Restricted accessResearch articleFirst published online 1997-01
Resolution of CNS lesions following treatment of experimental allergic encephalomyelitis in macaques with monoclonal antibody to the CD 18 leukocyte integrin
Experimental allergic encephalomyelitis (EAE) in macaques is an acute inflammatory and demyelinating disease of the central nervous system (CNS) which has been studied extensively as a model of the human demyelinating disease multiple sclerosis (MS). The in vivo administration of monoclonal antibodies against CD 18, the common β-chain of a leukocyte integrin, at the onset of clinical disease, significantly prolonged the survival of nine of 11 macaques (82%) and in some cases completely reversed the clinical appearance of disease. Treatment with anti-CD18 mAbs dramatically reduced the extent of inflammation in brain lesions as determined by magnetic resonance imaging (MRI). These improvements confirm that anti-CD18 mAbs are powerful anti-inflammatory agents in vivo and suggest that such mAbs may provide effective treatment of both demyelinating and inflammatory CNS diseases in man.
1 Wekerle H et al. (1994) Animal Models. Ann Neurology36: S47–S53.
2.
2 Lassmann H, Zimprich F, Rossler K, Vass K. (1991). Inflammation in the nervous system: Basic mechanisms and immunological concepts. Rev Neurol (Paris)12: 763–781.
3.
3 Raine CS, Mokhtarian F, McFarlin DE. (1984) Adoptively transferred chronic relapsing experimental autoimmune encephalitis in the mouse: Neuropathologic analysis. Lab Invest51: 534–546.
4.
4 Martin R, McFarland HF, McFarlin DE. (1992) Immunological aspects of demyelinating diseases. Ann Rev Immunol10: 153–187.
5.
5 Prineas JW, Wright RG. (1978) Macrophages, lymphocytes, and plasma cells in the perivascular compartment in chronic multiple sclerosis. Lab Invest38: 409–421.
6.
6 Waldor MK et al. (1985) Reversal of experimental allergic encephalomyelitis with monoclonal antibody to a T-cell subset marker. Science227: 415–417.
7.
7 Rose LM et al. (1987) In vivo administration of anti-CD4 monoclonal antibody prolongs survival in long-tailed macaques with experimental allergic encephalomyelitis. Clin Immunol Immunopathol45: 405–423.
8.
8 Yednock T et al. (1992) Prevention of experimental autoimmune encephalomyelitis by antibodies against α4β1 integrin. Nature356: 63–66.
9.
9 Hartung H-P et al. (1995) Circulating adhesion molecules and inflammatory mediators in demyelination: a review.Neurology34 (suppl 6) S22–S32.
10.
10 Hickey WF. (1991) Migration of hematogenous cells through the blood brain barrier and the initiation of CNS inflammation. Brain Pathol1: 97–105.
14 Hakkert BC et al. (1991) Neutrophil and maonocyte adherence to and migration across monolayers of cytokine-activated endothelial cells: The contribution of CD18, ELAM-1, and VLA-4. Blood78: 2721–2726.
15.
15 Stacker SA, Springer TA. (1991) Leukocyte integrin P150/95 (CD11c/CD18) functions as an adhesion molecule binding to a counter-receptor on stimulated endothelium. J Immunol146: 648–655.
16.
16 Sanchez-Madrid F et al. (1983) A human leukocyte differentiation antigen family with distinct α subunits and a common β subunit. The lymphocyte functionassociated antigen (LFA-1), the C3bi complement receptor (OKM1/Mac-1), and the p150, 95 molecule. J Exp Med158: 1785–1803.
17.
17 de Fougerolles AR, Qin X, Springer TA. (1994) Characterization of the function of intercellular adhesion molecule (ICAM)-3 and comparison with ICAM-1 and ICAM-2 in immune responses. J Exp Med179: 619–629.
18.
18 Harlan JM et al. (1985) The role of neutrophil membrane glycoprotein GP-150 in neutrophil adherence to endothelium in vitro. Blood66: 167–178.
19.
19 Zimmerman GA, McIntyre TM. (1988) Neutrophil adherence to human endothelium in vitro occurs by CDw18 (Mol, MAC-1/LFA-1/GP150/95) glycoprotein-dependent and-independent mechanisms. J Clin Invest81: 531–537.
20.
20 Luscinskas FW, Brock AF, Arnaout MA, Gimbrone MA, Jr. (1989) Endothelial-leukocyte adhesion molecule-1-dependent and leukocyte (CD11/CD18)-dependent mechanisms contribute to polymorphonuclear leukocyte adhesion to cytokine-activated human vascular endothelium. J Immunol142: 2257–2263.
21.
21 Bohnsack JF et al. (1989) Human neutrophil adherence to laminin in vitro: Evidence for a distinct neutrophil integrin receptor for laminin. J Exp Med171: 1221–1237.
