Biomedical subjects

M K Njenga

Publications and source records attributed to M K Njenga.

At least 19 recordsLinked to original sources

PubMed2004

Evidence of avian pneumovirus spread beyond Minnesota among wild and domestic birds in central North America.

To detect avian pneumovirus (APV) in central North America, nasal turbinates or choanal deft tissues from domestic turkeys and wild birds were examined for the presence of APV RNA by reverse transcriptase-polymerase chain reaction (RT-PCR), whereas serum samples from domestic turkeys were analyzed for APV antibodies by enzyme-linked immunosorbent assay (ELISA). In 2002, the seroprevalence of disease in domestic turkeys in Minnesota remained high (42.3% of the flocks). In addition, there is evidence the disease has spread to turkey flocks in North Dakota (8.2%), South Dakota (7%), Iowa (10%), and Wisconsin (8.6%) as detected by RT-PCR and/or ELISA. House sparrows and ring-billed gulls sampled in Minnesota and snow geese from Saskatchewan, Canada, were found to harbor APV RNA. Sequence analysis of wild bird APV strains showed high amino acid sequence identity among wild bird isolates (<97%) and between wild bird and turkey viral isolates (93.2%-99.3%). This study demonstrated that APV infections were present in domestic turkey flocks and wild birds outside the state of Minnesota; however, the role of wild birds in spreading APV to domestic turkeys remains unclear.

Amino Acid Sequence↗

PubMed2002

Role of intrabursal T cells in infectious bursal disease virus (IBDV) infection: T cells promote viral clearance but delay follicular recovery.

Infectious bursal disease virus (IBDV) induces an acute, highly contagious immunosuppressive disease in young chickens. We examined the role of T cells in IBDV-induced immunopathogenesis and tissue recovery. T cell-intact chickens and birds compromised in their T cell function by a combination of surgical thymectomy and Cyclosporin A treatment (Tx-CsA) were infected with an intermediate vaccine strain of IBDV (Bursine 2, Fort Dodge). Our data revealed that functional T cells were needed to control the IBDV-antigen load in the acute phase of infection at 5 days post infection. The target organ of IBDV, the bursa of Fabricius, of Tx-CsA-birds had a significantly higher antigen load than the one of T cell-intact birds (P < 0.05). Tx-CsA-treatment abrogated the IBDV-induced inflammatory response and significantly (P < 0.05) reduced the incidence of apoptotic bursa cells and the expression of cytokines such as interleukin 2 (IL-2) and interferon-gamma (IFN-gamma) in comparison to T cell-intact birds. T cell-released IL-2 and IFN-gamma may have mediated the induction of inflammation and cell death in T cell-intact birds. The IBDV-induced upregulation of tumor necrosis like-factor (TNF) expression was comparable between T cell-intact and Tx-CsA-birds. Tx-CsA-birds showed a significantly faster resolution of IBDV-induced bursa lesions than T cell-intact birds (P < 0.05). This study suggests that T cells modulate IBDV pathogenesis in two ways: a) they limit viral replication in the bursa in the early phase of the disease at 5 days post infection, and b) intrabursal T cells promote bursal tissue damage and delay tissue recovery possibly through the release of cytokines and cytotoxic effects.

Animals↗

PubMed2001

Theiler's virus-infected L-selectin-deficient mice have decreased infiltration of CD8(+) T lymphocytes in central nervous system but clear the virus.

