Caveat regarding immunoglobulin therapy in multiple sclerosis.
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Evoked Potentials, Visual↗
Biomedical subjects
A H Cross
Publications and source records attributed to A H Cross.
Development of reactivity to new myelin antigens during chronic relapsing autoimmune demyelination.
Cells from 25 mice at different stages of experimental autoimmune encephalomyelitis (EAE) adoptively transferred using lymph node cells sensitized to a synthetic encephalitogenic peptide of myelin basic protein (p87-99) were examined for reactivity to a different encephalitogenic myelin antigen, proteolipid protein (PLP). Cellular reactivity to a synthetic encephalitogenic peptide of PLP (pPLP) was found in 3/5 mice with acute EAE, 4/9 with chronic EAE, 1/6 mice with EAE in remission, and 0/5 during relapse. No proliferation to pPLP was seen in naive mice or in healthy mice immunized with p87-99. Two of 13 mice developed typical EAE after the serial transfer of cells from animals with p87-99-induced EAE had been activated with pPLP in vitro. Controls consisted of recipients of (a) pPLP-activated cells from naive donors or donors immunized with a nonencephalitogenic MBP peptide, (b) cells from mice immunized with MBP activated in vitro with irrelevant antigen, or (c) ovalbumin-activated cells serially transferred from mice with adoptively transferred EAE. No control mice developed signs. These results suggest that during the course of myelin breakdown caused by an immune response to one myelin component (MBP), autoimmune reactivity to at least one additional myelin antigen (PLP) can arise. Furthermore, the acquired cellular reactivity to additional myelin components may be sufficient in some cases to induce disease itself, perhaps lending insight into mechanisms involved in disease progression.
Amino Acid Sequence↗
Anti-adhesion molecule therapy in experimental autoimmune encephalomyelitis.
Based on previous observations showing that inflammatory episodes in the central nervous system (CNS) of SJL/J mice with adoptively transferred experimental allergic encephalomyelitis (EAE) are associated with a concomitant upregulation of adhesion-related molecules around CNS blood vessels, the present study was undertaken to block the development of EAE with injections of monoclonal antibodies (mAbs) to two different adhesion molecules. The mAbs selected were directed against intercellular adhesion molecule-1 (ICAM-1) and lymphocyte function-associated antigen-1 (LFA-1) and were administered at different doses (50 micrograms-1 mg), as single and multiple injections, and at various time points post-transfer of myelin basic protein-specific lymphocytes. Although one group of EAE mice given alpha LFA-1 displayed adverse effects after treatment, on the whole, neither mAb had a statistically significant effect on the outcome of EAE in this murine model. There was, however, down-regulation in the CNS of the respective adhesion molecules after treatment. Whether the lack of beneficial effect was related to the stage of EAE at which the mAbs were administered, remains to be proven. This is the first report suggesting that alpha ICAM-1 and alpha LFA-1 mAbs might have opposite effects (i.e. ameliorating or worsening) upon murine EAE and the different effect of alpha LFA-1 might be related to this molecule being involved in more cell signalling mechanisms than ICAM-1.
Animals↗
Phosphatidylserine, a putative inhibitor of tumor necrosis factor, prevents autoimmune demyelination.
We tested the effect of bovine cortex phosphatidylserine (BC-PS), a membrane phospholipid known to inhibit the release of the cytokine tumor necrosis factor (TNF), in SJL/J mice sensitized for adoptively transferred experimental autoimmune encephalomyelitis (EAE). Control, sensitized mice developed severe clinical and histologic EAE within 6 to 9 days, whereas only 20% of mice given BC-PS displayed clinical signs that were much less severe and minimal CNS pathology. Cessation of BC-PS treatment after 15 to 40 days led to disease within 1 to 2 weeks, but when treatment was more prolonged, animals remained healthy after cessation. Serial transfer of spleen cells (SC) from BC-PS-treated and control animals into naive recipients resulted in acute EAE within 6 to 7 days with cells from either donor type. Animals treated late with BC-PS failed to relapse and generally remained healthier than controls did over a 40-day period of observation. Cultures of lymph node cells or SC from BC-PS-treated and control animals showed an 80 to 90% reduction in TNF production in the BC-PS-treated group. Thus, we demonstrate that PS can abrogate or significantly reduce the severity of EAE without permanently inhibiting effector T cells. The approach might be considered a candidate for future therapies of relevance to MS.
