Improved efficacy of a tolerizing DNA vaccine for reversal of hyperglycemia through enhancement of gene expression and localization to intracellular sites.
Insulin is a major target for the autoimmune-mediated destruction of pancreatic beta 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-gamma-producing T cells, whereas prophylactic treatment was accompanied by enhanced IFN-gamma-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.
Solvason
Nanette
N
Bayhill Therapeutics, Palo Alto, CA 94304, USA.
Lou
Ya-Ping
YP
Peters
Wendy
W
Evans
Erica
E
Martinez
Josefina
J
Ramirez
Uriel
U
Ocampo
Andrea
A
Yun
Rui
R
Ahmad
Saira
S
Liu
Edwin
E
Yu
Liping
L
Eisenbarth
George
G
Leviten
Michael
M
Steinman
Lawrence
L
Garren
Hideki
H
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D006943:Hyperglycemia / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007108:Immune Tolerance / Q000235:genetics; D007424:Intracellular Fluid / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D011236:Prediabetic State / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D011384:Proinsulin / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D016032:Randomized Controlled Trials as Topic; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*
D001324:Autoantigens; D019444:Vaccines, DNA; D011384:Proinsulin