Ciba Foundation Symposium 129 - Autoimmunity and Autoimmune Disease, 2007
A number of rat monoclonal antibodies of the IgG2b subclass have been used to deplete mice of T l... more A number of rat monoclonal antibodies of the IgG2b subclass have been used to deplete mice of T lymphocyte subsets. It has been possible to produce long-term depletion where antibodies are administered to mice thymectomized in their adult life, or short-term depletion in euthymic animals. It is therefore feasible to ablate a T lymphocyte subpopulation at any stage in the course of an immune response and to examine in detail the role of a particular subset in the induction or effector phases of that response. We have used such ablative procedures to define the T cell subsets which participate in graft rejection, graft-versus-host disease, antigenic competition and antiviral and anti-self immunity and have attempted to exploit such knowledge to establish immunological tolerance in an adult animal.
IEEE transactions on bio-medical engineering, 2018
The blood-brain barrier (BBB) poses a unique challenge to the development of therapeutics against... more The blood-brain barrier (BBB) poses a unique challenge to the development of therapeutics against neurological disorders due to its impermeabi-lity to most of the chemical compounds. Most in vitro BBB models have limitations in mimicking in vivo conditions and functions. Here, we show a co-culture microfluidic BBB-on-a-chip that provides interactions between neurovascular endothelial cells and neuronal cells across a porous polycarbonate membrane, which better mimics the in vivo conditions, as well as allows in vivo level shear stress to be applied. A 4 × 4 intersecting microchannel array forms 16 BBB sites on a chip, with a multielectrode array integrated to measure the transendothelial electrical resistance (TEER) from all 16 different sites, which allows label-free real-time analysis of the barrier function. Primary mouse endothelial cells and primary astrocytes were co-cultured in the chip while applying in vivo level shear stress. The chip allows the barrier function to be anal...
International Archives of Allergy and Immunology, 1985
Thirty-six percent of Old English rabbits fed pasteurized cow’s milk developed early rheumatoid-l... more Thirty-six percent of Old English rabbits fed pasteurized cow’s milk developed early rheumatoid-like synovial lesions. All rabbits drinking milk developed high titres of serum and synovial fluid C1q-binding activity. This has been shown to be due to specific antibody to C1q, produced in response to Clq in cow’s milk. In addition, these rabbits responded to other bovine proteins present in cow’s milk, including conglutinin, β-lactoglobulin and IgG. There was no correlation between serum or synovial fluid titres of antibody to bovine milk proteins and synovial lesions.
Inflammation within the nervous system has become a highly researched area and has been implicate... more Inflammation within the nervous system has become a highly researched area and has been implicated not only in infectious and autoimmune diseases, but also in many neurodegenerative diseases. Drs. Minagar and Alexander have compiled an excellent book consisting of 18 chapters written by experts in each discipline. This book is part of a series in Current Clinical Neurology and is principally designed for clinicians as a continuing medical education publication, with questions at the end of each chapter. The first few chapters in the book set the stage for the reader by providing the latest research in CNS inflammation in general. The topics covered are: Endothelial cell– leukocyte interactions; Cytokines and chemokines in the CNS; and Circulating cell-derived microparticles in thrombotic and inflammatory disorders. The chapter on cytokines in the brain describes cytokine expression in the normal brain and then in bacterial meningitis and experimental brain abscess. Both bacterial me...
Sex Differences in the Central Nervous System, 2016
This chapter will focus on sex differences and the role of gonadal steroids in three neurologic d... more This chapter will focus on sex differences and the role of gonadal steroids in three neurologic diseases: cerebrovascular stroke (ischemic), multiple sclerosis (MS), and epilepsy. In the case of stroke, younger women are less likely to sustain a stroke than men; however, with age, females have a higher incidence of stroke and more severe outcomes than males. In preclinical studies, estrogen improves stroke outcomes in young animals, while its effects on older animals are controversial. In contrast, MS occurs more often in women compared with men, but paradoxically, ovarian/pregnancy hormones may be beneficial for patients with MS. In the case of epilepsy, women exhibit greater fluctuations in seizure susceptibility, usually associated with the menstrual cycle. The latter condition is called catamenial epilepsy and studies indicate that progestin therapy may offer benefit for this type of epilepsy. This chapter will also describe the role of inflammation in these diseases.
Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in immun... more Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in immune‐mediated demyelination in selective mouse strains. We have previously demonstrated that the males of C57L mice are significantly more susceptible to TMEV‐induced demyelinating disease. To assess further the hormonal influence for this gender‐associated differential susceptibility, estrogen‐treated, castrated C57L mice were infected with TMEV and compared with sham‐operated and/or placebo‐treated mice. Interestingly, castration further elevated the susceptibility to virally induced demyelinating disease compared with sham‐castrated control mice, and prolonged treatment of castrated mice with estrogen restored the resistance to the level of control mice. These results strongly suggest that sex hormone levels contribute to the gender‐biased susceptibility to TMEV‐induced demyelinating disease. Mice treated with estrogen showed a significantly decreased level of virus‐specific Th1 response...
Theiler's murine encephalomyelitis virus (TMEV) is a picornavirus which causes a biphasic cen... more Theiler's murine encephalomyelitis virus (TMEV) is a picornavirus which causes a biphasic central nervous system (CNS) disease in certain strains of mice. Lytic virus replication within the CNS causes acute damage at early times post-infection, with the surviving animals developing a chronic CNS demyelinating disease. This damage is thought to result both from direct viral damage and from an immunopathological CD4+ T-cell mediated delayed-type hypersensitivity response to virus. By contrast, CD4+ T cells have a vital protective role at early times post-infection, as mice specifically depleted of CD4+ T cells of this subset prior to infection with TMEV die within 3-5 weeks. In an investigation of how CD4+ T cells act to mediate protection in TMEV-infected mice, we show that CD4+ cell-depleted animals, which fail to make a significant antiviral antibody response, could be protected by passive transfer of neutralizing antibodies. However, surviving animals had high levels of persis...
Physical and psychosocial stressors have been shown to compromise immune function (Ader et al., 1... more Physical and psychosocial stressors have been shown to compromise immune function (Ader et al., 1991; Kielcolt-Glaser and Glaser, 1995). The immune suppressive effects of stress may be more pronounced in individ-uals that already have limited immune competence, such ...
A wide range of viruses cause neurological manifestations in their hosts. Infection by neurotropi... more A wide range of viruses cause neurological manifestations in their hosts. Infection by neurotropic viruses as well as the resulting immune response can irreversibly disrupt the complex structural and functional architecture of the brain, depending in part on host genetic background. The interaction between host genetic background, neurological response to viral infection, and subsequent clinical manifestations remains poorly understood. In the present study, we used the genetically diverse Collaborative Cross (CC) mouse resource to better understand how differences in genetic background drive clinical signs and neuropathological manifestations of acute Theiler’s murine encephalomyelitis virus (TMEV) infection. For the first time, we characterized variations of TMEV viral tropism and load based on host genetic background, and correlated viral load with microglial/macrophage activation. For five CC strains (CC002, CC023, CC027, CC057, and CC078) infected with TMEV, we compared clinica...
Host genetic background is a significant driver of the variability in neurological responses to v... more Host genetic background is a significant driver of the variability in neurological responses to viral infection. Here, we leverage the genetically diverse Collaborative Cross (CC) mouse resource to better understand how chronic infection by Theiler’s Murine Encephalomyelitis Virus (TMEV) elicits diverse clinical and morphologic changes in the central nervous system (CNS). We characterized the TMEV-induced clinical phenotype responses, and associated lesion distributions in the CNS, in six CC mouse strains over a 90 day infection period. We observed varying degrees of motor impairment in these strains, as measured by delayed righting reflex, paresis, paralysis, seizures, limb clasping, ruffling, and encephalitis phenotypes. All strains developed neuroparenchymal necrosis and mineralization in the brain, primarily localized to the hippocampal regions. Two of the six strains presented with axonal degeneration with myelin loss of the nerve roots in the lumbar spinal cord. Moreover, we s...
