Transgenic mouse model for central nervous system demyelination.

A common feature of demyelinating diseases such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis in rodents is the marked elevation in the expression of the major histocompatibility complex (MHC) antigens in the involved sites. By specific targeting of a syngeneic MHC class I gene to oligodendrocytes, we have generated transgenic mice which not only exhibit severe involuntary tremors and develop tonic seizures but also show extensive demyelination in both the brain and the spinal cord. The fact that demyelination in these mice occurs in the absence of immune infiltration dismisses an autoimmune involvement but suggests that the MHC class I antigens play a direct role in inducing disease. Our findings lend support to the possibility that demyelinating diseases are induced by infectious agents such as viruses which can either directly activate MHC gene expression in oligodendroglia or indirectly activate expression through the release by reactive T cells of gamma interferon in the brain.     

Attenuation of experimental autoimmune demyelination in complement-deficient mice

The exact mechanisms leading to CNS inflammation and myelin destruction in multiple sclerosis and in its animal model, experimental allergic encephalomyelitis (EAE) remain equivocal. In both multiple sclerosis and EAE, complement activation is thought to play a pivotal role by recruiting inflammatory cells, increasing myelin phagocytosis by macrophages, and exerting direct cytotoxic effects through the deposition of the membrane attack complex on oligodendrocytes. Despite this assumption, attempts to evaluate complement's contribution to autoimmune demyelination in vivo have been limited by the lack of nontoxic and/or nonimmunogenic complement inhibitors. In this report, we used mice deficient in either C3 or factor B to clarify the role of the complement system in an Ab-independent model of EAE. Both types of complement-deficient mice presented with a markedly reduced disease severity. Although induction of EAE led to inflammatory changes in the meninges and perivascular spaces of both wild-type and complement-deficient animals, in both C3(-/-) and factor B(-/-) mice there was little infiltration of the parenchyma by macrophages and T cells. In addition, compared with their wild-type littermates, the CNS of both C3(-/-) and factor B(-/-) mice induced for EAE are protected from demyelination. These results suggest that complement might be a target for the therapeutic treatment of inflammatory demyelinating diseases of the CNS.     

Treatment of encephalomyocarditis virus-induced central nervous system demyelination with monoclonal anti-T-cell antibodies.

Infection of BALB/c mice with the M variant of encephalomyocarditis virus resulted in the development of a paralytic syndrome in 7 to 10 days. The paralysis was maximal during the period of viral clearance; most of the animals recovered from the initial deficit and showed no delayed recurrences. Pathologically, the white matter of brain and spinal cord showed well-demarcated areas of perivascular cuffing, demyelination, and, during recovery, remyelination by oligodendrocytes--all suggestive of postinfectious encephalomyelitis. Depletion of either the CD4 or CD8 subset of T cells in vivo with the appropriate monoclonal antibody, GK1.5 or 2.43, respectively, administered one day (24 h) prior to infection was sufficient to limit the development of the paralytic syndrome by 79% (GK1.5) and 82% (2.43).     

Content of phospholipid, cerebroside and cerebroside sulfate in the central nervous system of mice with acute experimental viral demyelination

A study was made of the content of phospholipids, cerebrosides and cerebroside sulfates in the central nervous system of mice with experimental acute viral encephalomyelitis. No considerable changes in phospholipid content were revealed. A significant drop in the content of cerebrosides and cerebroside sulfates was defected in the CNS, being more pronounced in the spinal cord of sick animals. The reduction in the content of glycolipids can be explained by myelin disintegration and by the effect of viruses on the olygodendrocytes in which cerebrosides and cerebroside sulfates are synthesized.     

