Multiple sclerosis [MS], a demyelinating disease of the central nervous system associated with inflammation and gliosis, may be an autoimmune disease with T lymphocytes and autoantibodies to myelin protein(s). This study deals exclusively with B cell autoimmunity to myelin basic protein (MBP). T lymphocytes and anti-MBP share a common MBP epitope located between P85 and P96 which contains the essential contact residues H88FFK91 for the trimolecular complex. The purpose of this Phase I open label clinical study was to monitor CSF anti-MBP in patients with chronic progressive MS subsequent to IV administration of synthetic peptide (sp) MBP82-98 namely DEN85VVHFFKNIVTP96RT. Fifty-six patients who participated in this project were assigned to two groups: a `control group' of 15 patients who received IV saline injections every 6 months for the first 2 years of the study and a `peptide group' of 41 patients who received IV spMBP82-98 from the beginning of the study and then infrequently subsequent to a rise of their CSF anti-MBP. In the control group antibody levels remained persistently elevated during the 2 year period. Patients in the `peptide group' segregated into four kinetic profiles: Cohort A (15 patients) illustrated prolonged anti-BMP suppression into the normal range. Cohort B (10 patients) illustrated significant anti-MBP suppression into the normal range for shorter durations. Cohort C (eight patients) showed significant CSF anti-MBP suppression after the initial injection but lost the ability to suppress the autoantibody titer following subsequent injections. Cohort D (eight patients) failed to show significant CSF anti-MBP suppression. In conclusion the B cell tolerizing effect of spMBP82-98 segregated into four kinetic profiles; this molecular variability should be considered in attempts to develop specific `peptide therapies' for the broad range of clinical profiles currently diagnosed as `multiple sclerosis'.
Babinski J. (1885) é tude anatomique et clinique sur la sclérose en plaques pour Le doctorat en Médecine présenté et soutenu le 9 Mars, Paris.
2.
Schmidt S. (1999) Candidate autoantigens in multiple sclerosis . Multiple Sclerosis5: 147-160 .
3.
Mokhtarian F , McFarland DE , Raine CS. (1984) Adoptive transfer of myelin basic protein-specific T cells produces chronic relapsing demyelinating disease in mice . Nature309: 356-358 .
4.
Satoh Jet al. (1987) Experimental allergic encephalomyelitis mediated by murine encephalitogenic T cell lines specific for myelin proteolipid apoprotein . J Immunol138: 179-184 .
5.
van der Veen RC , Trotter JL , Clark HB , Kapp JA. (1989) The adoptive transfer of chronic relapsing experimental allergic encephalomyelitis with lymph node cells sensitized to myelin proteolipid protein . J Neuroimmunol21: 183-191 .
6.
Genain CP , Hauser SL. (1997) Creation of a model for multiple sclerosis in Callithrix jacchus marmosets . J Molec Med75: 187-197 .
7.
Burns J , Rosenzweig A , Zweiman B , Lisak R. (1983) Isolation of myelin basic protein reactive T cells from normal human blood . Cell Immunol81: 435-440 .
8.
Martin Ret al. (1990) Fine specificity and HLA restriction of myelin basic protein-specific cytotoxic T cell lines from multiple sclerosis patients and healthy individuals . J Immunol145(2): 540-548 .
9.
Sun Jet al. (1991) T and B cell responses to myelinoligodendrocyte glycoprotein in multiple sclerosis . J Immunol146: 1490-1495 .
10.
Giegerich Get al. (1992) Diversity of T cell receptor a and b chain genes expressed by human T cells, specific for similar myelin basic protein major histocompatibility complexes . Eur J Immunol22: 753-758 .
11.
Kerlero de Rosbo Net al. (1993) Reactivity to myelin antigens in multiple sclerosis: Peripheral blood lymphocytes respond predominantly to myelin oligodendrocyte glycoprotein . J Clin Invest92: 2602-2608 .
12.
Pelfrey Vet al. (1993) Identification of a novel epitope of human PLP (residues 40-60) recognized by proliferative and cytolytic CD4+ T cells from MS patients . J Neuroimmunol46: 33-42 .
13.
Plese Set al. (1995) T cell recognition of immunodominant and cryptic proteolipid protein epitopes in humans . J Immunol155: 982-992 .
14.
Vandenbark AA , Gill T , Offner H. (1985) A myelin basic protein specific T cell line that mediates experimental allergic encephalomyelitis . J Immunol135: 223-228 .
15.
Olsson Tet al. (1990) Autoreactive T lymphocytes in multiple sclerosis determined by antigen-induced secretion of interferon-g . J Clin Invest86: 981-985 .
16.
Salvetti Met al. (1993) Predominant and stable T cell responses to regions of myelin basic protein can be detected in individual patients with multiple sclerosis . Eur J Immunol23: 1232-1239 .
17.
