In multiple sclerosis (MS) myelin damage is the result of a chronic inflammatory process mediated by CD4 positive T helper/effector cells. In experimental allergic encephalomyelitis (EAE), the animal model of MS, treatment with anti-CD4 antibodies can prevent the onset of disease. Natural history studies have demonstrated that gadolinium enhanced magnetic resonance imaging (MRI) of the brain is more sensitive and objective in assessing inflammatory disease activity in MS than clinical monitoring, so that less patients and shorter studies suffice to reach the same statistical power as compared to trials using clinical outcome parameters. In this paper we describe the design of an exploratory trial of chimeric monoclonal anti-CD4 antibodies in the treatment of MS. For this study we chose the number of active MS lesions on monthly gadolinium enhanced MRI scans as the primary outcome measure.
1 ffrench-Constant C. (1994) Pathogenesis of multiple sclerosis. Lancet343: 271–275.
2.
2 Traugott U, Reinherz EL, Raine CS. (1982) Multiple sclerosis: distribution of T-cell subsets within active chronic lesions. Science219: 308–310.
3.
3 Traugott U. (1987) Multiple sclerosis: relevance of class I and class II MHC-expressing cells to lesion development. J Neuroimmunol16: 283–302.
4.
4 Hayashi T et al. (1988) Dual label immunocytochemistry of the active multiple sclerosis lesion: major histocompatibility, complex and activation antigens. Ann Neurol24: 523–531.
5.
5 Pettinelli CD, McFarlin DE. (1981) Adoptive transfer of experimental allergic encephalomyelitis in SJL/J mice after in vitro activation of lymph node cells by myelin basic protein: requirement for Lyt 1+2-lymphocytes. J Immunol127: 1420–1423.
6.
6 Holda JH, Swanborg RH. (1982) Autoimmune effector cells II. Transfer of experimental allergic encephalomyelitis with a subset of T lymphocytes. Eur J Immunol12: 453–455.
7.
7 Mokhtarian F, McFarlin DE, Raine CS. (1984) Adoptive transfer of myelin basic protein sensitised T cells produces chronic relapsing demyelinating disease in mice. Nature309: 356–358.
8.
8 Brostoff SW, Mason DW. (1984) Experimental allergic encephalomyelitis: successful treatment in vivo with a monoclonal antibody that recognized T helper cells. J Immunol133: 1938–1942.
9.
9 Waldor MK et al. (1985) Reversal of experimental allergic encephalomyelitis with monoclonal antibody to a T cell subset marker. Science227: 415–417.
10.
10 O'Neill JK et al. (1993) Control of immune-mediated disease of the central nervous system with monoclonal (CD4-specific) antibodies. J Neuroimmunol45: 1–14.
11.
11 Hodgkinson S et al. (1992) Phase I study of chimeric anti-CD4 monoclonal antibody in multiple sclerosis. Neurology42 (Suppl 3): 209.
12.
12 Lindsey JW et al. (1994) Phase clinical study of chimeric monoclonal anti-CD4 antibody in multiple sclerosis. Neurology44: 413–419.
13.
13 Lindsey JW et al. (1994) Repeated treatment with chimeric anti-CD4 antibody in multiple sclerosis. Ann Neurol36: 183–189.
14.
14 Harris JO et al. (1991) Serial gadolinium-enhanced magnetic resonance imaging scans in patients with early relapsing-remitting multiple sclerosis: implications for clinical trials and natural history. Ann Neurol29: 548–555.
15.
15 Thompson AJ et al. (1992) Serial gadolinium-enhanced MRI in relapsing/remitting multiple sclerosis of varying disease duration. Neurology42: 60–63.
16.
16 Thompson AJ et al. (1991) Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann Neurol29: 53–62.
17.
17 Miller DH, Barkhoff, Nauta JJP. (1993) Gadolinium enhancement increases the sensitivity of MRI in detecting disease activity in multiple sclerosis. Brain116: 1077–1094.
18.
18 Nauta JJP, Thompson AJ, Barkhoff, Miller DH. (1994) Magnetic resonance imaging in monitoring the treatment of multiple sclerosis patients: statistical power of parallel-groups and crossover designs. J Neurol Sci122: 6–14.
19.
19 McFarland HF et al. (1992) Using gadolinium-enhanced magnetic resonance imaging lesions to monitor disease activity in multiple sclerosis. Ann Neurol32: 758–766.
21 Poser CM et al. (1983) New diagnostic criteria for multiple sclerosis: guidelines for reasearch protocols. Ann Neurol13: 227–231.
22.
22 Kurtzke JF. (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology33: 1444–1452.
23.
23 Dalesandro MR et al. (1993) Effects of isotype and Fc region on in vitro function of a mouse/human chimeric CD4 antibody. Int Immunol5: 283–291.
24.
24 Miller DH et al. (1991) Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: Concerted Action Guidelines. J Neurol Neurosurg Psychiatry54: 683–688.
