A single treatment with IL-4 via retrovirally transduced lymphocytes partially protects against diabetes in BioBreeding (BB) rats.
BACKGROUND
Type 1 diabetes mellitus is a T cell mediated autoimmune disease with no known methods of prevention. The BioBreeding rat is used as an animal model for the study of human Type 1 diabetes. In spite of a severe lymphopenia, these animals develop spontaneous diabetes at the age of 10-12 weeks.


OBJECTIVE
To examine whether anti-inflammatory gene therapy could be used to prevent autoimmune diabetes in the BioBreeding rat.


METHODS
A retroviral DNA vector, MSCVneo.IL-4, carrying the DNA sequence encoding the rat interleukin-4, was designed to transfer interleukin-4 to BioBreeding rats. Spleen cells of prediabetic animals were activated and transduced in vitro with replication-defective retroviruses expressing the MSCVneo.IL-4 vector. These lymphocytes were subsequently administered intraperitoneally to 3-4 week old prediabetic BioBreeding rats. Control animals were reconstituted with spleen cells transduced with MSCVneo vector.


RESULTS
The neo gene marker was detectable by RT-PCR in rat spleen cells of up to 6 to 12 months after treatment. Fifty percent (6 out of 12) of the animals treated were protected from autoimmune disease development.


CONCLUSIONS
Our results suggest that the BioBreeding rat can be used as a useful model to develop gene therapy regimens for diabetes. These studies provide further support for the hypothesis that interleukin-4 based gene therapy may have potential clinical value for preventing autoimmune diabetes in humans.
Zipris
Danny
D
The Institute of Endocrinology, Diabetes, and Metabolism, Rambam Medical Center. B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
Karnieli
Eddy
E
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D002472:Cell Transformation, Viral / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D004334:Drug Administration Schedule; D005260:Female; D015967:Gene Expression Regulation, Viral; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007274:Injections, Intraperitoneal; D015847:Interleukin-4 / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000821:virology*; D008297:Male; D051379:Mice; D051381:Rats; D011913:Rats, Inbred BB; D011920:Rats, Inbred WF; D012190:Retroviridae / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000637:transplantation / Q000821:virology
D015847:Interleukin-4