Ciba Foundation Symposium 129 - Autoimmunity and Autoimmune Disease, 2007
A number of rat monoclonal antibodies of the IgG2b subclass have been used to deplete mice of T l... more A number of rat monoclonal antibodies of the IgG2b subclass have been used to deplete mice of T lymphocyte subsets. It has been possible to produce long-term depletion where antibodies are administered to mice thymectomized in their adult life, or short-term depletion in euthymic animals. It is therefore feasible to ablate a T lymphocyte subpopulation at any stage in the course of an immune response and to examine in detail the role of a particular subset in the induction or effector phases of that response. We have used such ablative procedures to define the T cell subsets which participate in graft rejection, graft-versus-host disease, antigenic competition and antiviral and anti-self immunity and have attempted to exploit such knowledge to establish immunological tolerance in an adult animal.
IEEE transactions on bio-medical engineering, 2018
The blood-brain barrier (BBB) poses a unique challenge to the development of therapeutics against... more The blood-brain barrier (BBB) poses a unique challenge to the development of therapeutics against neurological disorders due to its impermeabi-lity to most of the chemical compounds. Most in vitro BBB models have limitations in mimicking in vivo conditions and functions. Here, we show a co-culture microfluidic BBB-on-a-chip that provides interactions between neurovascular endothelial cells and neuronal cells across a porous polycarbonate membrane, which better mimics the in vivo conditions, as well as allows in vivo level shear stress to be applied. A 4 × 4 intersecting microchannel array forms 16 BBB sites on a chip, with a multielectrode array integrated to measure the transendothelial electrical resistance (TEER) from all 16 different sites, which allows label-free real-time analysis of the barrier function. Primary mouse endothelial cells and primary astrocytes were co-cultured in the chip while applying in vivo level shear stress. The chip allows the barrier function to be anal...
International Archives of Allergy and Immunology, 1985
Thirty-six percent of Old English rabbits fed pasteurized cow’s milk developed early rheumatoid-l... more Thirty-six percent of Old English rabbits fed pasteurized cow’s milk developed early rheumatoid-like synovial lesions. All rabbits drinking milk developed high titres of serum and synovial fluid C1q-binding activity. This has been shown to be due to specific antibody to C1q, produced in response to Clq in cow’s milk. In addition, these rabbits responded to other bovine proteins present in cow’s milk, including conglutinin, β-lactoglobulin and IgG. There was no correlation between serum or synovial fluid titres of antibody to bovine milk proteins and synovial lesions.
Inflammation within the nervous system has become a highly researched area and has been implicate... more Inflammation within the nervous system has become a highly researched area and has been implicated not only in infectious and autoimmune diseases, but also in many neurodegenerative diseases. Drs. Minagar and Alexander have compiled an excellent book consisting of 18 chapters written by experts in each discipline. This book is part of a series in Current Clinical Neurology and is principally designed for clinicians as a continuing medical education publication, with questions at the end of each chapter. The first few chapters in the book set the stage for the reader by providing the latest research in CNS inflammation in general. The topics covered are: Endothelial cell– leukocyte interactions; Cytokines and chemokines in the CNS; and Circulating cell-derived microparticles in thrombotic and inflammatory disorders. The chapter on cytokines in the brain describes cytokine expression in the normal brain and then in bacterial meningitis and experimental brain abscess. Both bacterial me...
Sex Differences in the Central Nervous System, 2016
This chapter will focus on sex differences and the role of gonadal steroids in three neurologic d... more This chapter will focus on sex differences and the role of gonadal steroids in three neurologic diseases: cerebrovascular stroke (ischemic), multiple sclerosis (MS), and epilepsy. In the case of stroke, younger women are less likely to sustain a stroke than men; however, with age, females have a higher incidence of stroke and more severe outcomes than males. In preclinical studies, estrogen improves stroke outcomes in young animals, while its effects on older animals are controversial. In contrast, MS occurs more often in women compared with men, but paradoxically, ovarian/pregnancy hormones may be beneficial for patients with MS. In the case of epilepsy, women exhibit greater fluctuations in seizure susceptibility, usually associated with the menstrual cycle. The latter condition is called catamenial epilepsy and studies indicate that progestin therapy may offer benefit for this type of epilepsy. This chapter will also describe the role of inflammation in these diseases.
Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in immun... more Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in immune‐mediated demyelination in selective mouse strains. We have previously demonstrated that the males of C57L mice are significantly more susceptible to TMEV‐induced demyelinating disease. To assess further the hormonal influence for this gender‐associated differential susceptibility, estrogen‐treated, castrated C57L mice were infected with TMEV and compared with sham‐operated and/or placebo‐treated mice. Interestingly, castration further elevated the susceptibility to virally induced demyelinating disease compared with sham‐castrated control mice, and prolonged treatment of castrated mice with estrogen restored the resistance to the level of control mice. These results strongly suggest that sex hormone levels contribute to the gender‐biased susceptibility to TMEV‐induced demyelinating disease. Mice treated with estrogen showed a significantly decreased level of virus‐specific Th1 response...
Theiler's murine encephalomyelitis virus (TMEV) is a picornavirus which causes a biphasic cen... more Theiler's murine encephalomyelitis virus (TMEV) is a picornavirus which causes a biphasic central nervous system (CNS) disease in certain strains of mice. Lytic virus replication within the CNS causes acute damage at early times post-infection, with the surviving animals developing a chronic CNS demyelinating disease. This damage is thought to result both from direct viral damage and from an immunopathological CD4+ T-cell mediated delayed-type hypersensitivity response to virus. By contrast, CD4+ T cells have a vital protective role at early times post-infection, as mice specifically depleted of CD4+ T cells of this subset prior to infection with TMEV die within 3-5 weeks. In an investigation of how CD4+ T cells act to mediate protection in TMEV-infected mice, we show that CD4+ cell-depleted animals, which fail to make a significant antiviral antibody response, could be protected by passive transfer of neutralizing antibodies. However, surviving animals had high levels of persis...
Physical and psychosocial stressors have been shown to compromise immune function (Ader et al., 1... more Physical and psychosocial stressors have been shown to compromise immune function (Ader et al., 1991; Kielcolt-Glaser and Glaser, 1995). The immune suppressive effects of stress may be more pronounced in individ-uals that already have limited immune competence, such ...
A wide range of viruses cause neurological manifestations in their hosts. Infection by neurotropi... more A wide range of viruses cause neurological manifestations in their hosts. Infection by neurotropic viruses as well as the resulting immune response can irreversibly disrupt the complex structural and functional architecture of the brain, depending in part on host genetic background. The interaction between host genetic background, neurological response to viral infection, and subsequent clinical manifestations remains poorly understood. In the present study, we used the genetically diverse Collaborative Cross (CC) mouse resource to better understand how differences in genetic background drive clinical signs and neuropathological manifestations of acute Theiler’s murine encephalomyelitis virus (TMEV) infection. For the first time, we characterized variations of TMEV viral tropism and load based on host genetic background, and correlated viral load with microglial/macrophage activation. For five CC strains (CC002, CC023, CC027, CC057, and CC078) infected with TMEV, we compared clinica...
Host genetic background is a significant driver of the variability in neurological responses to v... more Host genetic background is a significant driver of the variability in neurological responses to viral infection. Here, we leverage the genetically diverse Collaborative Cross (CC) mouse resource to better understand how chronic infection by Theiler’s Murine Encephalomyelitis Virus (TMEV) elicits diverse clinical and morphologic changes in the central nervous system (CNS). We characterized the TMEV-induced clinical phenotype responses, and associated lesion distributions in the CNS, in six CC mouse strains over a 90 day infection period. We observed varying degrees of motor impairment in these strains, as measured by delayed righting reflex, paresis, paralysis, seizures, limb clasping, ruffling, and encephalitis phenotypes. All strains developed neuroparenchymal necrosis and mineralization in the brain, primarily localized to the hippocampal regions. Two of the six strains presented with axonal degeneration with myelin loss of the nerve roots in the lumbar spinal cord. Moreover, we s...
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