874
Proc. roy. Soc. Med. Volume 70 December 1977
ments are taken into account in the decision about the treatment of selected MS patients, then immunosuppression is thoroughly justified. The restrictions I have given imply, nevertheless, that at the present time one cannot advocate the general application of immunosuppression as a standard form of MS treatment. However, in the framework of strictly controlled and monitored clinical trials the effects of immunosuppression in MS patients should be studied further, and this may not only be of some benefit for, I hope, an increasing number of patients, but may eventually also add to our knowledge about the pathological processes underlying this disease.
Swinburn W R & Liversedge L A (1973) Journal of Neurology, Neurosurgery and Psychiatry 36, 124-126 Thompson E J (1977) British Medical Bulletin 33, 28-33 Wisniewski H M (1977) British Medical Bulletin 33, 54-59 Wroblewska Z, Gilden D, Lisak R & Koprowski H (1976) The New Enqland Journal of Medicine 295, 732
Dr R A C Hughes, Dr I Gray, Dr R Clifford-Jones and Dr M Stern (Guy's Hospital Medical School, London Bridge, London SEJ 9RT) Immune Response to Myelin Basic Protein in Multiple Sclerosis
REFERENCES Arnon R (1975) In: Multiple Sclerosis Research. Eds. A N Davison et al. HMSO, London; pp 271-283 Bornstein M B (1973) In: Progress in Neuropathology. Vol 2. Ed. H M Zimmerman. Grune and Stratton, New York; p 69 Brendel W, Seifert J & Lob G (1972) Proceedings of the Royal Society of Medicine 65, 531-535 Cendrowski W S (1971) Acta neurologica Scandinavica 47, 254-260
CoombsRRA&GellPGH, (1975) In: Clinical Aspects of Immunology. 3rd edn. Eds. P G H Gell et al. Blackwell, Oxford &c.; p 761 DuPont B (1975) In: Multiple Sclerosis Research. Eds. A N Davison et al. HMSO, London; pp 291-314 Frick E (1976) Nervenarzt 47, 424-428 Jersild C, DuPont B, Fog T, Platz P J & Svejgaard A (1975) Transplantation Reviews 22, 148-163 Johnson R T (I1975) In: Multiple Sclerosis Research. Eds. A N Davison et al. HMSO, London; pp 155-183 Knight S C, Lance E M, Abbosh J, Munro A & O'Brien J (1975) Clinical and Experimental Immunology 21, 23-31 Lance E M, Kremer M, Abbosh J, Jones V E, Knight S & Medawar P B (1975) Clinical and Experimental Immunology 21, 1-12 Lance E M, Medawar P B & Taub R N (1973) Advances in Immunology 17, 1-92 McFarlin D E, Blank S E & Kibler R F (1974) The Journal of Immunology 113, 712-715 Mertin J & Meade C J (1977) British Medical Bulletin 33, 67-71 Milar J H D, Zilkha K J, Langman M J S, Payling Wright H, Smith A D, Belin J & Thompson R H S (1973) British Medical Journal i, 765-768 Paterson P Y (1973) Journal of Chronic Diseases 26, 119-126 Ring J, Seifert J, Angstwurm H, Frick E, Mertin J, Brass B, Backmund H & Lob G (1976) Postgraduate Medical Journal 52, 123-128 Rose A S, Kuzma J W, Kurtzke J F, Namerow N S, Sibley W A & Tourtelotte W W (1970) Neurology 20, 1-59 Seland T P, McPherson T A, Grace M, Lamoureaux G & Blain J G (1974) Neurology 24, 34-40 Sheramata W, Cosgrove J B R & Eylar E H (1974) The New England Journal of Medicine 291, 14-17 Smeraldi E & Scorza-Smeraldi R (1976) Nature 260, 532-533 Svejgaard A & Ryder L P (1976) Lancet ii, 547-549
For forty years cavalry brigades of research workers have attacked the fortress of multiple sclerosis (MS), spurred on by its alleged similarity with experimental allergic encephalomyelitis (EAE). The histological brigade report that EAE in large primates and human post-rabies vaccine encephalomyelitis resemble the active lesions of multiple sclerosis. The experimental pathologists have kept the battle going with descriptions of chronic, even relapsing, forms of EAE in the guinea-pig (Snyder et al. 1975). The brigade of immunologists have successfully demonstrated that EAE is caused by a T-cell mediated immune response against myelin basic protein (molecular weight 18 000). Antibody to myelin basic protein is produced but is not necessary for disease production. Antibodies to other myelin antigens are also produced but do not induce disease, and may even have a protective effect (Hughes 1974, Hughes & Leibowitz 1975). The onus is now on the immunological cavalry to identify similar phenomena in MS. The most easily detectable marker