TMEV-induced Demyelination Research Articles

Dexamethasone regulation of interleukin-1-receptors in the hippocampus of Theiler's virus-infected mice: effects on virus-mediated demyelination

Intracerebral (i.c.) inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelinating disease. Interleukin-1 receptors are expressed in the brain of mice, in particular in the hippocampus, and have been implicated in neuroimmunoendocrine interactions. In the present study we investigated the regulation of interleukin-1 receptors in the hippocampus of a susceptible (SJL/J) and a resistant (BALB/c) strain of mice infected with TMEV, at different time intervals of the disease. Our results show that interleukin-1 receptors in the hippocampus were decreased in TMEV-infected mice at early times post-infection (10 and 14 days p.i.). The reduction in interleukin-1 receptors only occurred in the susceptible strain of mice (SJL/J), whereas interleukin-1 binding in the hippocampus of TMEV-infected resistant mice (BALB/c) showed values similar to those in control animals. The TMEV-induced down-regulation of interleukin-1 receptors was secondary to a marked decrease in the affinity of the receptor (control: K d=10.5 pM; TMEV: K d=1.30 pM) accompanied by a decrease in receptor number (control: B max=2.189 fmol/mg protein; TMEV: B max=0.84 fmol/mg protein). We also investigated the effects of glucocorticoid treatment on the regulation of hippocampal interleukin-1 receptors of TMEV-infected mice. Dexamethasone treatment in the early phase (500 μg/kg or 1 mg/kg during days 5–10 p.i.) of the disease significantly reversed the deficits in hippocampal interleukin-1 receptors observed at 10 days p.i. in SJL/J mice, and suppressed neurological signs of demyelination. These results suggest that: (i) the reduction of interleukin-1 receptors may be a consequence, at least in part, of local production of interleukin-1 at early times during TMEV infection; (ii) interleukin-1 seems to be a critical factor for the susceptibility to TMEV-induced demyelination and (iii) the protective effect of dexamethasone appears to be related to its ability to reverse the reduction in interleukin-1 receptors during the early disease. These results suggest that interleukin-1 is a pivotal mediator in TMEV-induced demyelination.

Role of individual T-cell epitopes of Theiler's virus in the pathogenesis of demyelination correlates with the ability to induce a Th1 response.

Intracerebral inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelination. Three major T-cell epitopes have previously been identified within the VP1 (VP1233-250), VP2 (VP274-86), and VP3 (VP324-37) capsid proteins in virus-infected SJL/J mice. These epitopes appear to account for the majority ( approximately 90%) of major histocompatibility complex class II-restricted T-cell responses to TMEV. Interestingly, the effect of immunization with synthetic peptides bearing the predominant T-cell epitopes on the course of TMEV-induced demyelination indicates that T cells reactive to the VP1 and VP2 epitopes, but not VP3, accelerate the pathogenesis of demyelination. The predominant pathogenic role of the T cells is verified by similar immunization with the fusion proteins containing the entire individual capsid proteins. The order of appearance and level of T cells specific for the individual epitopes during the course of demyelination are similar to each other. However, cytokine profiles of T cells from virus-infected mice indicate that T cells specific for the VP1 (and perhaps the VP2) epitope are Th1, whereas T cells reactive to VP3 are primarily Th2. These results suggest that Th1-type cells specific for VP1 and VP2 are involved in the pathogenesis of viral demyelination induced by TMEV. Thus, a predominance of Th1-inducing viral epitopes is likely critical for the pathogenesis of demyelination.

Association between susceptibility to Theiler's virus-induced demyelination and T-cell receptor Jbeta1-Cbeta1 polymorphism rather than Vbeta deletion.

Theiler's murine encephalomyelitis virus (TMEV) induces demyelinating disease in susceptible mouse strains after intracerebral inoculation. The clinical symptoms and histopathology of the central nervous system appear to be similar to those of human multiple sclerosis (MS), and thus, this system provides an excellent infectious animal model for studying MS. The virus-induced demyelination is immune mediated, and the genes involved in the immune response such as those for the T-cell receptor beta-chain and major histocompatibility complex (MHC) haplotypes are known to influence disease susceptibility. To define whether the T-cell receptor Jbeta-Cbeta or Vbeta genes are associated with susceptibility, we have analyzed F2 mice from crosses of susceptible SJL/J (Vbeta(a)-JCbeta(b)) mice and resistant C57L (Vbeta(a)-JCbeta(a)) mice. Our results indicate that susceptibility to TMEV-induced demyelination is associated with restriction fragment length polymorphism reflecting the T-cell receptor Jbeta1-Cbeta1 region rather than the Vbeta polymorphism. This association becomes stronger when the MHC haplotype is considered in the linkage analysis. However, differences in the T-cell receptor alpha-chain haplotype have no significant influence on the pathogenesis of TMEV-induced demyelination.

