Induction and suppression of an autoimmune disease by oligomerized T cell epitopes: enhanced in vivo potency of encephalitogenic peptides.
T cell epitope peptides derived from proteolipid protein (PLP139-151) or myelin basic protein (MBP86-100) induce experimental autoimmune encephalomyelitis (EAE) in "susceptible" strains of mice (e.g., SJL/J). In this study, we show that the encephalitogenic effect of these epitopes when injected subcutaneously in complete Freund's adjuvant was significantly enhanced if administered to the animal in a multimerized form as a T cell epitope oligomer (i.e., as multiple repeats of the peptide epitope, such as 16-mers). Oligomer-treated SJL/J mice developed EAE faster and showed a more severe progression of the disease than animals treated with peptide alone. In addition, haplotype-matched B10.S mice, "resistant" to EAE induction by peptide, on injection of 16-mers developed a severe form of EAE. Even more striking, however, was the dramatic suppression of incidence and severity of the disease, seen after single intravenous injections of only 50 microg of the PLP139-151 16-mer, administered to SJL/J mice 7 d after the induction of the disease. Although relapse occurred at about day 45, an additional injection several days before that maintained the suppression. Importantly, the specific suppressive effect of oligomer treatment was also evident if EAE was induced with spinal cord homogenate instead of the single peptide antigen. By contrast, the PLP139-151 peptide accelerated rather than retarded the progression of disease.
Falk
K
K
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Rötzschke
O
O
Santambrogio
L
L
Dorf
M E
ME
Brosnan
C
C
Strominger
J L
JL
D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D000939:Epitopes / Q000276:immunology / Q000494:pharmacology*; D005620:Freund's Adjuvant; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D018991:Myelin Proteolipid Protein / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology; D013045:Species Specificity; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D013997:Time Factors
D000939:Epitopes; D007166:Immunosuppressive Agents; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D005620:Freund's Adjuvant