of any immune response to basic protein would be antibody. Attempts to find such antibody by radioimmunoassay in the serum of MS patients have been uniformly unsuccessful (Lisak et al. 1968, Lennon & Mackay 1972, Schmid et al. 1974). The cerebrospinal fluid (CSF) of MS patients contains oligoclonal bands of IgG which are not present in the serum, but antibody to basic protein has not been found in these bands. Possibly the excess basic protein present in the CSF of patients with active MS (Cohen et al. 1976) might mask the presence of antibodies. A multitude of different techniques have been used to detect cell-mediated immunity to basic protein, with conflicting results (Hughes & Leibowitz 1977). The most suggestive work is that of Sheremata et al. (1976) who claim that cellmediated immunity to basic protein is indeed present at the time of or shortly before a relapse of
875
Section ofNeurology mean ± SE 1400 multiple sclerosis and disappears during MS remissions. Their assay system depended on the Normal 1200 inhibition of guinea-pig macrophage migration by OND the patient's lymphocytes. The test is by no means e 1000 specific for multiple sclerosis and positive results are also obtained in patients with stroke. We have recently re-explored this problem using lae 800 a microculture technique for the estimation of 600 lymphocyte transformation in the presence of 5:) human myelin basic protein. Lymphocytes were 400 separated from venous blood on a Ficoll-triosil E 200] gradient. After washing, 200 pl of a cell suspension containing 2 x 105 cells in bicarbonate buffered tissue culture medium with 100% AB serum were 10 100 placed in each well of a flat-bottomed microtiter Myelin basic protein pg/ml tray. The wells were labelled with 0.166 pCi of 3-H Fig 3 Increment of 3-H thymidine incorporation in the thymidine after 5 days and harvested after 6 days. presence of human myelin basic protein The control uptake of 3-H thymidine in unstimulated cultures was greater in patients with MS 2500 and other neurological diseases (OND) than in > 10 years normal subjects (Fig 1). Responses to antigens or
Proc. roy. Soc. Med. Volume 70 December 1977
ments are taken into account in the decision about the treatment of selected MS patients, then immunosuppression is thoroughly justified. The restrictions I have given imply, nevertheless, that at the present time one cannot advocate the general application of immunosuppression as a standard form of MS treatment. However, in the framework of strictly controlled and monitored clinical trials the effects of immunosuppression in MS patients should be studied further, and this may not only be of some benefit for, I hope, an increasing number of patients, but may eventually also add to our knowledge about the pathological processes underlying this disease.
Swinburn W R & Liversedge L A (1973) Journal of Neurology, Neurosurgery and Psychiatry 36, 124-126 Thompson E J (1977) British Medical Bulletin 33, 28-33 Wisniewski H M (1977) British Medical Bulletin 33, 54-59 Wroblewska Z, Gilden D, Lisak R & Koprowski H (1976) The New Enqland Journal of Medicine 295, 732
Dr R A C Hughes, Dr I Gray, Dr R Clifford-Jones and Dr M Stern (Guy's Hospital Medical School, London Bridge, London SEJ 9RT) Immune Response to Myelin Basic Protein in Multiple Sclerosis
REFERENCES Arnon R (1975) In: Multiple Sclerosis Research. Eds. A N Davison et al. HMSO, London; pp 271-283 Bornstein M B (1973) In: Progress in Neuropathology. Vol 2. Ed. H M Zimmerman. Grune and Stratton, New York; p 69 Brendel W, Seifert J & Lob G (1972) Proceedings of the Royal Society of Medicine 65, 531-535 Cendrowski W S (1971) Acta neurologica Scandinavica 47, 254-260