Animals↗
Chronologic localization of myelin-reactive cells in the lesions of relapsing EAE: implications for the study of multiple sclerosis.
Although T cells play a pathogenetic role in MS, specific disease-inducing T cells have not been identified. T cells can be labeled and traced in adoptively transferred experimental autoimmune encephalomyelitis (EAE), a T-cell-mediated animal model for MS. We have followed the appearance and topographic localization of radio-labeled myelin basic protein-reactive (MBP+) T cells in evolving lesions as EAE extended to other regions of the CNS. By high-resolution autoradiography, we confirmed that MBP+ cells initially homed to perivascular regions in the lower spinal cord. With increasing time after cell transfer, labeled cells appeared in more recent lesions in rostral locations (upper spinal cord, cerebellum, and forebrain) and constituted a progressively smaller percentage of cells in lower spinal cord lesions. The presence of unlabeled inflammatory cells in the CNS parenchyma coincided temporally with clinical signs. In agreement with previous studies, we have shown that MBP+ cells constituted a minority (mean, < 1.5%) of the total infiltrating cells and were most numerous in fresh lesions. We suggest that the perivascular regions of recent lesions would be the most likely areas to detect putative antigen-specific cells in MS lesions.
Animals↗
Autoimmune demyelination in transgenic E alpha d-positive A.CA mice. Comparison with E-negative A.CA mice.
A body of literature exists implicating the major histocompatibility complex class II E molecule in development of immune tolerance and/or immunosuppression. To define better the regulatory mechanisms underlying susceptibility to experimental autoimmune encephalomyelitis, an autoimmune condition displaying major histocompatibility complex-II dependence, disease was induced in transgenic mice expressing a major histocompatibility complex-II E alpha d-transgene. This was compared with experimental autoimmune encephalomyelitis induced in age-matched E-negative, non-transgenic mice of the same strain. The results showed that experimental autoimmune encephalomyelitis could be induced by adoptive transfer methodology in both transgenic and non-transgenic mice of the A.CA (H-2f) strain. Virtually no differences were observed between the two mouse types with regard to disease onset, course, and neuropathology. The main difference noted was within nonirradiated recipient subgroups where the nonirradiated transgenic A.CA mice demonstrated greater inflammation and demyelination than the nonirradiated, non-transgenic mice throughout the disease course. Thus, the results did not support the idea that the E molecule, per se, is involved in the induction of tolerance or immunosuppressive mechanisms protecting against autoimmunity. In addition, histologic changes in the central nervous system of the A.CA strain, both transgenic and non-transgenic, differed in several respects from the changes observed in other more commonly studied susceptible strains. In A.CA mice, polymorphonuclear cells were a more prominent component of the acute inflammatory infiltrate and in chronic disease, large aggregates of lipid-laden macrophages and cholesterol clefts were present within white matter lesions. The present approach, using genetic manipulation of the immune system, may have relevance to the study of disease mechanisms in other putative autoimmune demyelinating disorders such as multiple sclerosis.
Animals↗
Anti-tumor necrosis factor therapy abrogates autoimmune demyelination.
To define a role for the cytokine tumor necrosis factor (TNF) in immune-mediated demyelination, the effect of anti-TNF antibody was investigated with a form of experimental autoimmune encephalomyelitis (EAE) in SJL/J mice induced by the adoptive transfer of myelin basic protein-(MBP)-sensitized T lymphocytes, an animal model of the human disease multiple sclerosis (MS). In three separate experiments, no mouse sensitized for EAE and then treated with anti-TNF by intraperitoneal injection developed signs of central nervous system (CNS) disease. Examination of CNS tissue from anti-TNF-treated animals showed no pathological changes. CNS tissue from control animals demonstrated extensive inflammatory cell infiltration and demyelination. To test whether anti-TNF therapy was inhibitory to encephalitogenic cells, preincubation of MBP-sensitized T lymphocytes with anti-TNF in vitro prior to injection into recipient mice was performed, and resulted in no diminution of their ability to transfer EAE. In addition, spleen cells from anti-TNF-treated mice were capable of serial transfer of EAE, similar to spleen cells from control animals. However, spleen cells from anti-TNF-treated mice did not produce TNF on stimulation with MBP or concanavalin A. This study showed that anti-TNF antibody can inhibit effectively the development of EAE by interfering with the effector, rather than the induction, phase of the disease. Anticytokine therapy may have important applications in the development of new therapeutic strategies for MS.
