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Biomedical subjects

A H Cross

Publications and source records attributed to A H Cross.

At least 37 records · Page 2Linked to original sources
PubMed1998

Nitric oxide synthase inhibitor, aminoguanidine, reduces inflammation and demyelination produced by Theiler's virus infection.

This study evaluated effects of the inducible nitric oxide synthase (iNOS) inhibitor, aminoguanidine (AG), on the neuropathology and clinical disease produced by Theiler's murine encephalomyelitis virus (TMEV) DA strain infection. Treatment with AG was started on day 7, 14, 28 or 66 post-inoculation and continued for a minimum of 21 days. Inflammation, demyelination and axonal necrosis were scored in a blinded fashion on spinal cord sections from each mouse. Reduction in inflammation, demyelination and axonal necrosis was observed in mice treated with AG. Apoptosis within the spinal cord parenchyma and perivascular cuffs was significantly decreased. AG treatment resulted in delayed onset of clinical disease.

Animals↗
PubMed1997

Fas and Fas ligand enhance the pathogenesis of experimental allergic encephalomyelitis, but are not essential for immune privilege in the central nervous system.

Mutations of CD95 and CD95L, lpr and gld, respectively, are associated with spontaneous autoimmune disease and alteration of immune privilege. In lpr or gld animals these processes would be expected to exacerbate experimental allergic encephalomyelitis (EAE), an animal model of the autoimmune demyelinating disease multiple sclerosis. However, here we show that the lpr and gld mutations did not overcome the MHC-defined limits of disease and, surprisingly, did not exacerbate the pathology of EAE on a sensitive haplotype. In fact, the mutations dramatically ameliorated clinical signs of EAE without affecting the development of a Th1 response or inflammatory cell infiltration into the central nervous system. Fewer apoptotic cells were detected in inflammatory lesions of lpr mice than in wild-type lesions of similar severity. Our results indicate that CD95L is not an instrumental component of immune privilege in the central nervous system, and that functional CD95 and CD95L are important for the progression of clinical disease.

Animals↗
PubMed1997

Measurement of upregulation of inducible nitric oxide synthase in the experimental autoimmune encephalomyelitis model using a positron emitting radiopharmaceutical.

Excess nitric oxide has been implicated in the pathogenosis of experimental autoimmune encephalomyelitis (EAE) which is an animal model for multiple sclerosis. Positron emission tomography (PET) is an imaging technique that has shown utility for studying enzyme systems in vivo. A positron-labeled inducible nitric oxide synthetase (iNOS) inhibitor has been studied in EAE-affected mice as well as controls. Greater uptake of the radiolabeled inhibitor was observed in the spinal cord of the affected mice than of control mice. Increased uptake was also observed in other organs not previously implicated in this experimental model. The increased uptake of the radiopharmaceutical in this model suggests that this tracer may have the potential for measuring increased levels of iNOS in humans by PET.

Animals↗
PubMed1997

HPRT mutant T-cell lines from multiple sclerosis patients recognize myelin proteolipid protein peptides.

Mutation of the hypoxanthine-guanine phosphoribosyl transferase (HPRT) gene in a T-cell is believed to be an indication that the T-cell has been activated and has proliferated in vivo. HPRT mutant T-cell lines were generated from peripheral blood mononuclear cells from patients with MS and control subjects. More lines were isolated from the MS patients than from the control subjects. Using stringent criteria for recognition, none of the lines from MS-affected or control subjects recognized intact myelin basic protein (MBP) or myelin proteolipid protein (PLP) molecules. Using stringent criteria, two of the 10 MS patients harbored mutant lines each recognizing distinct PLP peptides (PLP peptide 40-60 recognized by 3 lines from one patient and PLP peptide 178-191 recognized by 2 lines from the other patient). A single line recognizing PLP peptide 89-106 was derived from 1 of 7 normal controls. HPRT mutant lines recognizing multiple epitopes of PLP which spanned much of the molecule could be isolated from MS patients, and to a lesser extent, normal subjects.

Adult↗
PubMed1997

Evidence for the production of peroxynitrite in inflammatory CNS demyelination.

Peroxynitrite, which is generated by the reaction of nitric oxide (NO) with superoxide, is a strong oxidant that can damage subcellular organelles, membranes and enzymes through its actions on proteins, lipids, and DNA, including the nitration of tyrosine residues of proteins. Detection of nitrotyrosine (NT) serves as a biochemical marker of peroxynitrite-induced damage. In the present studies, NT was detected by immunohistochemistry in CNS tissues from mice with acute experimental autoimmune encephalomyelitis (EAE). NT immunoreactivity was displayed by many mononuclear inflammatory cells, including CD4+ cells. It was also observed in astrocytes near EAE lesions. Immunostaining for the inducible isoform of NO synthase (iNOS) was also observed, particularly during acute EAE. These data strongly suggest that peroxynitrite formation is a major consequence of NO produced via iNOS, and implicate this powerful oxidant in the pathogenesis of EAE.

