Leukocyte function antigen 1 (LFA-1) is essential for the formation of immune cell synapses and plays a role in the pathophysiology of various autoimmune diseases. We investigated the molecular details of LFA-1 activation during adhesion between cytotoxic cells and a target model leukemia cell. The cytolytic activity of a CD3-CD8+CD56+ natural killer (NK) subset was enhanced when LFA-1 was activated. In a comparison of LFA-1 ligands, intercellular adhesion molecule 2 (ICAM-2) and ICAM-3 promoted LFA-1-directed perforin release, whereas ICAM-1 had little effect. Ligand-induced LFA-1 clustering facilitated perforin release, demonstrating LFA-1 could regulate degranulation mechanisms. LFA-1 induced the activation of src family kinases, Vav1 and p44/42 mitogen-activated protein kinase (MAPK), in human CD56+ NK cells as evidenced by intracellular phospho-epitope measurements that correlated with effector-target cell binding and perforin-granzyme A-mediated cytolytic activity. These results identify novel, specific functional consequence of LFA-1-mediated cytolytic activity in perforin-containing human NK subsets.

Analysis of mRNA from multiple sclerosis lesions revealed increased amounts of transcripts for several genes encoding molecules traditionally associated with allergic responses, including prostaglandin D synthase, histamine receptor type 1 (H1R), platelet activating factor receptor, Ig Fc epsilon receptor 1 (Fc epsilon RI), and tryptase. We now demonstrate that, in the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), mediated by T helper 1 (Th1) T cells, histamine receptor 1 and 2 (H1R and H2R) are present on inflammatory cells in brain lesions. Th1 cells reactive to myelin proteolipid protein expressed more H1R and less H2R than Th2 cells. Pyrilamine, an H1R antagonist, blocked EAE, and the platelet activating factor receptor antagonist CV6209 reduced the severity of EAE. EAE severity was also decreased in mice with disruption of the genes encoding Ig Fc gamma RIII or both Fc gamma RIII and Fc epsilon RI. Prostaglandin D synthase and tryptase transcripts were elevated in EAE brain. Taken together, these data reveal extensive involvement of elements of the immune response associated with allergy in autoimmune demyelination. The pathogenesis of demyelination must now be viewed as encompassing elements of both Th1 responses and "allergic" responses.

The diversity of Ag-specific receptors on T cells homing to an inflammatory infiltrate in the central nervous system has been analyzed. Experimental autoimmune encephalomyelitis, a T cell-mediated inflammatory disease of the central nervous system, was induced in Lewis rats with a CD4+, CD8- T cell line specific for peptide 68-86 of myelin basic protein. Within the line a wide array of TCR Vbeta genes was transcribed including the Vbeta8, Vbeta10, Vbeta15, Vbeta16, and Vbeta19 families. Accumulation of T cells at the site of inflammation was determined by using RNA-polymerase chain reaction amplification of rearranged TCR Vbeta transcripts derived from brain. By 8 to 1 0 h after i.p. infusion of the pathogenic T cell line, TCR Vbeta transcripts, including mainly Vbeta families that were predominantly rearranged by the line, could be identified in brains. Restricted TCR V gene transcripts with predominance of the Vbeta8 family were identified in brain 48 h after injection, before onsetof disease. Paralysis was apparent by 4 to 5 days after injection. At this time diverse Vbeta gene transcripts were detected in brain, reaching a maximum by day 9, when paralyzed rats have recovered. By day 14 a second stage of limited heterogeneity in the T cell infiltrate could be identified with predominant expression of Vbeta8, Vbeta9, Vbeta10, and Vbeta19. Interestingly, three out of these four Vbeta families were predominantly expressed within the encephalitogenic line. Thus, T cell migration to brain in experimental autoimmune encephalomyelitis is characterized by a rapid penetration of T cells followed by a selective trapping of T cells before the clinical manifestations of disease. When clinical disease was present the T cell infiltrate was diverse, whereas in the post-acute phase of disease the T cells in the central nervous system had limited heterogeneity with selective accumulation of T cells transcribing the same V regions that were detected in the line that incited disease.

Lymphokine activity in seven myelin basic protein (MBP)-specific T cell clones was examined. All of the clones recognize MBP peptide 1-9 in the context of I-Au. A strong positive correlation was found between levels of lymphotoxin (LT) and tumor necrosis factor alpha (TNF-alpha) mRNA and biological activity on L929 cells and their capacity to induce paralysis, the clinical hallmark of experimental allergic encephalomyelitis (EAE). No correlation was found between interleukin-2 or gamma interferon production and encephalitogenicity. LT and/or TNF-alpha may play a central role in the pathogenesis of EAE.