Animals↗
Adoptive transfer of experimental allergic encephalomyelitis and localization of the encephalitogenic epitope in the SWR mouse.
Adoptively-transferred experimental allergic encephalomyelitis (EAE) was induced in the SWR (H-2q) strain of mouse using lymph node cells, spleen cells, or cell lines sensitized to whole myelin basic protein (MBP). With the aid of synthetic peptides, the minimal encephalitogenic epitope of MBP for the SWR strain was localized to amino acids 87-99 of the MBP molecule. The 87-99 sequence is also encephalitogenic for the SJL strain of mouse and the Lewis rat. EAE was induced with a protocol similar to that for the induction of EAE in the SJL strain with the exception that sublethal irradiation of recipients was necessary. Mice developed typical clinical and pathological EAE 6-14 days post-transfer of cells sensitized to either whole MBP or peptide 87-99, after which they remitted. No relapses were observed. Thus, adoptively transferred EAE can be induced in irradiated H-2q mice for which the encephalitogenic epitope is one of the nested encephalitogenic epitopes for SJL (H-2s) mice, namely residues 87-99.
Animals↗
Hypothesis: antigen-specific T cells prime central nervous system endothelium for recruitment of nonspecific inflammatory cells to effect autoimmune demyelination.
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Animals↗
Non-specific oligodendrocyte cytotoxicity mediated by soluble products of activated T cell lines.
Supernates from myelin basic protein (MBP)-reactive T cell lines have been tested by a battery of assays for cytotoxicity against oligodendrocytes in vitro. All supernates tested demonstrated cytotoxic activity in both a dose- and time-dependent manner that ranged from 29.1% to 55.8% after 48 h incubation. Oligodendrocyte cytotoxicity mediated by MBP-reactive T cell lines was not antigen specific since lines reactive with purified protein derivative (PPD) of tuberculin showed similar cytotoxicity. Supernates cytotoxic to oligodendrocytes were equally effective against syngeneic and non-syngeneic target cells, but had no effect upon astrocytes. Neutralization studies revealed that oligodendrocyte cytotoxicity mediated by MBP-reactive T cell supernates could only be partially attributed to lymphotoxin/tumor necrosis factor activity, and was not associated with perforin, serine proteinase or N-methyl-D-aspartate (NMDA) receptor agonists.
Animals↗
Relapsing autoimmune demyelination: a role for vascular addressins.
The expression of two vascular addressins, adhesion molecules implicated in lymphocyte traffic via high endothelial venules (HEV) within lymph node and mucosal tissues, and of an HEV differentiation antigen (Ag) has been followed immunocytochemically in the central nervous system (CNS) of SJL mice at different stages of adoptively-transferred, chronic relapsing experimental autoimmune encephalomyelitis (EAE). Monoclonal antibody (mAb), MECA-325, which defines an HEV cell differentiation Ag generally associated with vessels involved in lymphocyte traffic, gave consistently high levels of expression on and around blood vessels within spinal cord lesions during periods of inflammation (acute onset and relapses). Two mAbs, MECA-89 and MECA-367, both recognizing the same mucosal addressin showed an affinity for endothelial cells and some astrocytes but only in lesions from animals displaying relapses. MECA-79, an mAb against a peripheral lymph node vascular addressin, showed no CNS staining whatsoever. All four antibodies gave uniformly positive staining on control lymphoid tissue. Since some stages of EAE appeared to be associated with the expression of different addressins, the possibility of separate roles for these distinct molecules should be considered.
Animals↗
Adhesion-related molecules in the central nervous system. Upregulation correlates with inflammatory cell influx during relapsing experimental autoimmune encephalomyelitis.
The expression of a battery of adhesion-related molecules and cytokines was investigated by immunocytochemistry in the central nervous system (CNS) of SJL/J mice sensitized for experimental autoimmune encephalomyelitis (EAE). These molecules consisted of the ligands MECA-325, intercellular adhesion molecule-1, and major histocompatibility complex molecules I and II, plus the receptors lymphocyte function-associated antigen-1, CD8, and CD4. The cytokines comprised interferon-gamma and tumor necrosis factor-alpha. EAE was induced by the adoptive transfer of myelin basic protein-sensitized lymphocytes. MECA-325, a marker for murine high endothelial venules in lymph node tissue, was absent from normal CNS tissue, was expressed at low levels on venules 24 to 48 hours before the onset of clinical signs, rose to maximal levels during acute disease, decreased to preclinical levels during remissions, and rose again during relapses. Intercellular adhesion molecule-1, major histocompatibility antigen-I, and major histocompatibility antigen-II showed similar fluctuations around CNS vessels. The receptors lymphocyte function-associated antigen-1 and CD4 fluctuated in parallel with the above molecules, whereas CD8 remained at a similar low level. Interferon-gamma was present during the acute, remitting, and relapsing phases and was localized to inflammatory cells, whereas tumor necrosis factor occurred at low levels only. Thus, several molecules associated with lymphocyte traffic in lymphoid tissue are selectively expressed in a stage-specific manner within the target organ, the CNS, during EAE. This suggests that the CNS may act as an ancillary organ of the immune system, and that cellular traffic into the CNS during EAE is related to the fluctuating expression of several distinct adhesion-related molecules, frequently co-expressed on the same vessel. The findings may have relevance to the sequence of events in the developing CNS lesion of multiple sclerosis.
Animals↗
Central nervous system endothelial cell-polymorphonuclear cell interactions during autoimmune demyelination.
The homing and adhesion of circulating cells to target tissue vasculature precedes their subsequent invasion of inflamed tissue. Polymorphonuclear cells (PMNs), key players in most inflammatory events, are among the first cells to arrive. The present work, performed on CNS lesions from mice with experimental autoimmune encephalomyelitis, provides morphologic evidence for interactions between PMNs and unique, frondlike extensions from endothelial cells (EC) during early attachment. Platelets also were seen attached to these endothelial fronds. The structures projected into vessel lumina from the vicinity of tight junctions and were often branched and complex, the latter characteristics suggesting a possible role in cellular 'trapping'. Polymorphonuclear cells appeared to traverse the CNS vasculature between EC where the blood-brain barrier was severely compromised with junctional complexes reduced to simple contact points. The cells from which the fronds derived were often plump and possessed cytoplasm rich in organelles, perhaps indicative of activation. The present report contrasts with previous observations on lymphocytes in the same system where lymphocytic pseudopodia formed intimate contacts before their burrowing directly through the endothelium and where EC fronds were not involved.
Animals↗
Upregulation and coexpression of adhesion molecules correlate with relapsing autoimmune demyelination in the central nervous system.
The expression of adhesion molecules on central nervous system (CNS) vessels was examined during chronic relapsing experimental autoimmune encephalomyelitis in the SJL mouse. Two molecules associated with cell adhesion were studied: MECA-325, a murine lymph node high endothelial venule marker; and MALA-2, the murine homologue of intercellular adhesion molecule 1. During initial disease, upregulated coexpression of these two molecules occurred in the CNS. This correlated with inflammatory cell invasion. During remission, expression was downregulated, and each subsequent relapse was accompanied by corresponding upregulation. Thus, up- and downregulation of adhesion molecules in the target organ appeared to form an integral part of the inflammatory process in this autoimmune condition and support a role for receptor-mediated inflammatory cell invasion of relevance to the pathogenesis of multiple sclerosis.
Animals↗
Antigen processing of myelin basic protein is required prior to recognition by T cells inducing EAE.