CoombsRRA&GellPGH, (1975) In: Clinical Aspects of Immunology. 3rd edn. Eds. P G H Gell et al. Blackwell, Oxford &c.; p 761 DuPont B (1975) In: Multiple Sclerosis Research. Eds. A N Davison et al. HMSO, London; pp 291-314 Frick E (1976) Nervenarzt 47, 424-428 Jersild C, DuPont B, Fog T, Platz P J & Svejgaard A (1975) Transplantation Reviews 22, 148-163 Johnson R T (I1975) In: Multiple Sclerosis Research. Eds. A N Davison et al. HMSO, London; pp 155-183 Knight S C, Lance E M, Abbosh J, Munro A & O'Brien J (1975) Clinical and Experimental Immunology 21, 23-31 Lance E M, Kremer M, Abbosh J, Jones V E, Knight S & Medawar P B (1975) Clinical and Experimental Immunology 21, 1-12 Lance E M, Medawar P B & Taub R N (1973) Advances in Immunology 17, 1-92 McFarlin D E, Blank S E & Kibler R F (1974) The Journal of Immunology 113, 712-715 Mertin J & Meade C J (1977) British Medical Bulletin 33, 67-71 Milar J H D, Zilkha K J, Langman M J S, Payling Wright H, Smith A D, Belin J & Thompson R H S (1973) British Medical Journal i, 765-768 Paterson P Y (1973) Journal of Chronic Diseases 26, 119-126 Ring J, Seifert J, Angstwurm H, Frick E, Mertin J, Brass B, Backmund H & Lob G (1976) Postgraduate Medical Journal 52, 123-128 Rose A S, Kuzma J W, Kurtzke J F, Namerow N S, Sibley W A & Tourtelotte W W (1970) Neurology 20, 1-59 Seland T P, McPherson T A, Grace M, Lamoureaux G & Blain J G (1974) Neurology 24, 34-40 Sheramata W, Cosgrove J B R & Eylar E H (1974) The New England Journal of Medicine 291, 14-17 Smeraldi E & Scorza-Smeraldi R (1976) Nature 260, 532-533 Svejgaard A & Ryder L P (1976) Lancet ii, 547-549
For forty years cavalry brigades of research workers have attacked the fortress of multiple sclerosis (MS), spurred on by its alleged similarity with experimental allergic encephalomyelitis (EAE). The histological brigade report that EAE in large primates and human post-rabies vaccine encephalomyelitis resemble the active lesions of multiple sclerosis. The experimental pathologists have kept the battle going with descriptions of chronic, even relapsing, forms of EAE in the guinea-pig (Snyder et al. 1975). The brigade of immunologists have successfully demonstrated that EAE is caused by a T-cell mediated immune response against myelin basic protein (molecular weight 18 000). Antibody to myelin basic protein is produced but is not necessary for disease production. Antibodies to other myelin antigens are also produced but do not induce disease, and may even have a protective effect (Hughes 1974, Hughes & Leibowitz 1975). The onus is now on the immunological cavalry to identify similar phenomena in MS. The most easily detectable marker of any immune response to basic protein would be antibody. Attempts to find such antibody by radioimmunoassay in the serum of MS patients have been uniformly unsuccessful (Lisak et al. 1968, Lennon & Mackay 1972, Schmid et al. 1974). The cerebrospinal fluid (CSF) of MS patients contains oligoclonal bands of IgG which are not present in the serum, but antibody to basic protein has not been found in these bands. Possibly the excess basic protein present in the CSF of patients with active MS (Cohen et al. 1976) might mask the presence of antibodies. A multitude of different techniques have been used to detect cell-mediated immunity to basic protein, with conflicting results (Hughes & Leibowitz 1977). The most suggestive work is that of Sheremata et al. (1976) who claim that cellmediated immunity to basic protein is indeed present at the time of or shortly before a relapse of
875
Section ofNeurology mean ± SE 1400 multiple sclerosis and disappears during MS remissions. Their assay system depended on the Normal 1200 inhibition of guinea-pig macrophage migration by OND the patient's lymphocytes. The test is by no means e 1000 specific for multiple sclerosis and positive results are also obtained in patients with stroke. We have recently re-explored this problem using lae 800 a microculture technique for the estimation of 600 lymphocyte transformation in the presence of 5:) human myelin basic protein. Lymphocytes were 400 separated from venous blood on a Ficoll-triosil E 200] gradient. After washing, 200 pl of a cell suspension containing 2 x 105 cells in bicarbonate buffered tissue culture medium with 100% AB serum were 10 100 placed in each well of a flat-bottomed microtiter Myelin basic protein pg/ml tray. The wells were labelled with 0.166 pCi of 3-H Fig 3 Increment of 3-H thymidine incorporation in the thymidine after 5 days and harvested after 6 days. presence of human myelin basic protein The control uptake of 3-H thymidine in unstimulated cultures was greater in patients with MS 2500 and other neurological diseases (OND) than in > 10 years normal subjects (Fig 1). Responses to antigens or