Acute Disease↗
PubMed1996

Experimental allergic encephalomyelitis in the rat is inhibited by aminoguanidine, an inhibitor of nitric oxide synthase.

This study assessed the role of de novo nitric oxide (NO) production in the pathogenesis of experimental allergic encephalomyelitis (EAE) by using aminoguanidine (AG), an inhibitor of nitric oxide synthase (NOS), which preferentially inhibits the cytokine- and endotoxin-inducible isoform of NOS versus the constitutive isoforms consisting of endothelial and neuronal NOS. The maximum clinical severity of EAE and the duration of illness were significantly reduced or totally inhibited by twice daily subcutaneous injection of 100 mg/kg body weight AG. Histochemical staining for NADPH diaphorase, which detects enzymatic activity of NOS, revealed positive reactivity in untreated EAE rats both in parenchymal blood vessel walls and in anterior horn cell neurons, while normal rats and rats with EAE treated with AG showed predominantly the neuronal positivity. Moreover, this NADPH staining pattern was further supported by the immunohistochemical findings that endothelial NOS (eNOS) expression was increased in blood vessels in the inflamed lesions of untreated EAE rats and that inducible NOS (iNOS) was detected in some inflammatory cells, while treatment with AG could significantly reduce both iNOS and eNOS production. These results suggest that: (i) both iNOS and eNOS are upregulated in inflamed areas of the rat central nervous system in EAE; (ii) increased NO production plays a role in the development of clinical signs in EAE; and (iii) selective inhibitors of iNOS and/or eNOS may have therapeutic potential for the treatment of certain autoimmune diseases.

Animals↗
PubMed1996

Murine encephalitogenic lymphoid cells induce nitric oxide synthase in primary astrocytes.

A cytokine-inducible form of nitric oxide synthase (iNOS), capable of producing large quantities of nitric oxide (NO), can be induced in many cell types. We demonstrate that conditioned medium from encephalitogenic myelin basic protein-sensitized lymphoid cells (MBP-CM) induces the expression of iNOS in primary cultures of murine astrocytes in a time- and concentration-dependent manner. iNOS mRNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) as early as 3 h post-exposure. Accumulation of nitrite into the astrocyte culture medium, an indirect measure of NO, was measurable 3 h post-exposure, plateaued at 24 h, and was prevented by the simultaneous administration of the NOS inhibitors, L-N(G)-nitroarginine methyl ester, N(G)-nitro-L-arginine or aminoguanidine. Astrocyte expression of iNOS protein, detected by immunohistochemistry and immunoprecipitation/Western blot, was prevented by inhibitors of RNA or protein metabolism, consistent with its dependence on de novo protein synthesis.

Animals↗
PubMed1996

Postpartum cerebral vasospasm treated with hypervolemic therapy.

In a 23-year-old woman, gravida 1, para 1-0-0-1, headaches and seizures developed 1 week after an uncomplicated delivery. Cerebral angiography revealed severe, diffuse cerebral vasospasm. Her symptoms resolved with hyperosmolar, hypervolemic therapy and nimodipine. Magnetic resonance angiography on postpartum day 23 confirmed persistent, severe vasospasm, and repeat magnetic resonance angiography on postpartum day 33 demonstrated interval improvement. This report documents the time course of a case of postpartum vasospasm and its response to hypervolemic, hyperosmolar therapy and nimodipine.

Adult↗
PubMed1996

Inducible nitric oxide synthase gene expression and enzyme activity correlate with disease activity in murine experimental autoimmune encephalomyelitis.

Messenger RNA encoding inducible NO synthase (iNOS) was measured by competitive reverse transcriptase polymerase chain reaction (cRT-PCR) and ribonuclease protection assays in spinal cords from mice at varying stages of experimental allergic encephalomyelitis (EAE) and from control mice. iNOS mRNA was increased in spinal cords from mice with acute EAE. cRT-PCR assays revealed a 10-20-fold increase in iNOS mRNA in spinal cords during acute EAE compared with the level observed in normal mouse spinal cords. Functional iNOS activity, as assessed by assay of calcium-independent citrulline production, was also significantly increased in spinal cords from mice with acute EAE in comparison to normal controls. The correlation of functional iNOS expression with active disease in EAE in consistent with a pathogenic role for excess NO in this model of cell-mediated central nervous system autoimmunity.