Differential generation of class I H‐2D‐ versus H‐2K‐restricted cytotoxicity against a demyelinating virus following central nervous system infection

Despite the fact that both H-2K and D molecules are up-regulated in the central nervous system (CNS) following Theiler's murine encephalomyelitis virus (TMEV) infection, resistance in this virus model of multiple sclerosis maps exclusively to D. To address this paradox, we examined the ability of the K and D molecules to present viral antigens to cytotoxic T lymphocytes (CTL). Whereas no virus-specific CTL were detected in the CNS of susceptible B10.Q and B10.S mice 7 days post-infection, D-restricted CTL were identified readily in the CNS of resistant B10 animals. There was no evidence of K-restricted CTL in the CNS of B10 mice at day 7 post-infection. The presence of both K- and D-restricted virus-specific CTL in the spleen of immunized B10 mice demonstrates that the exclusive use of D molecules by CTL in the CNS of mice 7 days post-infection is not due to the inability of the K molecules to present viral peptides to lymphocytes. We conclude that the prominent role of the D locus in determining resistance or susceptibility to TMEV-induced demyelination is determined by factors governing the regulation of the immune response, and not by the presence or absence of CTL precursors capable of recognizing viral peptides presented by the K and D antigen-presenting molecules, or by differences in the ability of the K and D molecules to present viral peptides.

Adoptively transferred CD8+ T lymphocytes provide protection against TMEV-induced demyelinating disease in BALB/c mice.

On intracerebral infection with the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV), certain mouse strains develop a chronic demyelinating disease similar both clinically and pathologically to human multiple sclerosis. Other strains remain resistant. We previously established that differential susceptibility to this demyelinating disease exists among BALB/c substrains, with BALB/cAnNCr mice being susceptible while BALB/cByJ mice are resistant. BALB/cByJ mice are rendered susceptible to TMEV-induced demyelination on exposure to low dose gamma-irradiation before TMEV infection. BALB/cAnNCr and irradiated, infected BALB/cByJ animals are protected against TMEV-induced demyelination by the transfer of a splenic population from TMEV-infected BALB/cByJ donors. Resistance to demyelination appears to be mediated by a CD8+ radiosensitive population, which is induced on infection with TMEV and which must act early to establish resistance to TMEV-induced demyelination.

BALB/c substrain differences in susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating disease

We report differences among BALB/c substrains in susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease, an immune-mediated inflammatory demyelinating disease and experimental model for human multiple sclerosis. BALB/cJ and BALB/cAnNCr mice are susceptible, while BALB/cByJ and BALB/cCum are resistant. Hybrids between BALB/cBy and BALB/cAnNCr were intermediate, although closer to the resistant parent. Backcrosses gave results compatible with differential susceptibility being related to a single segregating locus. Exposure of resistant BALB/cByJ mice to low dose irradiation, 2 days prior to infection, rendered them susceptible to TMEV-induced demyelination. The susceptibility pattern of TMEV-induced demyelinating disease among BALB/c substrains is distinct from those of several autoimmune disorders.

Proteolipid protein gene expression in demyelination and remyelination of the central nervous system: a model for multiple sclerosis.

We asked whether nonlethal injury to the oligodendrocyte as manifested by altered myelin gene expression is an early event in the pathogenesis of demyelinating disease and subsequent remyelination. Using simultaneous in situ hybridization and immunocytochemistry, we studied expression of proteolipid protein (PLP) antigen and mRNA in spinal cords of normal adult mice and of mice infected with Theiler's virus which provides an excellent model for multiple sclerosis. Downregulation of PLP mRNA was observed within 3 days and persisted for as long as 367 days following intracerebral virus infection of SJL/J mice which are susceptible to chronic demyelination. Downregulation of myelin gene products preceded the development of prominent inflammation and demyelination observed following virus infection. In contrast, no change from control uninfected mice was observed in the expression of PLP mRNA following infection of C57BL/10SNJ mice which are resistant to demyelination. Treatment of chronically infected susceptible SJL/J mice with a regimen which promotes CNS-type (oligodendroglial) remyelination resulted in a 3- to 4-fold increase in PLP mRNA expression in oligodendrocytes. Actin mRNA expression in PLP antigen-positive cells was unchanged following TMEV-induced demyelination or remyelination indicating up- or downregulation of myelin gene products as compared to constitutively expressed actin gene. These experiments support the hypothesis that early regulation of myelin gene expression may be an important determinant in demyelination and in remyelination following nonlethal injury to oligodendrocytes.