Wucherpfennig KWet al. (1994) Structural requirements for binding of an immunodominant myelin basic protein peptide to DR2 isotypes and for its recognition by human Tcellclones . J Exp Med179: 279-290 .
18.
Zhang Jet al. (1994) Increased frequency of interleukin- 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis . J Exp Med179: 973-984 .
19.
Hafler DAet al. (1996) TCR usage in human and experimental demyelinating disease . Immunol Today17: 152-155 .
20.
Scolding N. (1999) Immunological and inflammatory disorders of the central nervous system. In: Scolding N editor. Multiple Sclerosis Oxford and Boston: Butter-worth-Heineman ; pp 21-73.
21.
Kerlero de Rosbo Net al. (1998) T cell responses to myelin antigens in multiple sclerosis: relevance of the predominant autoimmune reactivity to myelin oligodendrocyte glycoprotein . J Autoimmunity11: 287-299 .
22.
Warren KG , Catz I. (1993) Autoantibodies to MBP within MS CNS tissue . J Neurol Sci115: 169-176 .
23.
Reichert JRet al. (1989) Human cytotoxic T cell recognition of a synthetic peptide of myelin basic protein . Ann Neurol26: 342-346 .
24.
Pette Met al. (1990) Myelin autoreactivity in multiple sclerosis: Recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of MS patients and healthy donors . Proc Nat'l Acad Sci87: 7968-7972 .
25.
Ota Ket al. (1990) T-cell recognition of an immunodominant myelin basic protein epitope in multiple sclerosis . Nature346: 183-186 .
26.
Zhang Jet al. (1992) Myelin basic protein-specific T lymphocytes in multiple sclerosis and controls: Precursor frequency, fine specificity and cytotoxicity . Ann Neurol32: 330-338 .
27.
Vali Aet al. (1993) Binding of myelin basic protein peptides to human histocompatibility leukocyte antigen class II molecules and their recognition by T cells from multiple sclerosis patients . J Clin Invest91: 616-628 .
28.
Joshy N , Usuku K , Hauser SL. (1993) The T-cell response to myelin basic protein in familial multiple sclerosis: Diversity of fine specificity, restricting elements, and T-cell receptor usage . Ann Neurol34: 385-393 .
29.
Meinl Eet al. (1993) Myelin basic protein-specific T lymphocyte repertoire in multiple sclerosis. Complexity of the response and dominance of nested epitopes due to recruitment of multiple T cell clones . J Clin Invest92: 2633-2643 .
30.
Oksenberg JRet al. (1993) Selection for T-cell receptor Vb-Db-Jb gene rearrangements with specificity for myelin basic protein in brain lesions of multiple sclerosis . Nature362: 68-70 .
31.
Wucherpfennig KWet al. (1994) Clonal expansion and peristence of human T cells specific for an immunodominant myelin basic protein peptide . J Immunol152: 5581-5592 .
32.
Hemmer Bet al. (1997) Human T-cell response to myelin basic protein (83-99). Extensive heterogeneity in antigen recognition, function, and phenocyte . Neurology49: 1116-1126 .
33.
Carson JH , Barbarese E , Braun PE , McPherson TA. (1978) Components in multiple sclerosis cerebrospinal fluid that are detected by radioimmunoassay for myelin basic protein . Proc Nat'l Acad Sci USA75: 1976-1978 .
34.
Panitch HS , Hooper CJ , Johnson KP. (1980) CSF antibody to myelin basic protein: measurements in patients with multiple sclerosis and subacute sclerosing panencephalitis . Arch Neurol37: 206-209 .
35.
Bernard CCAet al. (1981) Antibody to myelin basic protein in extracts of multiple sclerosis brain . Immunology43: 447-457 .
36.
Brokstad KA , Page M , Nyland H , Haaheim LR. (1994) Autoantibodies to myelin basic protein are not present in the serum and CSF of MS patients . Acta Neurol Scand89: 407-411 .
37.
Warren KG , Catz I. (1986) Diagnostic value of cerebrospinal fluid anti-myelin basic protein in patients with multiple sclerosis . Ann Neurol20: 20-25 .
38.
Lamers KJB , de Reus HPM , Jongen PJ. (1998) Myelin basic protein in CSF as indicator of disease activity in multiple sclerosis . Multiple Sclerosis4: 124-126 .
39.
Warren KG , Catz I. (1987) A correlation between cerebrospinal fluid myelin basic protein and anti-myelin basic protein in multiple sclerosis patients . Ann Neurol21: 183-189 .
40.
Warren KG , Catz I. (1992) Synthetic peptide specificity of anti-myelin basic protein from multiple sclerosis cerebrospinal fluid . J Neuroimmunol39: 81-90 .
41.
Warren KG , Catz I , Steinman L. (1995) Fine specificity of the antibody response to myelin basic protein in the central nervous system in multiple sclerosis: the minimal B cell epitope and a model of its features . Proc Nat'l Acad Sci USA92: 11061-11065 .