Mice with targeted deletion of L-selectin gene (L-sel(-/-)) were used to investigate the role of adhesion molecule in immunologic responses following virus infection in the central nervous system (CNS). L-Sel(-/-) mice from a resistant H-2(b) genetic background and parental wild-type H-2(b) (C57BL/6) mice were infected with Theiler's murine encephalomyelitis virus (TMEV) intracerebrally and the kinetics of virus replication and infiltration of immune cells in the CNS determined. The levels of infectious TMEV, as measured by plaque assay at 3, 7, 14, and 28 days after infection were between 4 and 6 log(10) PFU of virus per gram of CNS tissues at days 3 and 7 post-infection, and then decreased to undetectable levels by day 14 after infection in both strains of mice. The L-sel(-/-) mice had decreased numbers of CD8(+) T lymphocytes (17.72%+/-2.4) infiltrating into the CNS at 7 days post-infection when compared to wild-type mice (31.02%+/-7.5). In addition, the L-sel(-/-) mice had significantly lower levels of TMEV-specific serum IgG resulting in lower virus neutralizing activity of the serum when compared to wild-type mice. However, the L-sel(-/-) mice had 2.5-fold increase in B lymphocytes in the CNS (8.29%+/-1.1) when compared to wild-type mice (3.2%+/-0.4). Taken together, these data indicate that L-selectin plays a role in recruitment of B and CD8(+) T lymphocytes into the CNS following virus infection, which, however, did not affect the ability of the mice to clear TMEV infection.

Animals↗

PubMed2001

Antigens to viral capsid and non-capsid proteins are present in brain tissues and antibodies in sera of Theiler's virus-infected mice.

Recombinant proteins to the LP, VP1, VP2, VP3, VP4, 2A, 2B, 2C, 3A, and 3D genes of Theiler's murine encephalomyelitis virus (TMEV) were generated and antibodies were produced against them for use in analysis of the TMEV epitopes responsible for eliciting the antibody responses observed during acute and chronic disease. Antibodies against recombinant VP1, VP2, and VP3 recognized the corresponding proteins from purified TMEV particles. In immunohistochemical analysis, antibodies against recombinant capsid (VP1, VP2, and VP3), and non-capsid (2A, 2C, 3A) proteins were reactive with PO-2D cells (astrocytes) infected with TMEV in vitro and with brain tissues of acutely infected mice. Antibodies against VP4, 2B, and 3D antigens were not reactive with corresponding viral proteins in infected astrocytes cells or brain tissues, but they reacted with TMEV precursor proteins produced during the early viral replication phase. Sera from SJL/J mice infected with TMEV acutely (14 days) and chronically (45 days) reacted with VP1, VP2, VP4, 2A, and 2C proteins. In an in vitro assay for neutralization, only anti-VP1 antibodies neutralized TMEV infection. These findings suggest that both capsid and non-capsid proteins of TMEV play a role in the immunopathology of the TMEV disease in the central nervous system.

Animals↗

PubMed2001

Porcine encephalomyocarditis virus persists in pig myocardium and infects human myocardial cells.

Recent advances toward using pig tissues in human transplantation have made it necessary to determine the risk of transmitting zoonotic viruses from pigs to humans or vice versa. We investigated the suitability of the porcine encephalomyocarditis virus (EMCV) model for such studies by determining its ability to persist in pigs, escape detection by routine serological methods, and infect human cells. Intraperitoneal inoculation of 5-week-old pigs with EMCV-30, a strain isolated from commercial pigs, resulted in acute cellular degeneration, infiltration of lymphocytes, and apoptosis in myocardium in 13 of 15 (86.7%) pigs during the acute phase of disease (3 to 21 days postinfection), followed by less-severe lymphocytic infiltration and apoptosis in 5 of 10 (50%) pigs during the chronic phase of the disease (day 45 to 90 postinfection). In the brain, lymphocytic infiltration, neuronal degeneration, and gliosis were observed in 26 to 33% of pigs in the acute phase of disease whereas perivascular cuffing was the predominant feature during chronic disease. EMCV antigens and RNA were demonstrated in the myocardium and brain during the chronic phase of disease. Analysis of 100 commercial pigs that were negative for EMCV antibodies identified two pig hearts positive for EMCV RNA. Porcine EMCV productively infected primary human cardiomyocytes as demonstrated by immunostaining using a monoclonal antibody specific for EMCV RNA polymerase, which is expressed only in productively infected cells, and by a one-step growth curve that showed production of 100 to 1,000 PFU of virus per cell within 6 h. The findings that porcine EMCV can persist in pig myocardium and can infect human myocardial cells make it an important infectious agent to screen for in pig-to-human cardiac transplants and a good model for xenozoonosis.

