Recruitment of leukocytes into the pancreatic islets of Langerhans is a necessary step in the pathogenesis of diabetes and in rejection of transplanted islets. Recent experimental evidence implicates a family of chemotactic cytokines, known as chemokines, in regulating leukocyte migration into the islets. Chemokines are expressed within the pancreatic islets in animal models of diabetes, by islet cells in culture, and by islet grafts. Moreover, as shown by our group and others, islet-specific transgenic expression of certain chemokines is sufficient to induce recruitment of lymphocytes and macrophages into the islets. Based on these findings, we suggest that blocking chemokine function in the pancreas may reduce leukocyte influx and prevent destruction of the islets. A potential broad spectrum chemokine antagonist has been recently identified. This antagonist is M3, a virus-encoded chemokine binding protein, that binds murine and human C, CXC, CX3C and CC chemokines with high affinity; blocks chemokine-induced calcium mobilization in leukocytes, and blocks chemotaxis in vitro and in vivo. We propose to investigate if M3 can block insulitis and allograft rejection when expressed locally, in the pancreas, or systemically. Specifically we will:
Aim 1. Define the expression profile of chemokines in murine islets of Langerhans during homeostasis and disease.
Aim 2. Determine if expression of M3 in the pancreatic islets will block chemokine-induced leukocyterecruitment and interfere wit the development of diabetes.
Aim 3. Determine if expression of M3 in pancreatic islets or systemically will affect graft rejection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067381-02
Application #
6998425
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Appel, Michael C
Project Start
2005-01-01
Project End
2008-12-31
Budget Start
2006-01-01
Budget End
2006-12-31
Support Year
2
Fiscal Year
2006
Total Cost
$339,310
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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