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease mediated by CD4+ T cells. Prior studies have established that monoclonal anti-CD4 antibodies can reverse EAE. To determine whether immunoglobulin isotype plays a role in the therapy of EAE with anti-CD4 antibody, an isotype switch variant family of the mouse IgG1 anti-rat CD4 antibody W3/25 was isolated with the fluorescence-activated cell sorter. The IgG1, IgG2b, and IgG2a W3/25 isotype variants all had identical binding capacities for rat CD4+ T cells. Although all three W3/25 isotypes showed some beneficial effects in the amelioration of EAE, the IgG1 and IgG2a W3/25 antibodies were superior to the IgG2b W3/25 in the treatment of EAE. Multiparameter fluorescence-activated cell sorter analysis of T cell subpopulations from treated rats showed that none of the antibodies of the W3/25 isotype switch variant family substantially depleted CD4+ target cells in vivo. These experiments demonstrate that immunoglobulin isotype is important in the monoclonal antibody therapy of autoimmune disease. They indicate that therapy of EAE may be successful without a major depletion of CD4+ lymphocytes. Immunotherapy may be optimized by selecting an appropriate isotype of a monoclonal antibody.

Annals of the New York Academy of SciencesVolume 475, Issue 1 p. 274-284 Therapy of Autoimmune Diseases with Antibody to Immune Response Gene Products or to T-Cell Surface Markersa LAWRENCE STEINMAN, LAWRENCE STEINMAN Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorMATTHEW K. WALDOR, MATTHEW K. WALDOR Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorSCOTT S. ZAMVIL, SCOTT S. ZAMVIL Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorMAE LIM, MAE LIM Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorLEANORE HERZENBERG, LEANORE HERZENBERG Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorLEONARD HERZENBERG, LEONARD HERZENBERG Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorHUGH O. McDEVITT, HUGH O. McDEVITT Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorDENNIS MITCHELL, DENNIS MITCHELL Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorSUBRAMANIAM SRIRAM, SUBRAMANIAM SRIRAM Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this author LAWRENCE STEINMAN, LAWRENCE STEINMAN Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorMATTHEW K. WALDOR, MATTHEW K. WALDOR Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorSCOTT S. ZAMVIL, SCOTT S. ZAMVIL Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorMAE LIM, MAE LIM Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorLEANORE HERZENBERG, LEANORE HERZENBERG Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorLEONARD HERZENBERG, LEONARD HERZENBERG Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorHUGH O. McDEVITT, HUGH O. McDEVITT Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorDENNIS MITCHELL, DENNIS MITCHELL Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this authorSUBRAMANIAM SRIRAM, SUBRAMANIAM SRIRAM Departments of Neurology and Pediatrics Stanford University School of Medicine Stanford, California 94305Search for more papers by this author First published: July 1986 https://doi.org/10.1111/j.1749-6632.1986.tb20876.xCitations: 10 a Financial support was derived from NIH grant no. NS18235, NIH contract no. NO1-NS-4-23178, an NIH Teacher Investigator Award, the National Multiple Sclerosis Society, the Kroc Foundation, the Kittredge Fund, the Fausel Foundation, and the Kramer Foundation. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References 1 Trotter, J., S. Sriram, L. Rassenti, C. Chou, R. B. Fritz & L. Steinman. 1985. Characterization of T cell lines and clones from SJL/J and (BALB/c × SJL)F1 mice specific for myelin basic protein. J. Immunol. 134: 2322– 2327. 2 Fritz, R. B., C-H. J. Chou & D. E. McFarlin. 1983. Induction of EAE in PL/J and (SJL/J × PL/J)F1 mice by myelin basic protein and its peptides: Localization of a second encephalitogenic determinant. J. Immunol. 130: 191. 3 Chou, C-H. J., R. Shapira & R. Fritz. 1984. Further delineation of encephalitogenic determinant for PL/J and (SJL × PL)F1 mice. In EAE: A Good Model for MS. M. Kies & E. A. Alvord, Eds.: 229– 234. Alan Liss. New York . 4 Zamvil, S., P. Nelson, D. Mitchell, R. Fritz & L. Steinman. 1985. Unusual bias in repertoire of T cells primed to MBP from (PL/J × SJL/J)F1 mice: Induction of EAE with T cell clones. Fed. Proc. Fed. Am. Soc. Exp. Biol. 44: 1179. 5 Steinman, L., J. Rosenbaum, S. Sriram & H. O. McDevitt. 1981. In vivo effects of antibodies to immune response gene products: Prevention of EAE. Proc. Natl. Acad. Sci. USA 78: 7111– 1714. 6 Steinman, L., D. Solomon, S. Zamvil, M. Lim & S. Sriram. 1983. Prevention of EAE with in vivo administration of anti-I-A antibody: Decreased accumulation of radiolabelled lymph node cells in the central nervous system. J. Neuroimmunol. 5: 91– 97. 7 Sriram, S. & L. Steinman. 1983. Anti-I-A antibody suppresses active encephalomyelitis: Treatment model for diseases linked to IR genes. J. Exp. Med. 158: 1362– 1367. 8 Perry, L. & M. Greene. 1982. Conversion of immunity to suppression by in vivo administration of I-A subregion specific antibodies. J. Exp. Med. 158: 480– 486. 9 Steinman, L., G. Schwartz, M. Waldor, M. O'Hearn, M. Lim & S. Sriram. 1984. Gene specific and antigen specific strategies for the induction of suppressor T cells to myelin basic protein. In EAE: A Good Model for MS. M. Kies & E. A. Alvord, Eds. Alan Liss. New York . 10 Sobel, R., B. Blanchette & R. Colvin. 1984. Preinflammatory expression of fibronectin and Ia in acute EAE. In EAE: A Good Model for MS. M. Kies & E. A. Alvord, Eds. Alan Liss. New York . 11 Waldor, M., S. Sriram, H. O. McDevitt & L. Steinman. 1983. In vivo therapy with monoclonal anti-I-A antibody suppresses immune responses to AChR. Proc. Natl. Acad. Sci. USA 80: 2713– 2717. 12 Adelman, N., D. Watling & H. O. McDevitt. 1983. Treatment of NZB/W F1 disease with monoclonal anti-I-A monoclonal antibodies. J. Exp. Med. 158: 1350– 1355. 13 Wooley, P. M., H. S. Luthra, W. P. Lafuse, A. Huse, J. Stuart & C. S. David. 1983. Type II collagen-induced arthritis in mice. III. Suppression of arthritis by using monoclonal and polyclonal anti-Ia antisera. J. Immunol. 134: 2361– 2371. 14 Vladutiu, A. & L. Steinman. 1984. Inhibition of experimental allergic thyroiditis in mice by monoclonal anti-I-A. Fed. Proc. Fed. Am. Soc. Exp. Biol. 43: 1991. 15 Rosenbaum, J., N. Adelman & H. O. McDevitt. 1981. In vivo effects of antibodies to IR gene products: Haplotype specific suppression of humoral immune responses with monoclonal anti-I-A. J. Exp. Med. 154: 1694– 1701. 16 Waldor, M., R. Hardy, K. Hayakawa, L. Steinman, L. A. Herzenberg & L. A. Herzenberg. 1984. Disappearance and reappearance of B cells following in vivo treatment with monoclonal anti-I-A antibody. Proc. Natl. Acad. Sci. USA 81: 2855– 2858. 17 Waldor, M., S. Sriram, R. Hardy, L. A. Herzenberg, L. A. Herzenberg, L. Lanier, M. Lim & L. Steinman. 1985. Reversal of EAE with a monoclonal antibody to a T cell subset marker (L3T4). Science 227: 415– 417. 18 Wofsy, D. & W. E. Seaman. 1985. Successful treatment of autoimmunity in NZB/NZW F1 mice with monoclonal antibody to L3T4. J. Exp. Med. 161: 378– 391. 19 Brostoff, S. W. & P. W. Mason. 1984. Experimental allergic encephalomyelitis: Successful treatment in vivo with a monoclonal antibody that recognizes T helper cells. J. Immunol. 133: 1938– 1942. 20 Morrison, S. L., J. M. Johnson, L. A. Herzenberg & V. T. Oi. 1984. Chimeric human antibody molecules: Mouse antigen-binding domains with human constant region domains. Proc. Natl. Acad. Sci. USA 81: 6851– 6855. Citing Literature Volume475, Issue1Autoimmunity: Experimental and Clinical AspectsJuly 1986Pages 274-284 ReferencesRelatedInformation