Animals↗

PubMed2001

Susceptibility of ducks to avian pneumovirus of turkey origin.

OBJECTIVE: To determine the susceptibility of ducks to avian pneumovirus (APV) of turkey origin. ANIMALS: 30 Pekin ducks that were 2 weeks old. PROCEDURE: Ducks were assigned to 3 groups (10 ducks/group). Ducks of groups 1 and 2 were inoculated (day 0) with 200 microl of cell-culture fluid containing APV of turkey origin (10(5.5) median tissue-culture infective dose/ml) by the oculonasal (group 1) or oral (group 2) route. Ducks of group 3 served as noninoculated control birds. Two ducks from each group were euthanatized 3, 6, 9, 15, and 21 days after inoculation. Blood samples, tissue samples from the lungs, trachea, nasal turbinates, duodenum, diverticulum vitellinum (Meckel's diverticulum), and cecum, and swab specimens from the choana, cloaca, and trachea were obtained from all birds during necropsy and examined for APV by use of reverse transcriptase-polymerase chain reaction (RT-PCR), virus isolation, and histologic examination. Blood samples also were examined for APV antibodies, using an ELISA. RESULTS: Tissue samples obtained up to 21 days after inoculation had positive results when tested by use of RT-PCR. Virus was isolated from nasal turbinates of birds inoculated via the oculonasal route. Serum samples obtained 15 and 21 days after inoculation had positive results when tested for APV-specific antibody. Clinical signs of disease were not observed in ducks inoculated with APV of turkey origin. CONCLUSIONS AND CLINICAL RELEVANCE: Ducks inoculated with APV of turkey origin may not develop clinical signs of disease, but they are suspected to play a role as nonclinical carriers of APV.

Animals↗

PubMed2000

Short-term treatment with interferon-alpha/beta promotes remyelination, whereas long-term treatment aggravates demyelination in a murine model of multiple sclerosis.

The mechanisms by which type I interferons (IFN) reduce the rate and severity of exacerbations in multiple sclerosis are unknown. We utilized a model of multiple sclerosis to determine the extent of demyelination and remyelination in Theiler's murine encephalomyelitis virus (TMEV)-infected SJL/J mice treated with mouse IFN-alpha/beta for a short (5 weeks) or a long (16 weeks) period. All mice were chronically infected with TMEV to simulate the clinical situation in multiple sclerosis. Short-term IFN-alpha/beta treatment increased the percent of remyelinated spinal cord white matter by threefold when compared with phosphate-buffered saline (PBS) treatment (P < 0.02), but it did not affect the extent of demyelination. In contrast, long-term IFN-alpha/beta treatment increased the extent of demyelination by twofold (P < 0.03). Long-term treatment increased the absolute area of remyelination, but the percent remyelination as a function of area of demyelination was not changed because of increased demyelination. An immunomodulatory mechanism may have contributed to the effect of IFN-alpha/beta on white matter pathology because treated mice had higher anti-TMEV IgGs in serum and demonstrated decreased numbers of B and T lymphocytes infiltrating the central nervous system (CNS). There was no correlation between the level of anti- IFN-alpha/beta antibodies and the extent of demyelination or remyelination. These results indicate that the length of type I IFN treatment may have paradoxical effects on demyelination and remyelination.

Animals↗

PubMed2000

Development of a highly sensitive and specific enzyme-linked immunosorbent assay based on recombinant matrix protein for detection of avian pneumovirus antibodies.