Neuroglial response after induction of experimental allergic encephalomyelitis in susceptible and resistant rat strains

Experimental allergic encephalomyelitis (EAE), the animal model for multiple sclerosis in humans, a T-cell mediated disease of the central nervous system is characterized by inflammatory infiltrates of myelin antigen(s)-specific T cells and consecutive demyelination. Spinal cord tissue emulsified in complete Freund's adjuvant clinical disease in the genetically susceptible Dark Agouti rats (DA) but not in Albino Oxford (AO) rats although similar inflammatory infiltrates in the CNS are observed in both strains 10-12 days after induction. We have shown that the resistance to clinical disease of AO rats is associated with rapid clearance of infiltrating mononuclear cells by a mechanism of apoptosis. Here, we demonstrate by immunohistochemical and FACS analyses of the expression of CD11b/c that microglial cells respond differently to disease induction in the two strains. Whereas microglial cells are activated throughout the period of day 10-28 days after EAE induction in AO rats they are only activated at the inception and resolution phases but not at the peak of clinical disease in DA rats when there is the highest level of CD4+ T cell infiltration. Our findings are compatible with the notion that microglia terminate effector T cells by apoptosis and that lack of this mechanism as evidenced by the lack of CD11b/c expression, support T cell survival and clinical expression of disease.     

Characterization of dopamine receptors involved in central thermoregulation in rabbits.

Intracerebroventricularly administered dopamine produced dose dependent hyperthermia in rabbits. Haloperidol, a D1 receptor blocker produced consistent hypothermia, whereas D2 receptor blocker metoclopramide produced hyperthermia, pretreatment with haloperidol competitively blocked the hyperthermic response of dopamine. Pretreatment with metoclopramide augmented the onset and peak response of dopamine. It is suggested that D1 receptors are involved in producing hyperthermia and D2 receptors in hypothermia.     

Growth of calvarial width. An experimental investigation in rabbits

This investigation was conducted to analyze growth in width of the rabbit calvarium. 15 male New Zealand white rabbits were subjected to regular stereometric examinations from 31 to 141 days of age after implantation of tantalum bone markers. The sagittal suture complex, i.e. the interfrontal and interparietal sutures, and the bilateral temporal sutures demonstrated similar growth rates in magnitude which moderately decelerated throughout the observation period. Transverse growth exhibited local growth fluctuations and short-term negative growth values in a well-balanced manner.     

Antigen-specific T cells can mediate demyelination in organotypic central nervous system cultures

To investigate a role for T lymphocytes in primary demyelination of central nervous system (CNS) tissue, antigen-specific T cell lines sensitized to myelin-associated and myelin-unrelated antigens were developed from SJL mice and tested on myelinated organotypic cultures of syngeneic spinal cord. Demyelination was assessed morphologically by electron microscopy. Antigen responsiveness and specificity, and the phenotypes of the cell lines, were determined by thymidine uptake (3H-TdR) assays and flow cytometry (FC), respectively. Although all T cell lines caused pathologic changes in myelin, the CNS-antigen-specific line induced the most pronounced effects. 3H-TdR uptake assays and FC showed that after three cycles of incubation in the presence of interleukin-2 (IL-2) or antigen, the T cell lines had increased specificity and responsiveness to the priming antigen and were enriched for the L3T4 (helper/inducer) phenotype. This represents the first direct demonstration of T-cell-mediated demyelination, supports a role for the helper/inducer subset in CNS lesion development, and may prove relevant to the human demyelinating disease multiple sclerosis.     

LINGO-1 siRNA nanoparticles promote central remyelination in ethidium bromide-induced demyelination in rats

Journal of Physiology and Biochemistry - Multiple sclerosis is among the most common causes of neurological disabilities in young adults. Over the past decade, several therapeutic strategies have...     

Phenotypes of dendritic cells in central lymph of healthy rabbits and during correction of experimental atherosclerosis]

Dendritic cells of central lymph of rabbits have been identified according to the form of the cell body, characteristics of formation and branchiness of its processes in health, in atherosclerosis, its correction with radon, polyphenol preparations made of Sanguisorba officinalis and in combination of the latter. Two main types of dendritic cells have been distinguished. Type I is characterized by a rounded body with clear outlines, protrusions and one compact process. Such cells are often found in lymph of intact animals. Type II has a cell body of various forms with two and more compact or branching processes. This type is mainly detected in atherosclerosis and its correction. The prevalence of the above phenotypes of dendritic cells is attributed to the response of the immune system to atherosclerosis and its correction.