Class I‐deficient resistant mice intracerebrally inoculated with Theiler's virus show an increased T cell response to viral antigens and susceptibility to demyelination

Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelination in susceptible mouse strains. The histology of TMEV-induced demyelination is similar to that seen in patients suffering from multiple sclerosis. It was previously shown that the susceptibility of mice to TMEV-induced demyelination in certain strain combinations is closely associated with the major histocompatibility complex (MHC) class I locus. Here we examine disease susceptibility of beta 2-microglobulin (beta 2M)-deficient transgenic mice lacking class I expression and functional CD8+ T cells. In contrast to TMEV-infected parental C57BL/6 mice, the transgenics develop high levels of virus-specific DTH and T cell proliferation accompanied by an increased frequency of central nervous system (CNS) demyelinating lesions. However, clinical signs of demyelination were not noted. Neither antibody titer nor viral persistence were significantly affected in the beta 2M-deficient mice. These results suggest that in the absence of functional class I/CD8+ cells, the class II-restricted T cell response to TMEV is enhanced and CNS pathogenesis is heightened, although the level is not severe enough to result in clinical disease. When the TMEV-infected mice were subcutaneously immunized with virus, however, the beta 2M-deficient mice displayed clinical symptoms. Therefore, our results strongly suggest that CD8+ T cells do not directly contribute to CNS demyelination. In contrast, such T cells appear to be primarily involved in down-regulation of a potentially damaging CD4+ T cell response in resistant animals, although some of the T cells may play a role in clearing viral persistence in the CNS, resulting in the protection of the host from viral demyelination.

Interleukin-6 production by brain tissue and cultured astrocytes infected with Theiler's murine encephalomyelitis virus.

Theiler's murine encephalomyelitis virus (TMEV) is known to interact with cells of the central nervous system (CNS). Here we report that, interestingly, it is a potent inductor of interleukin-6 (IL-6) in the CNS of infected animals and in pure cultures of astrocytes. Maximal IL-6 gene transcription in glial cells, as detected by bioassay and ELISA, was observed at 6 and 24 h after infection. Astrocytes from both SJL/J and Balb/c (strains of mice susceptible and resistant, respectively, to TMEV-induced demyelination) produced similar amounts of IL-6, measured in tissue culture supernatants. These results indicate that although an immunomodulatory effect can be exercised by IL-6 synthesized by astrocytes, it does not play a crucial role in immune-mediated demyelination induced by TMEV.

Expression of T cell receptor Vβ transcripts in central nervous system of mice susceptible and resistant to Theiler's virus-induced demyelination

We utilized the polymerase chain reaction (PCR) to examine for preferential expression of T cell receptor (TcR) Vβs in T cells infiltrating the central nervous system (CNS) of mice infected with Theiler's virus. Infection of susceptible strains of mice with Theiler's virus results in demyelinating disease similar to multiple sclerosis. At 7 days following infection, no difference was observed in TcR Vβ usage in lymphocytes infiltrating the CNS between resistant (B10.K) and susceptible (B10.Q or SJL/J) mice. In susceptible mice with prominent demyelination (day 45 and 238 following infection), no preferential expression of TcR Vβs was observed in the CNS. There is strong evidence that T cells play a major role in pathogenesis of TMEV-induced demyelination. There is increasing evidence using recombinant inbred strain mice with TcR Vβ deletions that T cells expressing certain TcR Vβ genes may be critical in the disease process. Yet, analysis of TcR Vβ expression on T cells in CNS using PCR technology did not provide a way to dissect which antigen-specific T cells play a role in disease. These results confirm that during active demyelination specific as well as non-specific T cells are recruited to the CNS. Even though the pathogenesis of TMEV-induced disease may not be identical to that in multiple sclerosis, it is unlikely that similar approaches utilizing polymerase chain reaction will provide insights to the role of T cell receptors in the pathogenesis of multiple sclerosis.