The matrix (M) protein of avian pneumovirus (APV) was evaluated for its antigenicity and reliability in an enzyme-linked immunosorbent assay (ELISA) for diagnosis of APV infection, a newly emergent disease of turkeys in United States. Sera from APV-infected turkeys consistently contained antibodies to a 30-kDa protein (M protein). An ELISA based on recombinant M protein generated in Escherichia coli was compared with the routine APV ELISA that utilizes inactivated virus as antigen. Of 34 experimentally infected turkeys, 33 (97.1%) were positive by M protein ELISA whereas only 18 (52.9%) were positive by routine APV ELISA 28 days after infection. None of the serum samples from 41 uninfected experimental turkeys were positive by M protein ELISA. Of 184 field sera from turkey flocks suspected of having APV infection, 133 (72.3%) were positive by M protein ELISA whereas only 99 (53.8%) were positive by routine APV ELISA. Twelve serum samples, which were negative by M protein ELISA but positive by routine APV ELISA, were not reactive with either recombinant M protein or denatured purified APV proteins by Western analysis. This indicates that the samples had given false-positive results by routine APV ELISA. The M protein ELISA was over six times more sensitive than virus isolation (11.5%) in detecting infections from samples obtained from birds showing clinical signs of APV infection. Taken together, these results show that ELISA based on recombinant M protein is a highly sensitive and specific test for detecting antibodies to APV.

Animals↗

PubMed2000

Avian pneumovirus (APV) RNA from wild and sentinel birds in the United States has genetic homology with RNA from APV isolates from domestic turkeys.

Nasal turbinates or swabs were collected from wild ducks, geese, owls, sparrows, swallows, and starlings and from sentinel ducks placed next to turkey farms experiencing avian pneumovirus (APV) infections and were analyzed for APV genome and infectious particles. APV RNA was detected in samples examined from geese, sparrows, and starlings. APV RNA and antibodies were also detected in two different groups of sentinel ducks. Infectious APV was recovered from sentinel duck samples. The APV M gene isolated from the wild birds had over 96% predicted amino acid identity with APV/Minnesota 2A, which was isolated earlier from domestic turkeys showing respiratory illness, suggesting that wild birds may be involved in spreading APV infection.

Amino Acid Sequence↗

PubMed1999

Absence of spontaneous central nervous system remyelination in class II-deficient mice infected with Theiler's virus.

We previously showed that Theiler's murine encephalomyelitis virus (TMEV)-infected major histocompatibility complex (MHC) class II-deficient mice develop both demyelination and neurologic deficits, whereas MHC class I-deficient mice develop demyelination but no neurologic deficits. The absence of neurologic deficits in the class I-deficient mice was associated with preserved sodium channel densities in demyelinated lesions, a relative preservation of axons, and extensive spontaneous remyelination. In this study, we investigated whether TMEV-infected class II-deficient mice, which have an identical genetic background (C57BL/6 x 129) as the class I-deficient mice, have preserved axons and spontaneous myelin repair following chronic TMEV-infection. Both class I- and class II-deficient mice showed similar extents of demyelination of the spinal cord white matter 4 months after TMEV infection. However, the class I-deficient mice demonstrated remyelination by oligodendrocytes, whereas class II-deficient mice showed minimal if any myelin repair. Demyelinated lesions, characterized by inflammatory infiltrates in both mutants, revealed disruption of axons in class II- but not class I-deficient mice. Further characterization revealed that even though class II-deficient mice lacked TMEV-specific IgG, they had virus-specific IgM, which, however, did not neutralize TMEV in vitro. In addition, class II-deficient mice developed TMEV-specific cytotoxic T-lymphocytes in the CNS during the acute (7 days) disease, but these cytotoxic lymphocytes were not present in the chronic stage of disease, despite a high titer of infectious virus throughout the disease. We envision that the presence of demyelination, high virus titer, absence of remyelination, and axonal disruption in chronically infected class II-deficient mice contributes to the development of paralytic disease.

Acute Disease↗

PubMed1999

Prevalent class I-restricted T-cell response to the Theiler's virus epitope Db:VP2121-130 in the absence of endogenous CD4 help, tumor necrosis factor alpha, gamma interferon, perforin, or costimulation through CD28.

