Abstract
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 (PLP139–151) and an intercellular adhesion molecule-1-binding peptide derived from αL integrin (CD11a237–246), 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, PLP139–151 peptide only, CD11a237–246 peptide only, unlinked mixture of PLP139–151, and CD11a237–246 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 PLP139–151-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.
Footnotes
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This work is supported by National Institutes of Health Grant R01-AI-063002 and General Research Funds from The University of Kansas (to T.J.S.) and by a postdoctoral fellowship (to N.K.) from the American Heart Association, Heartland Affiliate.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.123257.
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ABBREVIATIONS: MS, multiple sclerosis; APC, antigen presenting cell; TCR, T-cell receptor; MHC, major histocompatibility complex; LFA, lymphocyte function-associated antigen; ICAM, intercellular adhesion molecule; BPI, bifunctional peptide inhibitor; GAD, glutamic acid decarboxylase; PLP, proteolipid protein; EAE, experimental autoimmune encephalomyelitis; PBS, phosphate-buffered saline; CFA, complete Freund's adjuvant; TGF, transforming growth factor; PE, phycoerythrin; IFN, interferon; OVA, ovalbumin; IL, interleukin; APL, altered peptide ligand; MBP, myelin basic protein; Th, T-helper.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received March 24, 2007.
- Accepted May 21, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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