Differential IL-1 Synthesis by Astrocytes from Theiler's Murine Encephalomyelitis Virus-Susceptible and -Resistant Strains of Mice

Increasing evidence shows that interleukin-1 (IL-1) contributes to inflammatory processes, such as experimental allergic encephalomyelitis (EAE) and virus-induced demyelination, inside the central nervous system (CNS). Using primary cultures of mouse astrocytes, we show that these glial cells can be induced to produce IL-1α when infected with Theiler's murine encephalomyelitis virus (TMEV). This was true for astrocytes from SJL/J mice, a strain susceptible to TMEV-induced demyelination. Conversely, BALB/c astrocytes, derived from animals genetically resistant to demyelination, did not produce IL-1α in detectable amounts. Therefore, a differential IL-1 gene expression, which is strain specific, is demonstrated after TMEV infection in astrocytes. The release of IL-1α by SJL astrocytes was studied from kinetic, infectivity, and immunochemical points of view. Since IL-1 plays a critical role in the immune response, its production by astrocytes in some strains of mice may contribute to virus-induced susceptibility and to inflammation associated with this experimental model of multiple sclerosis.

Coexpression of class I major histocompatibility antigen and viral RNA in central nervous system of mice infected with Theiler's virus: a model for multiple sclerosis.

Chronic infection of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in central nervous system (CNS) demyelination similar to multiple sclerosis. Demyelination induced by TMEV is mediated, in part, by class I-restricted CD8+ T lymphocytes. For these T cells to function, they must recognize virus-infected CNS targets in the presence of class I major histocompatibility complex (MHC) antigen. Therefore, we studied in vivo expression of class I MHC antigen and viral antigen-RNA in prototypic mouse strains that are susceptible (SJL/J) or resistant (C57BL/10SNJ) to TMEV-induced demyelination. In brains of resistant mice, viral antigen-RNA expression peaked on day 3 after infection and was effectively diminished by day 5 such that few virus-infected cells were ever detected in the spinal cord. In contrast, susceptible mice demonstrated delay in clearance of TMEV from the brain and a subsequent increase and persistence of viral antigen-RNA in the spinal cord for as long as 277 days. Viral infection resulted in "upregulation" of class I MHC expression in the CNS. Class I MHC antigens were expressed as early as 1 day after infection in the choroid plexus of both strains of mice before detection of viral antigen or inflammation. In resistant mice, class I MHC expression predominated in the gray matter of the brain and spinal cord on day 7 after infection but returned to undetectable levels by day 28. In susceptible mice, class I MHC expression in the CNS persisted and was intense in the white matter of the spinal cord throughout chronic infection and demyelination. No class I MHC expression was detected in the CNS of uninfected mice. Coexpression of viral RNA and class I MHC antigen was demonstrated in CNS cells by using simultaneous in situ hybridization and immunoperoxidase technique. These results support the hypothesis that a class I-restricted immune response directed against virus-infected cells may be important in the mechanism of demyelination.

Identification and localization of a limited number of predominant conformation-independent antibody epitopes of Theiler's murine encephalomyelitus virus.

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease in mice is a well established animal model for human multiple sclerosis (MS). Identification of pathogenic epitopes may be helpful in understanding the pathogenesis of this immune-mediated disease. In order to analyze the viral epitopes, we have generated approx. 150 recombinant lambda gt11 clones expressing various capsid areas of TMEV. Six predominant areas, ranging from 13-26 amino acid residues, (3 in VP1, 2 in VP2 and 1 in VP3) are readily recognized by conformation-independent antibodies from virus-infected mice. These areas have been designated as A-1A (VP1 13-27th residues), A-1B (VP1 145-167), A-1C (VP1 251-276), A-2A (VP2 2-14), A-2B (VP2 165-179), and A-3A (tentatively VP3 24-43). Antibodies from TMEV-infected susceptible SJL/J mice strongly react with A-1B, A-2A and A-2B, in contrast to antibodies from resistant BALB/c mice which mainly recognize A-1A and A-2A. Interestingly, the reactivity pattern of antibodies from TMEV-infected mice are somewhat different from that of antibodies from TMEV-immunized mice. Although the majority of antibodies in TMEV-infected mice recognizes conformation-dependent epitopes, the differential recognition of the conformation-independent antibody epitopes by susceptible mice may play a role in TMEV-induced demyelination.