Experimental allergic encephalomyelitis (EAE) serves as a model for autoimmune diseases mediated by T lymphocytes. Following sensitization to rat, mouse or guinea pig myelin basic protein (MBP) in complete Freund's adjuvant, inbred mouse strains PL/J (H-2u), SJL/J (H-2s) and (PL/J X SJL/J)F1((PLSJ)F1) develop EAE. Whereas sensitization to the N-terminal 37 amino-acid peptide of rat or guinea pig MBP [MBP(1-37)] induces EAE in PL/J mice, immunization to the C-terminal peptide (89-169) leads to EAE in SJL/J mice. The immune response to MBP in (PLSJ)F1 mice is not co-dominant; sensitization to the N-terminal peptide induces EAE, while sensitization to the C-terminal peptide does not. We have generated MBP-specific T-cell clones restricted to class II (Ia) antigens of the major histocompatibility complex (MHC) from PL/J and (PLSJ)F1 mice following sensitization to rat MBP. Two such I-Au-restricted T-cell clones that proliferate in response to the encephalitogenic N-terminal MBP peptide and recognize a shared determinant with mouse (self) MBP cause paralysis in 100% of (PLSJ)F1 mice tested. Paralysis is induced even when recipients are injected with as few as 1 X 10(5) cloned T cells. Relapsing paralysis followed in two-thirds of the recipients after recovery from acute paralysis, whereas one-third developed chronic persistent paralysis, a form of EAE not usually seen. Histopathology revealed intense perivascular inflammation, demyelination and remyelination within the central nervous system of paralysed mice. The experimental disease induced with these clones shares important features with human demyelinating diseases such as multiple sclerosis. This is the first demonstration that T-cell clones that respond to a defined self-antigen can induce clinical and histological autoimmune disease.