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Biomedical subjects

A H Cross

Publications and source records attributed to A H Cross.

At least 19 recordsLinked to original sources
PubMed2001

B cells and antibodies in CNS demyelinating disease.

There is much evidence to implicate B cells, plasma cells, and their products in the pathogenesis of MS. Despite unequivocal evidence that the animal model for MS, EAE, is initiated by myelin-specific T cells, there is accumulating evidence of a role for B cells, plasma cells, and their products in EAE pathogenesis. The role(s) played by B cells, plasma cells, and antibodies in CNS inflammatory demyelinating diseases are likely to be multifactorial and complex, involving distinct and perhaps opposing roles for B cells versus antibody.

Animals↗
PubMed2001

Oligoclonal band number as a marker for prognosis in multiple sclerosis.

The natural course of disease in multiple sclerosis varies. Multiple sclerosis that is clinically apparent but causes minimal disability over time has been labeled benign multiple sclerosis. The ability to predict the subsequent clinical course of multiple sclerosis on the basis of clinical and other supportive data at presentation would be invaluable. In this article we report our findings based on a retrospective analysis of 1800 patients diagnosed as having multiple sclerosis, of which 44 patients met our inclusion criteria. There was a suggestion that a low or absent number of oligoclonal bands in the cerebrospinal fluid at the time of diagnosis predicts a better prognosis. However, quantification of oligoclonal bands in cerebrospinal fluid remains an insensitive prognostic indicator and must not be used to influence decisions regarding therapeutic options.

Adult↗
PubMed2001

Neurological and neuropathologic heterogeneity in two brothers with cobalamin C deficiency.

Two adult brothers, one documented to have methylmalonic acidemia with homocystinuria, or cobalamin C deficiency, after autopsy, displayed severe but divergent neurological presentations. One exhibited a myelopathy and the other chronic endocrine problems (Schmidt's syndrome) followed by a neuropsychiatric and dementing disorder owing to cerebral perivascular demyelination. The recognition of cobalamin C deficiency has practical implications because it is one of the few inherited diseases of central white matter that is treatable.

Adult↗
PubMed2000

Astrocytes and central nervous system endothelial cells do not express B7-1 (CD80) or B7-2 (CD86) immunoreactivity during experimental autoimmune encephalomyelitis.

The identity of cell types within the central nervous system (CNS) capable of activating T lymphocytes is a fundamental issue in the understanding of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). To become fully activated, a T cell must recognize its antigen and receive co-stimulation, the latter being optimally delivered via B7-1 and/or B7-2 molecules expressed by the antigen presenting cell (APC). There are conflicting reports regarding whether astrocytes or CNS endothelial cells (EC) can act as fully competent APCs. The present studies were performed to determine whether astrocytes or CNS EC express B7-1 or B7-2 immunoreactivity during EAE. No expression of B7-1 or B7-2 by either astrocytes or EC was detected during acute, remitting, relapsing or chronic EAE, whether EAE was induced by active immunization or cell transfer using five different myelin antigens. These results suggest that neither astrocytes nor CNS EC can deliver co-stimulatory signals via B7 molecules in the setting of murine EAE, rendering them incapable of acting as fully competent APCs.

Animals↗
PubMed2000

A catalyst of peroxynitrite decomposition inhibits murine experimental autoimmune encephalomyelitis.

Peroxynitrite (PN), the product of nitric oxide (NO) reacted with superoxide, is generated at sites of inflammation. Nitrotyrosine (NT), a marker of PN formation, is abundant in lesions of acute experimental autoimmune encephalomyelitis (EAE), and in active multiple sclerosis (MS) plaques. To determine whether PN plays a role in EAE pathogenesis, mice induced to develop EAE were treated with a catalyst specific for the decomposition of PN. Because this catalyst has no effect upon NO, using it allowed differentiation of PN-mediated effects from NO-mediated effects. Mice receiving the PN decomposition catalyst displayed less severe clinical disease, and less inflammation and demyelination than control mice. Encephalitogenic T cells could be recovered from catalyst-treated mice, indicating that the PN decomposition catalyst blocked the pathogenic action of PN at the effector stage of EAE, but was not directly toxic to encephalitogenic T cells. PN plays an important role distinct from that of NO in the pathogenesis of EAE, a major model for MS.

Animals↗
PubMed2000

Acute aphasia in multiple sclerosis.

Acute aphasia is rare in multiple sclerosis. We describe 3 patients with multiple sclerosis who had acute exacerbations presenting as aphasias. One patient had a mixed transcortical aphasia, 1 had a transcortical motor aphasia, and 1 had a Broca aphasia. Magnetic resonance imaging scans of the brain with contrast enhancement revealed new white matter lesions in the left hemisphere in all 3 patients. Two of the 3 patients had a good response to treatment with methylprednisolone sodium succinate. Arch Neurol. 2000;57:1207-1209

Acute Disease↗
PubMed1999

Increased frequency of recognition of delipidated versus intact CNS myelin in multiple sclerosis and control subjects.

The proliferative response of mononuclear cells from MS patients and normal control subjects to intact and delipidated myelin membranes was examined. The mean frequency of recognition in both groups of human subjects was greater for delipidated myelin than for intact myelin. Human T cell lines established using intact or delipidated myelin as the antigen were highly heterogeneous in response, and were each able to recognize myelin basic protein and myelin proteolipid protein peptides. However, there was no difference in the frequency of recognition of either form of myelin membrane when MS patients were compared to control subjects. Our results suggest that the presentation of delipidated forms of membrane proteins might enhance the response to myelin antigens in vivo, and be relevant to demyelinating diseases.

Adult↗
PubMed1999

Oral administration of myelin basic protein is superior to myelin in suppressing established relapsing experimental autoimmune encephalomyelitis.

Oral administration of a myelin component, myelin basic protein (MBP), induces immunological unresponsiveness to CNS Ags and ameliorates murine relapsing experimental autoimmune encephalomyelitis (REAE). However, a recent clinical trial in which multiple sclerosis patients were treated with repeated doses of oral myelin was unsuccessful in reducing disease exacerbations. Therefore, we directly compared the tolerizing capacity of myelin vs MBP during REAE in B10.PL mice. Oral administration of high doses of myelin, either before disease induction or during REAE, did not provide protection from disease or decrease in vitro T cell responses. In contrast, repeated oral administration of high doses of MBP suppressed established disease and MBP-specific T cell proliferation and cytokine responses. The frequency of IL-2-, IFN-gamma-, and IL-5-secreting MBP-specific T cells declined with MBP feeding, implicating anergy and/or deletion as the mechanism(s) of oral tolerance after high Ag doses. We have previously shown that the dosage and timing of Ag administration are critical parameters in oral tolerance induction. Studies presented here demonstrate that Ag homogeneity is also important, i.e., homogeneous Ag (MBP) is more effective at inducing oral tolerance than heterogeneous Ag (myelin).

Administration, Oral↗
PubMed1999

CTLA-4-Fc treatment of ongoing EAE improves recovery, but has no effect upon relapse rate. Implications for the mechanisms involved in disease perpetuation.

Several laboratories including ours have shown that T cell co-stimulation mediated through B7-1 or B7-2 is critical to the initiation of EAE. The role of T cell co-stimulation in ongoing EAE is less clear. In the present study, 32 mice with established EAE were randomly assigned to receive treatment with either CTLA-4-Fc or control Ig. Mice were followed daily by clinical scoring for 2 months post-immunization. A significant improvement in the degree of recovery following the acute episode and following relapses of EAE was observed in those mice randomized to CTLA-4-Fc treatment. Full clinical remission occurred twice as often in the CTLA-4-Fc group as in those mice receiving placebo, whereas placebo-treated mice were more likely to develop a stable prolonged neurologic deficit. Serial clinical scoring revealed no effect of CTLA-4-Fc upon relapse rate, with greater than 80% of the mice in each group displaying at least one clinical EAE relapse. In that the activation of memory T cells is relatively independent of T cell co-stimulation, these results indicate that development of chronic disease is associated with the activation of naive T cells and the recruitment of the latter cells into the disease process. Blocking B7 molecules may be beneficial in the treatment of established CNS inflammatory demyelinating diseases such as multiple sclerosis.

Abatacept↗
PubMed1999

Dual role for Fas ligand in the initiation of and recovery from experimental allergic encephalomyelitis.

We have previously demonstrated a role for Fas and Fas ligand (FasL) in the pathogenesis of experimental allergic encephalomyelitis (EAE). However, using an active induction paradigm we could not distinguish between FasL expressed on activated CD4(+) T cells from that expressed on other inflammatory or resident central nervous system (CNS) cells. To address this issue, we have conducted reciprocal adoptive transfer experiments of nontransgenic or myelin basic protein-specific T cell receptor transgenic wild-type, lpr, or gld lymphocytes into congenic wild-type, lpr, and gld hosts. We found that FasL expressed on donor cells is important for the development of EAE, as FasL-deficient lymphocytes transfer attenuated disease. Furthermore, Fas expressed in the recipient animals is important for the progression of EAE, as clinical signs of disease in lpr recipients were dramatically attenuated after transfer of either wild-type or lpr T cells. Surprisingly, these experiments also identified CNS cells as a source of functional FasL. Host-derived FasL appears to be especially important in the recovery from EAE, as many gld recipients of wild-type lymphocytes develop prolonged clinical signs of disease. Thus it appears that FasL plays distinct roles in EAE during the initiation of and recovery from disease.

Animals↗
PubMed1999

T cells are the main cell type expressing B7-1 and B7-2 in the central nervous system during acute, relapsing and chronic experimental autoimmune encephalomyelitis.

