cell clones generated from (PLSJ)F1 mice, only one is I-As-restricted, reflecting a lack of priming to MBP in association with I-As. T cell clones restricted to I-Au and to I-E (E alpha u E beta s) molecules recognize mouse (self) MBP. Furthermore, only the five T cell clones restricted to I-Au molecules recognize a determinant in common with mouse (self) MBP within the encephalitogenic N-terminal peptide. Three such I-Au restricted T cell clones, derived independently, cause paralysis in 100% of (PL/J X SJL/J)F1 mice tested. Acute, chronic unremitting, and chronic relapsing paralysis are all induced following injection of these clones. Administration of greater numbers of cloned T cells causes acute and fatal experimental allergic encephalomyelitis, while administration of lower numbers of cloned T cells is associated with chronic unremitting and relapsing paralysis. Paralysis induced with T cell clones shares many clinical, immunologic, and histologic aspects with human demyelinating diseases such as multiple sclerosis. Histopathology reveals perivascular lymphocytic infiltration, demyelination, and remyelination. These studies demonstrate the utility of T cell clones for analyzing the association between class II major histocompatibility complex molecules and disease susceptibility.

Topics: Animals; Antigen-Presenting Cells; Autoimmune Diseases; Clone Cells; Crosses, Genetic; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Female; H-2 Antigens; Histocompatibility Antigens; Histocompatibility Antigens Class II; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Myelin Basic Protein; Paralysis; Peptide Fragments; T-Lymphocytes

Topics: Animals; Antibodies, Viral; Autoantibodies; Herpesviridae Infections; Herpesvirus 1, Equid; Horse Diseases; Horses; Myelin Basic Protein; Myelin P2 Protein; Paralysis

Topics: Acetylcholine; Animals; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Female; Guinea Pigs; Ileum; Male; Myelin Basic Protein; Paralysis; Receptors, Serotonin; Serotonin

The potential evoked at the surface of the cerebral cortex of a guinea pig, by stimulation of the contralateral forepaw, usually consists of an initial double positive wave whose waveform remains unchanged during rapid stimulation. In a guinea pig with experimental allergic encephalomyelitis (EAE) the response is attenuated at low frequencies of stimulation. Observations were also made on animals with experimental allergic neuritis (AEN). These animals showed a peripheral specificity for decreased conduction velocity, but have normal cortical evoked responses. Histological studies were undertaken in parallel with the electrophysiological studies and the concordance and discordance between the two is discussed. We conclude that there is no evident correlation between the severity of the electrophysiological effects and the histological lesions. An attempt was also made to induce an immunological challenge in guinea pigs, in the same way that EAE and EAN is produced, by the injection of synaptosomes. No clinical signs or alterations in the histology or electrophysiology of the animals were seen. A discussion is included on the elucidation of the site of action of EAE by discriminating between the direct effects on myelin and synapses and by the indirect effects of myelin damage on synapses. No firm conclusion is reached and the matter is left for further analysis in the subsequent paper. Finally, the neurophysiological alterations, demonstrated in the EAE and EAN situations, are discussed in terms of a humoral factor possibly acting on the myelin sheath and indirectly affecting synaptic function. This matter is further discussed in the subsequent paper.

Topics: Animals; Central Nervous System; Cerebral Cortex; Disease Models, Animal; Electric Stimulation; Encephalomyelitis, Autoimmune, Experimental; Evoked Potentials; Fecal Incontinence; Forelimb; Guinea Pigs; Humans; Myelin Basic Protein; Myelin Sheath; Neural Conduction; Neuritis; Paralysis; Rats; Sciatic Nerve; Synaptosomes; Urinary Incontinence

Topics: Age Factors; Animals; Brain; Encephalomyelitis, Autoimmune, Experimental; Freund's Adjuvant; Guinea Pigs; Humans; Immunization Schedule; Injections, Intradermal; Mice; Mice, Inbred Strains; Microscopy, Electron; Myelin Basic Protein; Myelin Sheath; Paralysis; Rabies Vaccines