Adoptive Transfer↗
PubMed1995

Mediation of inflammation by encephalitogenic cells: interferon gamma induction of nitric oxide synthase and cyclooxygenase 2.

Experimental autoimmune encephalomyelitis (EAE) is a T cell-mediated inflammatory demyelinating disorder of the central nervous system (CNS) which serves as a prime animal model for the human disease multiple sclerosis. Previous studies from these laboratories demonstrated excess nitric oxide (NO) in the CNS of EAE-affected mice, and amelioration of EAE with a selective inhibitor of the inducible nitric oxide synthase (iNOS). Recent studies from other laboratories have indicated that prostaglandin PGE2 is increased in CNS tissues of EAE-affected rodents and that EAE is prevented by the inhibition of cyclooxygenase activity. The present study investigated the ability of encephalitogenic lymphoid cells to induce NOS and cyclooxygenase (COX-2) in the murine macrophage line, RAW 264.7. In order to mimic the extracellular milieu present in EAE lesions, conditioned medium (CM) of activated EAE-inducer cells was added to this macrophage line. CM caused a time-dependent increase in nitrite, indicating NO production. Reverse-transcriptase PCR demonstrated iNOS mRNA in RAW 264.7 cells, first detected at 3 h, and Western blots confirmed the induction in RAW cells of the 130-kDa iNOS protein. Production of nitrite by CM-exposed RAW 264.7 cells was blocked by inhibitors of NOS (L-N-methylarginine or aminoguanidine) or by antibodies to murine IFN-gamma or IL-1 beta. CM of activated encephalitogenic cells induced production of PGE2 by RAW 264.7 cells, as determined by ELISA, and Western blots identified the presence of the 70-80-kDa inducible COX (COX-2) protein. Induction of COX-2 could be inhibited by antibody to IFN-gamma. Thus, encephalitogenic cells are capable of inducing the expression of the inflammatory enzymes iNOS and COX-2 in a murine macrophage line via the T cell cytokine IFN-gamma, alone or in combination with IL-1 beta.

Animals↗
PubMed1995

Long-term inhibition of murine experimental autoimmune encephalomyelitis using CTLA-4-Fc supports a key role for CD28 costimulation.

T cell activation involves not only recognition of antigen presented by the MHC, but also nonspecific interactions termed "costimulation." The costimulatory molecules B7-1 and B7-2 are ligands on antigen-presenting cells for the CD28 and CTLA-4 receptors on T cells. Previously, a fusion protein consisting of human CTLA-4 linked to human Fc was shown to bind B7-1 and B7-2 with high avidity and to prevent specific T cell activation. Here we investigated the effects of a recombinant fusion protein consisting of the extracellular domain of human CTLA-4 bound to mouse IgG2a Fc (CTLA-4-Fc) upon experimental autoimmune encephalomyelitis, a T cell-mediated disease that serves as a model for multiple sclerosis. CTLA-4-Fc prevented experimental autoimmune encephalomyelitis in 26 of 28 CTLA-4-Fc-treated mice (median maximum score 0), whereas 28 of 30 mice treated with control mouse IgG2a developed disease (median maximum score 2.75). Less inflammation and virtually no demyelination or axonal loss occurred in CTLA-4-Fc-treated compared with control-treated mice. Activated splenocytes from CTLA-4-Fc-treated mice were able to transfer disease adoptively to naive recipients. These results indicate a key role for the B7/CD28 system in the development of actively induced murine experimental autoimmune encephalomyelitis, suggesting an area of investigation with therapeutic potential for multiple sclerosis.

Abatacept↗
PubMed1995

Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo.

OBJECTIVE: To determine the relative efficacy of amantadine, pemoline, and placebo in treatment of multiple sclerosis (MS)-related fatigue. BACKGROUND: Fatigue is a complication of MS. Both pemoline and amantadine have been used to treat MS fatigue, but their relative efficacy is not known. METHODS: Amantadine, pemoline, and placebo were compared in a randomized, double-blind, placebo-controlled study using a parallel-group design. Ninety-three ambulatory MS patients completed the study. Primary outcome measures were the fatigue severity scale (FSS); the MS-specific fatigue scale (MS-FS); and subjective response determined by verbal self-report. Secondary outcome measures consisted of assessments of sleep, depression, and vitality. Repeated-measures analysis of variance with planned post-hoc contrasts and Fisher's exact test were used to compare treatment response. RESULTS: Amantadine-treated patients showed a significantly greater reduction in fatigue, as measured by the MS-FS, than did patients treated with placebo (p = 0.04). By verbal report at the end of the study, 79% of patients treated with amantadine versus 52% treated with placebo and 32% treated with pemoline preferred drug therapy compared with no treatment (p = 0.03). No significant differences in any primary outcome measures were noted between pemoline and placebo. Neither amantadine nor pemoline affected sleep or depression relative to placebo. CONCLUSION: Amantadine was significantly better than placebo in treating fatigue in MS patients, whereas pemoline was not. The benefit of amantadine was not due to changes in sleep, depression, or neurologic disability.

