Treatment of murine experimental autoimmune encephalomyelitis with a myelin basic protein peptide analog alters the cellular composition of leukocytes infiltrating the cerebrospinal fluid.
Experimental autoimmune encephalomyelitis (EAE) can be effectively treated during disease exacerbation by administration of a peptide corresponding to the major T cell epitope of myelin basic protein (MBP), but the mechanism by which T cell tolerance leads to clinical improvement is not well-defined. Acute exacerbations of EAE are accompanied by an infiltration of blood-borne leukocytes into the brain and spinal cord, where they mediate inflammation and demyelination. To investigate peptide effects on infiltrating cells, we collected cerebrospinal fluid (CSF) from (PL/JxSJL)F1 mice with MBP-induced EAE. Pleiocytosis by lymphocytes, neutrophils, and macrophages was seen throughout the course of relapsing-remitting disease. A single administration of the MBP peptide analog, Ac1-11[4Y], reduced disease severity, accompanied by a dramatic and selective loss of neutrophil pleiocytosis. A longer course of peptide therapy resulted in complete recovery from clinical signs of disease, and decreased pleiocytosis by all cell types. Clinical severity throughout the course of disease and therapy was directly related to the degree of infiltration by neutrophils and macrophages, and the clinical improvement following peptide therapy was accompanied by decreased central nervous system (CNS) expression of chemoattractants for these cell types. These observations support a model of disease exacerbation mediated by phagocytic cellular infiltration under the ultimate control of T cell-derived factors, amenable to treatment by down-regulation of the T cell activation state.
Reiseter
B S
BS
ImmuLogic Pharmaceutical, Waltham, MA 02451-2186, USA.
Miller
G T
GT
Happ
M P
MP
Kasaian
M T
MT
D000199:Actins / Q000235:genetics / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D018845:CD11 Antigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002555:Cerebrospinal Fluid / Q000166:cytology*; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000134:cerebrospinal fluid / Q000276:immunology*; D005260:Female; D015870:Gene Expression / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000276:immunology; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D015345:Oligonucleotide Probes; D010587:Phagocytosis / Q000276:immunology; D014158:Transcription, Genetic / Q000276:immunology
D000199:Actins; D018845:CD11 Antigens; D018932:Chemokine CCL2; D004676:Myelin Basic Protein; D015345:Oligonucleotide Probes