Combined administration of plasmids encoding IL-4 and IL-10 prevents the development of autoimmune diabetes in nonobese diabetic mice.
Studies of animals with spontaneous autoimmune diabetes have revealed that autoreactive T cells that mediate islet beta-cell destruction belong to the Th1 subset (producing IL-2 and IFN-gamma), whereas regulatory T cells are Th2 type (producing IL-4 and IL-10). Here, we evaluate the effect of combined delivery of plasmid DNA encoding IL-4 and IL-10 using a degradable, cationic polymeric carrier, poly[gamma-(4-aminobutyl)-L-glycolic acid] (PAGA), in nonobese diabetic (NOD) mice. In the liver of NOD mice, we detected mouse Il4 and Il10 mRNA 5 days after intravenous injection of both PAGA-Il4 and PAGA-Il10 plasmid complexes. We found that 6 weeks after injection, 75% of observed islets were intact compared with less than 3% in the control group. Furthermore, in the treatment group, only 5% of the islets were severely infiltrated by the lymphocytes compared with over 30% in the control group. We measured glucose levels weekly up to the age of 32 weeks, revealing that co-injection of PAGA-Il4 and PAGA-Il10 plasmids prevented the development of diabetes in 75% of the treated animals. Thus, combined administration of mouse Il4 and Il10 plasmids prevents the development of autoimmune diabetes in NOD mice.
Ko
K S
KS
Department of Pharmaceutics and Pharmaceutical Chemistry, Center for Controlled Chemical Delivery, University of Utah, Salt Lake City, Utah 84112, USA. k.ko@m.cc.utah.edu
Lee
M
M
Koh
J J
JJ
Kim
S W
SW
D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D005947:Glucose / Q000032:analysis; D007275:Injections, Intravenous; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use*; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012333:RNA, Messenger; D016753:Interleukin-10; D015847:Interleukin-4; D005947:Glucose