Adolescent↗
PubMed1995

Interleukin-2 binding proteins in sera from normal subjects and multiple sclerosis patients.

We previously reported elevations of interleukin 2 (IL-2) in the serum of patients with chronic progressive MS. Using gel chromatography, protein A sepharose affinity chromatography, and ELISAs for IL-2 and the IL-2 soluble receptor, we now demonstrate that this cytokine is bound to serum proteins. These serum proteins include antibodies to IL-2, soluble IL-2 receptors, and high-molecular-weight proteins. Using a CTLL cell assay, a serum fraction corresponding to IgG antibodies to IL-2 inhibited the activity of this cytokine. Thus, we present evidence for potential immunomodulation of a pivotal cytokine in MS by serum proteins.

Blood Proteins↗
PubMed1994

Aminoguanidine, an inhibitor of inducible nitric oxide synthase, ameliorates experimental autoimmune encephalomyelitis in SJL mice.

Previous work from our laboratory localized nitric oxide to the affected spinal cords of mice with experimental autoimmune encephalomyelitis, a prime model for the human disease multiple sclerosis. The present study shows that activated lymphocytes sensitized to the central nervous system encephalitogen, myelin basic protein, can induce nitric oxide production by a murine macrophage cell line. Induction was inhibited by amino-guanidine, a preferential inhibitor of the inducible nitric oxide synthase isoform, and by NG-monomethyl-L-arginine. Aminoguanidine, when administered to mice sensitized to develop experimental autoimmune encephalomyelitis, inhibited disease expression in a dose-related manner. At 400 mg aminoguanidine/kg per day, disease onset was delayed and the mean maximum clinical score was 0.9 +/- 1.2 in aminoguanidine versus 3.9 +/- 0.9 in placebo-treated mice. Histologic scoring of the spinal cords for inflammation, demyelination, and axonal necrosis revealed significantly less pathology in the aminoguanidine-treated group. The present study implicates excessive nitric oxide production in the pathogenesis of murine inflammatory central nervous system demyelination, and perhaps in the human disease multiple sclerosis.

Amino Acid Oxidoreductases↗
PubMed1993

Nitric oxide localized to spinal cords of mice with experimental allergic encephalomyelitis: an electron paramagnetic resonance study.

Experimental allergic encephalomyelitis (EAE) is a demyelinating autoimmune disorder that can be induced in susceptible mice by T lymphocytes sensitized to central nervous system (CNS) myelin components and is a prime animal model for the human CNS demyelinating disorder, multiple sclerosis (MS). Although CNS inflammation in which T lymphocytes and activated macrophages are the predominant cell types is observed in mice with EAE and in humans with MS, the exact mechanisms underlying the CNS damage and demyelination are not understood. Nitric oxide (NO), a gaseous free radical, has recently been shown to be a cytolytic product of activated macrophages. Using electron paramagnetic resonance spectroscopy, the nitric oxide free radical complexed with iron-sulfur proteins has been identified in affected spinal cords of mice with EAE, concurrent with the diminution of iron-sulfur proteins. These results indicate NO may play a role in the disease process of EAE, and perhaps MS.

Animals↗
PubMed1993

Multiple encephalitogenic peptides of myelin basic protein in A.CA mice.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system. It is mediated by T cells and is an animal model for the human disease multiple sclerosis. In most mouse strains that are susceptible to induction of EAE by myelin basic protein, a dominant peptide of myelin basic protein is recognized by encephalitogenic T cells. We report here the susceptibility of the A.CA strain (H-2f) to myelin basic protein induced EAE and that multiple peptides of myelin basic protein (1-11, 9-20, and 87-99) can induce disease in these mice. The finding that multiple epitopes of the same self-antigen can elicit EAE in an inbred strain of mouse raises the possibility of more heterogeneity in encephalitogenic peptides of the putative autoantigen in human disease than previous studies have suggested.

Amino Acid Sequence↗