Cytotropism of Theiler's murine encephalomyelitis viruses in oligodendrocyte-enriched cultures

The cytotropism of two strains, GDVII and DA, of Theiler's murine encephalomyelitis viruses (TMEV) was studied in the oligodendrocyte-enriched murine neural cell cultures. Both GDVII and DA caused cytopathic effects in the neural cell cultures, and double immunostaining for galactocerebroside (Gal-Cer), a marker molecule for oligodendrocyte, and viral antigens disclosed a dual expression of Gal-Cer and viral antigens in over 80% of cells in both cultures 24 h after infection with either GDVII or DA. The kinetics of cell-free and cell-associated infectivity were not significantly different between two cultures. These in vitro observations suggest that neither replication in oligodendrocyte nor cell-associated infectivity is a sole factor in discriminating those two subgroups of TMEV with regard to the demyelinating activity, and that virus cell binding may play an important role in virus persistence and TMEV-induced demyelination.

Influence of sex on susceptibility in the Theiler's murine encephalomyelitis virus model for multiple sclerosis

Multiple sclerosis (MS) is a demyelinating disease in humans which affects females more frequently than males. Theiler's murine encephalomyelitis virus (TMEV) induces demyelination similar to human MS in susceptible strains of mice after intracerebral inoculation. In this paper we report that sex influences susceptibility to TMEV-induced demyelination in certain genotypes derived from C57L/J and SJL/J or SWR/J mice. This is the first report of an animal model for MS that shows an association between sex and susceptibility, and this information may facilitate the investigation of human MS.

Abrogation of resistance to Theiler's virus-induced demyelination in C57BL mice by total body irradiation

Theiler's murine encephalitis virus (TMEV) produces an unusual biphasic disease in susceptible mice characterized by poliomyelitis with early viral replication in neurons, followed by chronic demyelination with viral antigen expression in spinal cord white matter. In addition, infectious virus persists in the central nervous system (CNS) throughout the chronic pahse of disease. Previous studies have indicated an important role for major histocompatibility complex (MHC)-gene products in determining resistance/susceptibility to disease. In particular, certain calss I gene products of the D region of the H-2 gene complex render mice of the C57BL lineage resistant to induction of demyelination. Intracerebral infection of B10.S(D S) mice results in demyelination in the spinal cord while infection of C57BL/10(D b) or with gamma irradiation renders normally resistant B10.S(9R) and C57BL/10 mice susceptible to TMEV-induced demyelination and allowed for increased viral replication. In addition, the majority of irradiated C57BL/10 mice infected with virus showed extensive areas of CNS remyelination by oligodendrocytes beginning at 63 days post-infection. In contrast, immunosuppression of normally susceptible B10.S mice resulted in acute disease and high mortality accompanied by overwhelming destruction of neurons. The study supports the hypothesis that MHC-conferred resistance in C57L mice is associated MHC D region products and indicate an important active role for the immune system early in infection in limiting vital infection during disease induction in nonimmunosuppressed mice.

Theiler's virus-induced demyelination in mice immunosuppressed with anti-IgM and in mice expressing the xid gene

Intracerebral infection with Theiler's murine encephalomyelitis virus produces chronic immune-mediated demyelination in susceptible strains of mice. We examined the role of Ig in the pathogenesis of demyelination. In susceptible SJL/J mice (H-2 s), suppression of B cell responses with IgG fraction of goat anti-mu (anti-mu IgG) from birth resulted in increased numbers and severity of demyelinating lesions in the spinal cord 35 days after infection. In contrast, treatment of resistant C57BL/10 (H-2 b), C57BL/6 (H-2 b), or B10.D2 (H-2 d) mice with anti-mu IgG had no apparent effect since these mice did not develop demyelination or inflammation in the spinal cord following infection. Similar results were obtained with certain strains of B-cell deficient mice that exhibit the xid gene mutation. Male CBA/NJ ( xid) showed increased meningeal inflammation and demyelination compared to male CBA/J mice. However, B6.CBAN, C3.CBAN, or C.CBAn mice showed no or minimal evidence of demyelination despite the presence of the xid mutation. In the SJL/J mouse, the majority of the humoral immune response to virus antigen was restricted to the IgG2b and IgM isotypes. These data indirectly support the hypothesis that immunoglobulins protect partially against development of virus-induced demyelination in susceptible but not resistant animals. In addition, the data argue strongly against the hypothesis that TMEV-induced demyelination is mediated predominantly by humoral autoimmune or humoral viral immune mechanisms.