42.
Wucherpfennig KWet al. (1997) Recognition of the immunodominant myelin basic protein peptide by autoantibodies and HLA-DR2-restricted T cell clones from multiple sclerosis patients: identity of key contact residues in the B cell and T cell epitopes . J Clin Invest100: 1114-1122 .
43.
Goebels Net al. (1998) Long-term development of the human MBP specific T cell repertoire: Epitope spreading versus clonal persistence . Neurology50 (Suppl. 4): A359-A359 .
44.
Warren KG , Catz I. (1999) An extensive search for autoantibodies to myelin basic protein in CSFR of nonMS patients: implications for the pathogenesis of MS . Eur Neurol42: 95-104 .
45.
Asakura K , Rodriguez M. (1998) A unique population of circulating autoantibodies promotes central nervous system demyelination . Multiple Sclerosis4: 217-221 .
46.
Schluesener HJ , Sobel RA , Linington C , Weiner HL. (1987) A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyeli-nation in central nervous system autoimmune disease . J Immunol139: 4016-4021 .
47.
Genain CPet al. (1995) Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate . JClin Invest96: 2966-2974 .
48.
Genain CPet al. (1996) Late complications of immune deviation therapy in a nonhuman primate . Science274: 2054-2057 .
49.
Warren KG , Catz I. (1995) Administration of myelin basic protein synthetic peptide to multiple sclerosis patients . J Neurol Sci133: 85-94 .
50.
Warren KG , Catz I. (1997) The effect of intrathecal MBP synthetic peptides containing epitope P85VVHFFKNIVTP96 on free anti-MBP levels in acute relapsing multiple sclerosis . J Neurol Sci148: 67-78 .
51.
Warren KG , Catz I , Wucherpfennig KW. (1997) Tolerance induction to myelin basic protein by intravenous synthetic peptides containing epitope P85VVHFFKNIVTP96 in chronic progressive multiple sclerosis . J Neurol Sci152: 31-38 .
52.
Genain CP , Cannella B , Hauser SL , Raine CS. (1999) Identification of autoantibodies associated with myelin damage in multiple sclerosis . Nature Med5: 170-175 .
53.
Raine CS , Cannella B , Hauser SL , Genain CP. (1999) Demyelination in primary autoimmune encephalomyelitis and acute multiple sclerosis lesions: A case for antigen-specific antibody mediation . Ann Neurol46: 144-160 .
54.
Siskind GW. (1984) Immunologic tolerance. In: Paul WE (ed.). Fundamental Immunology. Raven Press: New York . pp 537-558.
55.
Schumacher GAet al. (1965) Problems of experimental trials of therapy in MS. Report by the panel on evaluation of experimental trials in MS . Ann NY Acad Sci122: 552-568 .
56.
Poser Cet al. (1983) New diagnostic criteria for multiple sclerosis . Ann Neurol13: 227-231 .
57.
Warren KG , Catz I , Johnson ES , Mielke B. (1994) Anti-MBP and anti-PLP specific forms of MS . Ann Neurol35: 280-289 .
58.
Deibler GE , Martenson RE , Kies MW. (1972) Large scale preparation of myelin basic protein from central nervous system tissue of several mammalian species . Prep Biochem2: 129-165 .
59.
Hafler DAet al. (1988) Oligoclonal T lymphocytes in the cerebrospinal fluid of patients with multiple sclerosis . J Exp Med167: 1313-1322 .
60.
Allegretta M , Nicklas JA , Sriram S , Albertini RJ. (1990) T cells responsive to myelin basic protein in patients with multiple sclerosis . Science247: 718-721 .
61.
Warren KG , Catz I. (1991) Purification of autoantibodies to myelin basic protein by antigen specific affinity chromatography from cerebrospinal fluid IgG of multiple sclerosis patients. Immunoreactivity studies with human myelin basic protein . J Neurol Sci103: 90-96 .
62.
Rathmell JCet al. (1995) CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+ T cells . Nature376: 181-184 .
63.
Van Parijs Let al. (1997) Functional responses and apoptosis of CD25 (IL-2R alpha)-deficient T cells expressing a transgenic antigen receptor . J Immunol158: 3738-3745 .
64.
Van Parijs L , Abbas AK. (1998) Homeostasis and self-tolerance in the immune system: turning lymphocytes off . Science280: 243-248 .
65.
von Boehmer H , Kisielow P. (1991) How the immune system learns about self . Sci Am265: 74-81 .
66.
Burns J , Bartholomew B , Lobo S. (1999) Isolation of myelin basic protein-specific T-cells predominantly from the memory T-cell compartment in multiple sclerosis . Ann Neurol45: 33-39 .
67.
Ridgway WM , Fasso M , Fathman CG. (1999) A new look at MHC and autoimmune disease . Science284: 749-751 .