22.
22 Arfors KE et al. (1987) A monoclonal antibody to the membrane glycoprotein complex CD18 inhibits polymorphonuclear leukocyte accumulation and plasma leakage in vivo. Blood60: 338–340.
23.
23 Price TH, Beatty PG, Corpuz SR. (1987) In vivo inhibition of neutrophil function in the rabbit using monoclonal antibody to CD18. J Immunol139: 4174–4177.
24.
24 Doerschuk CM, Winn RK, Coxson HO, Harlan JM. (1990) CD18-dependent and-independent mechanisms of neutrophil emigration in the pulmonary and systemic microcirculation of rabbits. J Immunol144: 2327–2333.
25.
25 Whitcup SM et al. (1993) Monoclonal antibodies against ICAM-1 (CD54) and LFA-1 (CD11a/CD18) inhibit experimental autoimmune uveitis. Clin Immunol Immunopathol67: 143–150.
26.
26 Ma X-L, Tsao PS, Lefer AM. (1991) Antibody to CD-18 exerts endothelial and cardiac protective effects in myocardial ischemia and reperfusion. J Clin Invest88: 1237–1243.
27.
27 Sadahiro M, McDonald TO, Allen MD. (1993) Reduction in cellular and vascular rejection by blocking leukocyte adhesion molecule receptors. Am J Pathol142: 675–683.
28.
28 Huitinga I, Damoiseaux JGMC, Dopp EA, Dijkstra CD. (1993) Treatment with anti-CR3 antibodies ED7 and ED8 suppresses experimental allergic encephalomyelitis in Lewis rats. Eur J Immunol23: 709–715.
29.
29 Welsh CT, Rose JW, Hill KE, Townsend JJ. (1993) Augmentation of adoptively transferred experimental allergic encephalomyelitis by administration of a monoclonal antibody specific for LFA-1α. Neuroimmunol43: 161–168.
30.
30 Rose LM, Richards TL, Alvord EC Jr. (1989) Magnetic resonance imaging and peripheral blood abnormalities in experimental allergic encephalomyelitis. Biomed Pharmacother43: 347–353.
31.
31 Beatty PG et al. (1983) Definition of a common leukocyte cell-surface antigen (Lp95–150) associated with diverse cell-mediated immune functions. J Immunol131: 2913–2918.
32.
32 Rose LM., inventor; ICOS Corporation, Board of Regents of the University of Washington, applicants. Alleviation of Symptoms Associated with Inflammatory Disease States. International Publication Number WO 94/02175. 1994 February 3.
33.
33 Hildreth JEK, Gotch FM, Hildreth PDK, McMichael AJ. (1983) A human lymphocyte-associated antigen involved in cell mediated lympholysis. Eur J Immunol13: 202–205.
34.
34 Sires LR et al. (1981) Species restrictions of a monoclonal antibody reacting with residues 130 to 137 in encephalitogenic myelin basic protein. Science214: 87–89.
35.
35 Kil E (1972) Block-face application of a 7 : 3 propylene glycol-water mixture to facilitate cutting of large frozen sections. Stain Technology47: 271.
36.
36 Richards TL, Peterson J, Rose LM, Alvord EC Jr. (1990) Proton chemical shift imaging of primates during experimental allergic encephalomyelitis. In, Abstracts; New York, Soc. Mag. Reson. Med., Vol 2, p. 1043.
37.
37 Shaw CM, Alvord EC Jr. (1973) Treatment of experimental allergic encephalomyelitis in monkeys. II. Histopathological studies. In: Shiraki H, Yonezawa T and Kuroiwa Y. (Eds.) International Symposium on the Aetiology and Pathogenesis of the Demyelinating Diseases, Japan Science Press, Kyoto, pp. 377–395.
38.
38 Richards TL et al. (1995) Experimental allergic encephalomyelitis in non-human primates: Diffusion imaging of acute and chronic brain lesion. Multiple Sclerosis1: 109–117.
39.
39 Somersalo K, Tarkkanen J, Patarroyo M, Saksela E. (1992) Involvement of β2-integrins in the migration of human natural killer cells. J Immunol149: 590–598.
40.
40 Lundgren-Akerlund E, Olof sson AM, Berger E, Arfors K-E. (1993) CD11b/CD18-dependent polymorphonuclear leukocyte interaction with matrix proteins in adhesion and migration. Scand J Immunol37: 569–574.
41.
41 Wall HS, Worthman C, Else JG. (1985) Effect of ketamine anesthesia, stress and repeated bleeding on the hematology of vervet monkeys. Lab Animals19: 138–144.
42.
42 Thomas J, Carver M, Haisch C. (1982) Differential effects of intravenous anesthetic agents on cell-mediated immunity in the rhesus macaque. Clin Exp Immunol47: 457–466.
