Immunotherapy of spontaneous type 1 diabetes in nonobese diabetic mice by systemic interleukin-4 treatment employing adenovirus vector-mediated gene transfer.
We have previously shown that systemic injection of multiple low doses of recombinant murine interleukin-4 (mIL-4) can prevent type 1 diabetes (T1D) in nonobese diabetic (NOD) mice by activating regulatory T helper (Th) 2 cells in vivo. Here, we have developed a gene transfer approach to the prevention of T1D by testing the therapeutic potential of an adenovirus gene transfer vector engineered to express mIL-4. We found that only two systemic injections of a recombinant adenovirus type 5 vector-expressing mIL-4 (Ad5mIL-4) reduces destructive insulitis and protects NOD mice from the onset of diabetes by eliciting intrapancreatic Th2 cell responses. Host immune responses against the adenovirus vector were detectable; however, the levels of antibody production were insufficient to preclude Ad5mIL-4 treatment as a possible therapeutic agent against T1D. Thus, adenovirus-mediated delivery of IL-4 provides protection of NOD mice from T1D and represents a clinically viable therapeutic approach.
Cameron
M J
MJ
Autoimmunity/Diabetes Group, The John P Robarts Research Institute, London, Ontario, Canada.
Arreaza
G A
GA
Waldhauser
L
L
Gauldie
J
J
Delovitch
T L
TL
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D007073:Immunoglobulin E / Q000276:immunology; D016233:Immunotherapy, Active / Q000379:methods*; D007267:Injections; D015847:Interleukin-4 / Q000235:genetics* / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014162:Transfection / Q000379:methods*
D015847:Interleukin-4; D007073:Immunoglobulin E