The processing and presentation of whole myelin basic protein (MBP) and a 12 amino acid encephalitogenic peptide were investigated using MBP-immune and peptide-immune murine T cell lines. Myelin basic protein is the major component of central nervous system (CNS) white matter capable of inciting an autoimmune response which leads to the disease, experimental allergic encephalomyelitis (EAE), in a number of animal species. MBP-immune T cell lines caused a form of adoptively transferred EAE when injected into naive, syngeneic recipients. It has been found that both whole MBP and peptide required processing in order to induce proliferation of the T cell lines. The proliferative response was greatest when MBP was processed under conditions in which proteolysis was prevented. The demonstration that activation of encephalitogenic MBP immune T cells requires a processed form of MBP may have relevance to the human inflammatory CNS demyelinating condition, multiple sclerosis, for which EAE is the EAE is the prime animal model.
Amino Acid Sequence↗
Adhesion molecules on endothelial cells in the central nervous system: an emerging area in the neuroimmunology of multiple sclerosis.
The observation of lymphocyte adhesion/homing molecules with ligands (integrins and vascular addressins) on endothelial cells (EC) within target organs during a number of nonlymphoid chronic inflammatory conditions is occurring with increasing frequency. On the basis of evidence from the literature and pilot data on the localization of the putative vascular addressin for humans, HECA-452, in central nervous system (CNS) tissue, it is suggested that molecular recognition on CNS EC might play a pathogenetic role during immune-mediated demyelination in multiple sclerosis (MS). In one of six cases of MS, a case displaying a particularly malignant course, HECA-452 was specifically and reproducibly demonstrated on postcapillary venules in periplaque white matter beyond the zone of active inflammation. In the same case, CD8+ T cells predominated over CD4+ cells. In no case studied were EC positive for HLA-DR (Ia), in contrast to previous reports. Perivascular Ia positivity was common and was always associated with foamy macrophages or pericytes. In view of the occurrence of semiorganized lymphoid collections in a number of chronic inflammatory conditions, several of which are associated with expression of HEV markers, and in MS, it is concluded that examination of molecular recognition events on lymphocytes and EC within the CNS in MS is an area worthy of further study and an area with considerable therapeutic import.
Adolescent↗
Serial adoptive transfer of murine experimental allergic encephalomyelitis: successful transfer is dependent on active disease in the donor.
In an attempt to understand the mechanisms underlying disease progression in adoptively transferred experimental allergic encephalomyelitis (EAE), and perhaps multiple sclerosis (MS), this study has examined the transfer of EAE serially from primary to secondary and tertiary recipients using myelin basic protein (MBP)-responsive lymphocytes. It was found that EAE could be serially transferred only when there was acute or relapsing disease activity in the donor animal. Cells from donors with quiescent disease did not transfer EAE. Autoradiographic attempts to locate primary adoptively transferred cells in the central nervous system of secondary and tertiary recipients were uniformly unsuccessful. These findings implicate the requirement of effector cell activation in the donor and the recruitment of augmenting autoimmune cells in lesion formation.
Acute Disease↗
Homing to central nervous system vasculature by antigen-specific lymphocytes. I. Localization of 14C-labeled cells during acute, chronic, and relapsing experimental allergic encephalomyelitis.
Chronic relapsing experimental allergic encephalomyelitis was induced by the passive transfer of [14C]thymidine-labeled myelin basic protein (MBP)-sensitized lymphocytes from MBP-immunized mice to naive syngeneic recipients. Labeled lymphocytes were localized and quantitated in the central nervous system during acute and chronic disease and clinical relapses. The results have shown that MBP-immune T cells home to the central nervous system endothelium 24 hours prior to and during initial clinical disease (5 to 7 days posttransfer). Unexpectedly, labeled MBP-immune cells never migrated far from blood vessels and, despite the presence of massive parenchymal inflammatory cell infiltration, almost invariably remained within the perivascular area. Quantitation revealed that labeled cells represented a minority (usually 1% to 4%) of the inflammatory cells during acute and early chronic disease. Furthermore, labeled cells could not be demonstrated in the central nervous system at the time of clinical relapse. We conclude that in this model, MBP-immune lymphocytes act exclusively from a perivascular location to orchestrate the influx of inflammatory cells that are predominantly of recipient derivation.
Acute Disease↗