Anti-adhesion molecule therapy in experimental autoimmune encephalomyelitis

doi:10.1016/0165-5728(93)90232-N

Journal of Neuroimmunology

Volume 46, Issues 1–2, July 1993, Pages 43-55

https://doi.org/10.1016/0165-5728(93)90232-N Get rights and content

Abstract

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 μg-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 αFLA-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 αICAM-1 and αLFA-1 mAbs might have opposite effects (i.e. ameliorating or worsening) upon murine EAE and the different effect of αLFA-1 might be related to this molecule being involved in more cell signaling mechanisms than ICAM-1.

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Bharadwaj et al. (2013b) previously suggested that in humans, ICAM-1/LFA-1 interaction is the preferential pathway for lymphocytes to cross the inner BRB, but our results suggest that VCAM-1 could have a more important role retaining locally activated lymphocytes in the retina. This is also supported by early reports in the EAE model, showing that the administration of antibodies targeting LFA-1 is more effective in disease prevention while anti-VLA-4 antibodies are superior as a curative treatment of EAE (Yednock et al., 1992), (Welsh et al., 1993), (Cannella et al., 1993). In summary, this work provides the first full description of ICAM-1 in the retina during EAU and the first study of LFA-1 and VLA-4 membrane expression on uveitogenic cells.
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Recent reports suggest that β2-integrin and their ligands are critical for autoaggressive lymphocyte trafficking into the brain and spinal cord during the development and progression of MS and the EAE model [58]. For instance, antibodies to the α-chains of LFA-1 and Mac-1 provide protection from disease, primarily by attenuating disease severity rather than completely blocking disease development [65–67]. In this context, to gain further insight into the mechanisms through which euphol modulates cell migration and improves the clinical symptoms induced by EAE in C57BL/6 mice, we assessed the levels of chemotactic factors and the expression of adhesion molecules after induction of EAE.
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Effector and suppressor roles for LFA-1 during the development of experimental autoimmune encephalomyelitis
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LFA-1 (CD11a/CD18) is a member of the β₂-integrin family of adhesion molecules important in leukocyte trafficking and activation. Although LFA-1 is thought to contribute to the development of experimental autoimmune encephalomyelitis (EAE) primarily through its functions on effector T cells, its importance on other leukocyte populations remains unexplored. To address this question, we performed both adoptive transfer EAE experiments involving CD11a^−/− mice and trafficking studies using bioluminescent T cells expressing luciferase under the control of a CD2 promoter (T-lux cells). Transfer of encephalitogenic CD11a^−/− T cells to wild type mice resulted in a significant reduction in overall EAE severity compared to control transfers. We also observed, using in vivo imaging techniques, that CD11a^−/− T-lux cells readily infiltrated lymph nodes and the CNS of wild type recipients with kinetics comparable to CD11a^+/+ transfers, although their overall numbers in these organs were reduced. Surprisingly, transfer of encephalitogenic wild type T cells to CD11a^−/− mice induced a severe and sometimes fatal EAE disease course, associated with massive T cell infiltration and proliferation in the CNS. These data indicate that LFA-1 expression on leukocytes in recipient mice plays an important immunomodulatory role in EAE. Thus, LFA-1 acts as a key regulatory adhesion molecule during the development of EAE, serving both pro- and anti-inflammatory roles in disease pathogenesis.
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Research paperAnti-adhesion molecule therapy in experimental autoimmune encephalomyelitis

Abstract

Cell

J. Neuroimmunol.

Sem. Neurosci.

Cell

Blood

Cell. Immunnol.

J. Neuroimmunol.

Surface expression of α4 integrin by CD4 T cells is required for entry into brain parenchyma

J. Exp. Med.

Vaccination against autoimmune encephalomyelitis with T-lymphocyte line cells reactive against myelin basic protein

Nature (London)

The chronologic neuropathology of relapsing experimental allergic encephalomyelitis in the mouse

Lab. Invest.

Upregulation and coexpression of adhesion molecules correlates with relapsing autoimmune demyelination in the central nervous system

J. Exp. Med.

Adhesion-related molecules in the central nervous system. Upregulation correlates with inflammatory cell influx during relapsing experimental autoimmune encephalomyelitis

Lab. Invest.

Homing to central nervous system vasculature by antigen specific lymphocytes. I. Localization of 14C-labeled cells during acute, chronic and relapsing experimental allergic encephalomyelitis

Lab. Invest.

Chronologic localization of myelin-reactive cells in the lesions of relapsing EAE. Implications for the study of multiple sclerosis

Neurology

Role of ICAM-1 in antigen presentation demonstrated by ICAM-1 defective mutants

J. Immunol.

The function of human intercellular adhesion molecule-1 (ICAM-1) in the generation of an immune response

Eur. J. Immunol.

Lymphocyte function associated antigen-1 (LFA-1) interaction with intercellular adhesion molecule-1 (ICAM-1) is one of at least 3 mechanisms for lymphocyte adhesion to cultured endothelial cells

J. Cell. Biol.

Late treatment with anti-LFA-1 (CD11a) antibody prevents cerebral malaria in a mouse model

Eur. J. Immunol.

Late administration of monoclonal antibody to leukocyte function-antigen-1 abrogates incipient murine cerebral malaria

Eur. J. Immunol.

Monoclonal antibodies to cell adhesion antigens LFA-1 ga and MALA-2 reduce graft-versus-host disease and increase survival in allogeneic mice

Transplantation

Migration of hematogenous cells through the blood-brain barrier and the initiation of CNS inflammation

Brain Pathol.

Research paper
Anti-adhesion molecule therapy in experimental autoimmune encephalomyelitis

Homing to central nervous system vasculature by antigen specific lymphocytes. I. Localization of ¹⁴C-labeled cells during acute, chronic and relapsing experimental allergic encephalomyelitis