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Synthetic Peptide Dendrimers Block the Development and Expression of Experimental Allergic Encephalomyelitis¹

Keith W. Wegmann^*,, Cynthia R. Wagner^*,,, Ruth H. Whitham^*, and David J. Hinrichs^2,*,

^* Veterans Affairs Medical Center, Immunology Research Group, Department of Neurology, and Department of Cardiology, Oregon Health & Science University, Portland, OR 97239

Multiple Ag peptides (MAPs) containing eight proteolipid protein (PLP)_139–151 peptides arranged around a dendrimeric branched lysine core were used to influence the expression and development of relapsing experimental allergic encephalomyelitis (EAE) in SJL mice. The PLP_139–151 MAPs were very efficient agents in preventing the development of clinical disease when administered after immunization with the PLP_139–151 monomeric encephalitogenic peptide in CFA. The treatment effect with these MAPs was peptide specific; irrelevant multimeric peptides such as guinea pig myelin basic protein GPBP_72–84 MAP (a dendrimeric octamer composed of the 72–84 peptide) and PLP_178–191 MAP (a dendrimeric octamer composed of the PLP_178–191 peptide) had no treatment effect on PLP_139–151-induced EAE. PLP_139–151 MAP treatment initiated after clinical signs of paralysis also altered the subsequent course of EAE; it limited developing signs of paralysis and effectively limited the severity and number of disease relapses in MAP-treated mice over a 60-day observation period. PLP_139–151 MAP therapy initiated before disease onset acts to limit the numbers of Th17 and IFN--producing cells that enter into the CNS. However, Foxp3⁺ cells entered the CNS in numbers equivalent for nontreated and PLP_139–151 MAP-treated animals. The net effect of PLP_139–151 MAP treatment dramatically increases the ratio of Foxp3⁺ cells to Th17 and IFN--producing cells in the CNS of PLP_139–151 MAP-treated animals.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Merit Review funds from the Department of Veterans Affairs.

² Address correspondence and reprint requests to Dr. David J. Hinrichs, R&D 21, Portland Veterans Affairs Medical Center, Oregon Health & Science University, Portland, OR 97201. E-mail address: hinrichs{at}ohsu.edu

³ Abbreviations used in this paper: EAE, experimental allergic encephalomyelitis; MAP, multiple Ag peptide; GPBP, guinea pig myelin basic protein; PLP, proteolipid protein; RTL, recombinant T cell ligand; T_reg, regulatory T cell.