C57BL/6 mice mount a cytotoxic T-lymphocyte (CTL) response against the Daniel's strain of Theiler's murine encephalomyelitis virus (TMEV) 7 days after infection and do not develop persistent infection or the demyelinating syndrome similar to multiple sclerosis seen in susceptible mice. The TMEV capsid peptide VP2121-130 sensitizes H-2Db+ target cells for killing by central-nervous-system-infiltrating lymphocytes (CNS-ILs) isolated from C57BL/6 mice infected intracranially. Db:VP2121-130 peptide tetramers were used to stain CD8(+) CNS-ILs, revealing that 50 to 63% of these cells bear receptors specific for VP2121-130 presented in the context of Db. No T cells bearing this specificity were found in the cervical lymph nodes or spleens of TMEV-infected mice. H-2(b) mice lacking CD4, class II, gamma interferon, or CD28 expression are susceptible to persistent virus infection but surprisingly still generate high frequencies of CD8(+), Db:VP2121-130-specific T cells. However, CD4-negative mice generate a lower frequency of Db:VP2121-130-specific T cells than do class II negative or normal H-2(b) animals. Resistant tumor necrosis factor alpha receptor I knockout mice also generate a high frequency of CD8(+) CNS-ILs specific for Db:VP2121-130. Furthermore, normally susceptible FVB mice that express a Db transgene generate Db:VP2121-130-specific CD8(+) CNS-ILs at a frequency similar to that of C57BL/6 mice. These results demonstrate that VP2121-130 presented in the context of Db is an immunodominant epitope in TMEV infection and that the frequency of the VP2121-130-specific CTLs appears to be independent of several key inflammatory mediators and genetic background but is regulated in part by the expression of CD4.

Animals↗

PubMed1998

Perforin-dependent neurologic injury in a viral model of multiple sclerosis.

In this study we demonstrate perforin-mediated cytotoxic effector function is necessary for viral clearance and may directly contribute to the development of neurologic deficits after demyelination in the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis. We previously demonstrated major histocompatability complex (MHC) class I-deficient (beta2m-deficient) mice with an otherwise resistant genotype develop severe demyelination with minimal neurologic disease when chronically infected with TMEV. These studies implicate CD8(+) T cells as the pathogenic cell in the induction of neurologic disease after demyelination. To determine which effector mechanisms of CD8(+) T cells, granule exocytosis or Fas ligand expression, play a role in the development of demyelination and clinical disease, we infected perforin-deficient, lpr (Fas mutation), and gld (Fas ligand mutation) mice with TMEV. Perforin-deficient mice showed viral persistence in the CNS, chronic brain pathology, and demyelination in the spinal cord white matter. Perforin-deficient mice demonstrated severely impaired MHC class I-restricted cytotoxicity against viral epitopes, but normal MHC class II-restricted delayed-type hypersensitivity responses to virus antigen. Despite demyelination, virus-infected perforin-deficient mice showed only minimal neurologic deficits as indicated by clinical disease score, activity monitoring, and footprint analysis. Perforin- and MHC class II-deficient mice (with functional CD8(+) T cells and perforin molecules and an H-2(b) haplotype) had comparable demyelination and genotype, however, only the latter showed severe clinical disease. Gld and lpr mice demonstrated normal TMEV-specific cytotoxicity and maintained resistance to TMEV-induced demyelinating disease. These studies implicate perforin release by CD8(+) T cells as a potential mechanism by which neurologic deficits are induced after demyelination.

Animals↗

PubMed1997

The immune system preferentially clears Theiler's virus from the gray matter of the central nervous system.