Inhibition of Theiler's Virus-induced demylination in vivo by tumor necrosis factor alpha

Employing a murine model of multiple sclerosis which utilizes intracranial injection of Theiler's virus murine encephalomyelitis (TMEV) into SJL/J mice, we tested the potential role of tumor necrosis factor alpha (TNF-alpha) in ameliorating CNS demyelination. Infection with TMEV caused early grey matter inflammation (7 days post-infection) in the brain and spinal cord followed by chronic demyelination (35 days post-infection) in the spinal cord. Administration of recombinant human or mouse TNF-alpha starting 12 h prior to infection and then three times weekly had minimal effect on development of grey matter inflammation in the spinal cord. In contrast, TNF-alpha dramatically reduced demyelination present in spinal cord on days 14 and 35 after TMEV infection (P less than 0.01) when compared to controls. CNS virus titers of TMEV were not modified by TNF-alpha administration as measured on days 7, 14, and 35 following infection. In vivo administration of TNF-alpha inhibits TMEV-induced demyelination in susceptible SJL/J mice without affecting virus replication in the CNS.

Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. I. Cross-specificity among TMEV substrains and related picornaviruses, but not myelin proteins.

Following intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV), susceptible mouse strains develop a chronic demyelinating disease characterized by mononuclear cell-rich infiltrates in the central nervous system. Current evidence strongly supports an immune-mediated basis for myelin breakdown, with an effector role proposed for TMEV-specific, major histocompatibility class II-restricted delayed-type hypersensitivity, which temporally correlates with disease onset and remains chronically elevated in susceptible mice. This study examined the fine specificity of class II-restricted T cell responses in TMEV-infected mice to better define the relevant virus-encoded T cell determinant(s) responsible for triggering the demyelinating process, and to determine if class II-restricted neuroantigen-specific autoimmune responses could be detected in mice with TMEV-induced demyelination. The data clearly show that T cell responses in TMEV-infected mice are directed against determinants shared by closely related TMEV strains and are cross-reactive with related picornaviruses, such as encephalomyocarditis virus. In contrast, class II-restricted autoimmune responses against syngeneic mouse spinal cord homogenate and the two major protein components of myelin, myelin basic protein and proteolipid protein, are not demonstrable in susceptible SJL/J mice undergoing chronic TMEV-induced demyelinating disease, but are readily seen in SJL/J mice displaying chronic, relapsing experimental allergic encephalomyelitis. Cross-reactivity (or lack thereof), as determined by functional T cell analyses, was found to correlate with the extent of exact amino acid homology between the TMEV capsid proteins, the two neuroantigens, and related picornaviruses. The data thus do not support a major role for autoimmune responses against myelin proteins in TMEV-induced demyelinating disease, but are consistent with our previously proposed hypothesis that TMEV-specific T cell responses constitute a major effector mechanism of myelin breakdown.

The effect of L3T4 T cell depletion on the pathogenesis of Theiler's murine encephalomyelitis virus infection in CBA mice.

Theiler's murine encephalomyelitis virus (TMEV) gives rise to a biphasic disease of the central nervous system (CNS) following intracranial inoculation of susceptible strains of mice. The early phase, during the first month, resembles poliomyelitis and in the late phase the mice suffer from inflammatory demyelination reminiscent of multiple sclerosis. In order to investigate the role of helper T cells in the acute and chronic phases of the disease we depleted mice of their L3T4 T cells in vivo with rat monoclonal antibodies, prior to infection and prior to the onset of clinical signs of demyelination. Mice depleted of their helper cells failed to produce antibodies to TMEV and consequently were unable to clear virus from the CNS and died within the first month of infection. Depletion of T cells before the demyelinating phase of the disease resulted in a marked decrease in the incidence of disease from 77% of the immunocompetent animals with clinical signs of paralysis to 36%. Immunocompetent TMEV-infected mice also developed antibodies against myelin suggesting that autoimmune mechanisms may play a role in TMEV-induced demyelination.