HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Solvason, N. Articles by Garren, H. Search for Related Content PubMed PubMed Citation Articles by Solvason, N. Articles by Garren, H.

Improved Efficacy of a Tolerizing DNA Vaccine for Reversal of Hyperglycemia through Enhancement of Gene Expression and Localization to Intracellular Sites

Nanette Solvason^1,*, Ya-Ping Lou^*, Wendy Peters^*, Erica Evans^*, Josefina Martinez^*, Uriel Ramirez^*, Andrea Ocampo^*, Rui Yun^*, Saira Ahmad^*, Edwin Liu, Liping Yu, George Eisenbarth, Michael Leviten^*, Lawrence Steinman and Hideki Garren^*

^* Bayhill Therapeutics, Palo Alto, CA 94304; Barbara Davis Center for the Study of Childhood Diabetes, Aurora, CO 80010; and Stanford University, Stanford, CA 94305

Insulin is a major target for the autoimmune-mediated destruction of pancreatic β cells during the pathogenesis of type I diabetes. A plasmid DNA vaccine encoding mouse proinsulin II reduced the incidence of diabetes in a mouse model of type I diabetes when administered to hyperglycemic (therapeutic mode) or normoglycemic (prophylactic mode) NOD mice. Therapeutic administration of proinsulin DNA was accompanied by a rapid decrease in the number of insulin-specific IFN--producing T cells, whereas prophylactic treatment was accompanied by enhanced IFN--secreting cells and a decrease in insulin autoantibodies. Adoptive transfer experiments demonstrated that the protection was not mediated by induction of CD25⁺/CD4⁺ T regulatory cells. The efficacy of the DNA vaccine was enhanced by increasing the level of expression of the encoded Ag, more frequent dosing, increasing dose level, and localization of the protein product to the intracellular compartment. The efficacy data presented in this study demonstrate that Ag-specific plasmid DNA therapy is a viable strategy for preventing progression of type I diabetes and defines critical parameters of the dosing regime that influences tolerance induction.

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 Address correspondence and reprint requests to Dr. Nanette Solvason, Bayhill Therapeutics, 3400 W. Bayshore Road, Palo Alto, CA 94304. E-mail address: nsolvason{at}bayhilltx.com

² Abbreviations used in this paper: T1D, type 1 diabetes; BG, blood glucose; IAA, insulin autoantibody; LN, lymph node; pDNA, plasmid DNA; Treg, T regulatory; UG, urine glucose.