Infection of susceptible strains of mice with Daniel's (DA) strains of Theiler's murine encephalomyelitis virus (DAV) results in virus persistence in the central nervous system (CNS) white matter and chronic demyelination similar to that observed in multiple sclerosis. We investigated whether persistence is due to the immune system more efficiently clearing DAV from gray than from white matter of the CNS. Severe combined immunodeficient (SCID) and immunocompetent C.B-17 mice were infected with DAV to determine the kinetics, temporal distribution, and tropism of the virus in CNS. In early disease (6 h to 7 days postinfection), DAV replicated with similar kinetics in the brains and spinal cords of SCID and immunocompetent mice and in gray and white matter. DAV RNA was localized within 48 h in CNS cells of all phenotypes, including neurons, oligodendrocytes, astrocytes, and macrophages/microglia. In late disease (13 to 17 days postinfection), SCID mice became moribund and permitted higher DAV replication in both gray and white matter. In contrast, immunocompetent mice cleared virus from the gray matter but showed replication in the white matter of their brains and spinal cords. Reconstitution of SCID mice with nonimmune splenocytes or anti-DAV antibodies after establishment of infection demonstrated that both cellular and humoral immune responses decreased virus from the gray matter; however, the cellular responses were more effective. SCID mice reconstituted with splenocytes depleted of CD4+ or CD8+ T lymphocytes cleared virus from the gray matter but allowed replication in the white matter. These studies demonstrate that both neurons and glia are infected early following DAV infection but that virus persistence in the white matter is due to preferential clearance of virus from the gray matter by the immune system.

Animals↗

PubMed1997

Interferon alpha/beta mediates early virus-induced expression of H-2D and H-2K in the central nervous system.

Cells of the central nervous system (CNS) normally do not express detectable levels of major histocompatibility complex (MHC) Class I antigens. However, MHC Class I expression can be induced after virus infection. We tested the hypothesis that virus-induced Class I expression is mediated by lymphocytes or cytokines using lymphocyte- and cytokine-deficient mice. We used Theiler's murine encephalomyelitis virus (TMEV), which induces CNS demyelination that maps genetically to the D region of MHC Class I and is associated with high levels of Class I products. TMEV infection of severe combined immunodeficiency (SCID) and recombination activation gene-1-deficient mice, which lack B and T lymphocytes, resulted in equivalent H-2D and H-2K expression in brain and spinal cord, according to analysis of the area and intensity of immunoperoxidase staining. Class I antigens were demonstrated as early as 6 hours after infection, and they were more widely distributed than viral RNA, indicating that expression was induced indirectly via a soluble factor. To determine whether cytokines induced the expression, we infected mice lacking receptors for interferon-alpha/beta (IFN-alpha/beta R (-/-)), interferon-gamma (IFN-gamma R(-/-)), and tumor necrosis factor-alpha (TNFRp55(-/-)). TMEV-infected IFN-gamma R(-/-) and TN-FRp55(-/-) mice expressed Class I antigens in the CNS, whereas IFN-alpha/beta R(-/-) mice did not, establishing that IFN-alpha/beta mediated the expression. In contrast to the equivalent expression in SCID mice, we observed greater area and higher intensity of H-2D versus H-2K antigens in infected SCID mice reconstituted with normal spleen cells. Collectively, the data indicate that after TMEV infection, early generalized MHC Class I expression is mediated by IFN-alpha/beta independently of lymphocytes, but the differential regulation of H-2D over H-2K may be controlled by B and/or T lymphocytes.

Animals↗

PubMed1996

The balance between persistent virus infection and immune cells determines demyelination.

We addressed the contributions of persistent virus infection and immune cells to the pathogenesis of Theiler's virus-induced demyelination, a model for human multiple sclerosis. We developed a model involving the transfer of spleen cells into immunodeficient C.B-17-scid (SCID) mice, which normally die of overwhelming virus encephalitis without demyelination when infected with Theiler's virus. Adoptive transfer of nonimmune spleen cells from BALB/c mice into SCID mice resulted in the survival of all mice. However, these mice developed extensive demyelination and virus Ag/RNA persistence in the spinal cord white matter. The most demyelination was observed when mice received an intermediate number of spleen cells (1.8-7.5 x 10(6)), whereas too few cells (0.5 x 10(6)) did not ameliorate the SCID phenotype, and too many cells (30 x 10(6)) resulted in almost complete viral clearance with minimal demyelination. Adoptive transfer of spleen cells depleted of either CD4+ or CD8+ T cells produced vacuolar demyelination associated with virus persistence. In contrast, reconstitution with both CD4+ and CD8+ T cells produced less severe demyelination and partial clearance of virus. These experiments support the hypothesis that demyelination is the result of a balance between persistent virus infection and immune injury mediated by either CD4+ or CD8+ T cells.

