Antigen-specific suppression of experimental autoimmune encephalomyelitis by a novel bifunctional peptide inhibitor.
The objective of this study is to evaluate the activity of a novel peptide, i.e., bifunctional peptide inhibitor (BPI), which targets the immunological synapse and inhibits autoimmune responses in an antigen-specific manner. Proteolipid protein (PLP)-BPI was designed by conjugating two peptides, an encephalitogenic epitope of proteolipid protein (PLP(139-151)) and an intercellular adhesion molecule-1-binding peptide derived from alpha(L) integrin (CD11a(237-246)), via a spacer peptide. The therapeutic effect of PLP-BPI was studied in experimental autoimmune encephalomyelitis (EAE) in female SJL/J mice as a model for human multiple sclerosis. Mice that received i.v. injections of PLP-BPI showed significantly lower EAE disease scores and incidence than those treated with vehicle, PLP(139-151) peptide only, CD11a(237-246) peptide only, unlinked mixture of PLP(139-151), and CD11a(237-246) peptides, or other control peptides. Multiple injections of antigenic peptide can produce anaphylactic responses; interestingly, PLP-BPI-treated animals have significantly lower anaphylactic response than do the PLP(139-151)-treated group. Therefore, PLP-BPI can effectively inhibit the disease severity and incidence of EAE with a lower possibility of inducing fatal anaphylaxis. These results suggest that BPI-type molecules can be used to treat different autoimmune diseases in which antigenic epitopes have been identified.
Kobayashi
Naoki
N
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047-3729, USA.
Kobayashi
Hitomi
H
Gu
Leo
L
Malefyt
Thomas
T
Siahaan
Teruna J
TJ
D000595:Amino Acid Sequence; D000707:Anaphylaxis / Q000139:chemically induced / Q000276:immunology; D000818:Animals; D000941:Antigens / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D040881:CD11a Antigen / Q000737:chemistry; D036022:Capsid Proteins / Q000737:chemistry; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D051379:Mice; D008815:Mice, Inbred Strains; D018448:Models, Immunological; D008969:Molecular Sequence Data; D018991:Myelin Proteolipid Protein / Q000737:chemistry / Q000276:immunology; D010047:Ovalbumin / Q000737:chemistry; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D010455:Peptides / Q000276:immunology / Q000627:therapeutic use* / Q000633:toxicity; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014611:Vaccination
D000941:Antigens; D040881:CD11a Antigen; D036022:Capsid Proteins; D018991:Myelin Proteolipid Protein; C573814:PLP-BPI peptide; D010446:Peptide Fragments; D010455:Peptides; D016212:Transforming Growth Factor beta; C442556:VP2 protein, Theilovirus; C435023:myelin proteolipid protein (139-151); D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin