Intravenous antigen administration as a therapy for autoimmune demyelinating disease.
Experimental allergic encephalomyelitis is a prototypic autoimmune disease characterized by central nervous system inflammation and demyelination. Previously, we demonstrated that intravenous administration of high doses of myelin basic protein abrogated the clinical and pathological signs of experimental allergic encephalomyelitis by causing the deletion of encephalitogenic, CD4+, myelin basic protein-specific T cells through antigen-induced programmed cell death. In the present study, we further characterized the ability of intravenous antigen administration to attenuate an immune response by myelin basic protein-reactive encephalitogenic T cells. We demonstrated that multiple injections of myelin basic protein are required to achieve a therapeutic response, and that this form of therapy is effective even after prolonged chronic disease. These studies showed that although interleukin-2-stimulated cell cycling is an important factor leading to T-cell death, the administration of exogenous interleukin-2 with antigen can result in the aggravation of clinical disease compared to administration of antigen alone. More importantly, administration of myelin basic protein alone without interleukin-2 was sufficient to reduce autoreactive T cells and clinical disease in experimental autoimmune encephalomyelitis. Our experiments support the rationale for antigen-specific therapy aimed at inducing the programmed death of autoreactive T cells in autoimmune diseases, potentially including the human demyelinating disease multiple sclerosis.
Racke
M K
MK
Neuroimmunology Branch, National Institute of Neurological Diseases and Stroke, National Institutes of Health, Bethesda, MD, USA.
Critchfield
J M
JM
Quigley
L
L
Cannella
B
B
Raine
C S
CS
McFarland
H F
HF
Lenardo
M J
MJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D004359:Drug Therapy, Combination; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology*; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D007262:Infusions, Intravenous; D007376:Interleukin-2 / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D009103:Multiple Sclerosis / Q000188:drug therapy; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*
D007376:Interleukin-2; D004676:Myelin Basic Protein; D011994:Recombinant Proteins