Adoptive Transfer↗

PubMed1996

A monoclonal natural autoantibody that promotes remyelination suppresses central nervous system inflammation and increases virus expression after Theiler's virus-induced demyelination.

We have used an established experimental model of multiple sclerosis to investigate the potential beneficial relationship between natural autoimmunity and remyelination after central nervous system (CNS) demyelination. Intracerebral infection of SJL/J mice with Theiler's murine encephalomyelitis virus (TMEV) produces chronic, progressive, inflammatory CNS demyelination. Chronically infected SJL/J mice show minimal spontaneous remyelination, which is in part due to a T cell-mediated immune response inhibiting myelin repair. We previously identified a monoclonal natural autoantibody, designated SCH94.03, that promotes remyelination when passively transferred to chronically infected SJL/J mice. The mechanism whereby SCH94.03 promotes remyelination is unknown, although previous reports suggest that natural autoantibodies can modulate immune system function. In this report we demonstrate that treatment with SCH94.03 reduced by 2- to 3-fold the number of CD4(+) and CD8(+) cells infiltrating the CNS of SJL/J mice chronically infected with TMEV, in the absence of global lymphocyte depletion. Associated with the decreased inflammation was a 2- to 3-fold increase in virus antigen expression without a significant increase in viral RNA or virus titers. Treatment with SCH94.03 also suppressed the humoral immune response to a T cell-dependent antigen in chronically infected mice. Immunohistochemical staining showed that SCH94.03 labeled MHC class II-positive dendritic cells in peripheral lymphoid organs. These results are consistent with the proposed immunomodulatory function of natural autoantibodies and suggest that one mechanism whereby SCH94.03 promotes CNS remyelination in chronically infected SJL/J mice is through inhibition of a pathogenic immune response.

Animals↗

PubMed1996

Animal models of demyelination.

In the past year, animal studies on central nervous system demyelination have focused on therapeutic strategies and the functional characterization of T-cells, cytokines, and adhesion molecules. Significant progress has been realized in the treatment of animals with experimentally induced demyelinating disease using glial cell transplants, autoantibodies, cytokines, growth factors, and by inhibiting adhesion molecules and cytokines. In this review, we summarize the important contributions made in those respective areas.

Animals↗

PubMed1996

Theiler's virus persistence and demyelination in major histocompatibility complex class II-deficient mice.

Mice with targeted disruption of the A beta gene of major histocompatibility complex class II molecules (Abo) were used to investigate the role of class II gene products in resistance or susceptibility to virus-induced chronic demyelination in the central nervous system (CNS). Class-II-deficient mice from the resistant H-2b [H-2b(Abo)] and nonmutant H-2b backgrounds were infected with Theiler's murine encephalomyelitis virus intracerebrally and examined for CNS virus persistence, demyelination, and neurologic clinical signs. Virus titers measured by plaque assays showed that 8 of 10 normally resistant nonmutant H-2b mice had cleared the virus within 21 days, whereas the other 2 mice had low titers. In contrast, all class II-deficient Abo mice had high virus titers for up to 90 days after infection (4.30 log10 PFU per g of CNS tissue). Virus antigens and RNA were localized to the brains (cortex, hippocampus, thalamus, and brain stem) and spinal cords of Abo mice. Colocalization identified persistent Theiler's murine encephalomyelitis virus in oligodendrocytes and astrocytes but not in macrophages. There was demyelination in 11 of 23 and 6 of 9 Abo mice 45 and 90 days after virus infection, respectively, whereas no demyelination was observed in infected nonmutant H-2b mice. Demyelinating lesions in Abo mice showed virus-specific CD8+ T cells and macrophages but no CD4+ T cells. Spasticity and paralysis were observed in chronically infected Abo mice but not in the nonmutant H-2b mice. These findings demonstrate that class II gene products are required for virus clearance from the CNS but not for demyelination and neurologic disease.

Animals↗