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* Division of Endocrinology and Metabolism, and Departments of Internal Medicine and
Microbiology, University of Virginia, Charlottesville, VA 22908;
Recanati/Miller Transplantation Institute, Mount Sinai Medical Center, New York, NY 10029; and
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
Th1 cell activation and cytokine production shift the balance
between Th1 and Th2, favoring the up-regulation of proinflammatory
activity that leads to destruction of insulin-producing pancreatic 
cells in type 1 diabetes. Th2-type cytokines, such as IL-10, have
immune regulatory function. Administration of IL-10, or IL-10 gene
transfer, prevents autoimmune diabetes in nonobese diabetic (NOD) mice.
However, constant administration of purified rIL-10 is not practical
for long-term therapy to prevent diabetes. In this study, we
transferred the BCRF-1 gene, an open reading frame in
the Epstein-Barr viral genome with remarkable homology to mouse IL-10
(viral IL-10 or vIL-10), by an adeno-associated viral (AAV) vector to
NOD mice to attain sustained vIL-10 gene expression. Like endogenous
mouse IL-10, vIL-10 has potent immunoregulatory and immunosuppressive
functions, but can be specifically distinguished from endogenous mouse
IL-10 for monitoring of the transgene expression. A single systemic
administration of AAV vIL-10 significantly reduced insulitis and
prevented diabetes development in NOD mice. This protective effect
correlated with sustained transgene expression and protein production.
Moreover, splenocytes from the treated mice blocked diabetes transfer
to NOD recipients, suggesting that vIL-10 induces an active suppression
of autoimmunity. This study provides evidence to support the
possibility of using vIL-10 gene therapy to prevent type 1
diabetes.
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