T cell co-stimulation through the CD28 receptor on T cells is critical to the induction of experimental autoimmune encephalomyelitis (EAE). In this study, expression of the co-stimulatory ligands B7-1 (CD80) and B7-2 (CD86), as well as the receptors CD28 and CTLA-4, were quantitated in central nervous system (CNS) tissues from mice at various stages of EAE. Immunohistochemistry and flow cytometry of CNS-infiltrating cells revealed a high percentage of infiltrating T cells expressing B7-1 and B7-2 during acute, chronic and relapsing EAE. Of the infiltrating cells 10-20% were CTLA-4(+), most of which were CD4(+) T cells. B7-1 and B7-2 expression within the CNS during active EAE might increase the potential for local activation of autoimmune T cells; however, the high level of expression of B7 molecules may also provide a mechanism for the autoregulation of activated CTLA-4(+) T cells.

Abatacept↗
PubMed1999

B cells are critical to induction of experimental allergic encephalomyelitis by protein but not by a short encephalitogenic peptide.

While the pathology of multiple sclerosis implicates a role for B cells and antibodies in the disease process, results from animal models have yielded conflicting results. To further characterize the role of B cells in experimental allergic encephalomyelitis (EAE), wild-type and B cell-deficient C57BL/6 mice were immunized with either a recombinant form of myelin oligodendrocyte glycoprotein (MOG) or with the encephalitogenic MOG(35-55) peptide. B cell-deficient mice did not develop EAE when immunized with MOG, although they were susceptible to MOG(35-55)-induced disease. In contrast, wild-type mice were fully susceptible to both MOG and MOG(35-55)-induced EAE. B cell-deficient mice immunized with MOG were primed to the encephalitogenic MOG(35- 55) epitope, as their spleen cells responded with Th1 cytokine production in a fashion similar to WT cells when challenged in vitro with MOG protein or MOG(35-55) peptide. These results demonstrate that the form of inducing antigen (protein vs. peptide) plays a role in the pathogenesis of EAE and may be relevant when applying results from the EAE model to multiple sclerosis.

Amino Acid Sequence↗
PubMed1999

Role of Fas--FasL interactions in the pathogenesis and regulation of autoimmune demyelinating disease.

Multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) represent complex processes that lead to destruction of oligodendrocytes (ODCs) and myelin. T cells are integral to the development of these diseases, but whether T cell-mediated cytolytic mechanisms are involved in the destruction of MHC Class II-negative targets, such as oligodendroglia and myelin, in the CNS is unclear. The primary lytic mechanism employed by CD4+ T cells is Fas-dependent, but can be MHC-unrestricted. Thus, T cell-mediated Fas-FasL interactions could directly contribute to the pathology of EAE and MS. This review summarizes studies from our laboratory and others that implicate Fas-FasL interactions in both the pathogenesis and regulation of demyelinating diseases.

Animals↗
PubMed1998

Peroxynitrite formation within the central nervous system in active multiple sclerosis.

Peroxynitrite, generated by the reaction of nitric oxide (NO) with superoxide at sites of inflammation, is a strong oxidant capable of damaging tissues and cells. Detection of nitrotyrosine (NT) at inflammatory sites serves as a biochemical marker for peroxynitrite-mediated damage. In this study, NT was detected immunohistochemically within autopsied CNS tissues from six of nine multiple sclerosis (MS) patients, and in most of the MS sections displaying inflammation. Nitrite and nitrate, the stable oxidation products of NO and peroxynitrite, respectively, were measured in cerebrospinal fluid samples obtained from MS patients and controls. Levels of nitrate were elevated significantly during clinical relapses of MS. These data suggest that peroxynitrite formation is a major consequence of NO produced in MS-affected CNS and implicate a role for this powerful oxidant in the pathogenesis of MS.

Central Nervous System↗
PubMed1998

Regulation of experimental autoimmune encephalomyelitis with insulin-like growth factor (IGF-1) and IGF-1/IGF-binding protein-3 complex (IGF-1/IGFBP3).

Insulin-like growth factor (IGF)-1 is a cytokine that promotes oligodendrocyte development and myelin production. This study investigated whether treatment of chronic, relapsing murine experimental autoimmune encephalomyelitis (EAE) with IGF-1 or IGF-1 associated with its binding protein, IGFBP3, altered the course of disease. Administration of IGF-1/IGFBP3 (1-100 mg/kg per day) delayed the onset of disease in a dose-dependent manner and histologic examination showed a delay in inflammatory cells entering the central nervous system. However, once signs of EAE developed, disease was enhanced in the mice that had been given the highest dose of IGF-1/IGFBP3. Treatment with IGF-1/IGFBP3 after the onset of signs resulted in a severe relapse. Administration of free IGF-1 (10 mg/kg per day) provided mild protection when given before disease onset, but did not significantly alter the course of disease if given after disease onset. Possible mechanisms that could explain the altered disease in IGF-1/IGFBP3-treated mice included (a) IGF-1/IGFBP3 administration delayed the onset of EAE by downregulating ICAM-1 gene expression in the central nervous system, and (b) IGF-1/IGFBP3 treatment of EAE resulted in more severe disease due to enhanced expansion of encephalitogenic T cells. Although IGF-1 may enhance remyelination, these results indicate that administration of IGF-1 associated with IGFBP3 may also accentuate autoimmune demyelinating disease.

Animals↗