Islet transplantation for the treatment of type I diabetes has failed to fulfill its promise, which was generated by a large number of highly successful experiments in rodents. Recent evidence suggests that the failure of islets to engraft and survive for prolonged periods of time is due to many nonspecific as well as allospecific reactions. The overall objective of this proposal is to define the mechanisms of injury produced by these host immune responses. The investigators are planning to examine the requirement for functional interaction between host pro-inflammatory cytokines that accumulate at the graft site and corresponding cytokine receptors expressed by the transplanted islets. It is hypothesized that accumulation of pro-inflammatory cytokines such as TNF and IL-1 produced by the host have direct adverse effects on islet isograft functional outcome. It is also hypothesized that this mechanism of islet transplant injury occurs in the setting of host T_cell-dependent, perforin and Fas-independent, non-cytolytic alloimmune responses, and that the adverse effects are operative via functional interactions between the host pro-inflammatory cytokines and the corresponding cytokine receptors expressed by the transplant islets. The investigators, for this purpose, will transplant islets from mice with genetic functional deletion of TNF and IL-1 receptors into streptozotocin-induced diabetic recipients in a functional mouse islet transplant model. By defining these cytokine ligand receptor interactions, the investigators hope to develop new strategies utilizing gene-targeted therapeutics to modulate islet cytokine receptor expression ex-vivo prior to transplantation, strategies designed to ameliorate early detrimental effects of specific pro-inflammatory cytokines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK052919-04
Application #
6177950
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Harmon, Joan T
Project Start
1997-09-15
Project End
2001-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$189,202
Indirect Cost
Name
Northwestern University at Chicago
Department
Surgery
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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Blomeier, Herman; Zhang, Xiaomin; Rives, Christopher et al. (2006) Polymer scaffolds as synthetic microenvironments for extrahepatic islet transplantation. Transplantation 82:452-9
Baker, Marshall S; Chen, Xiaojuan; Rotramel, Alizah et al. (2003) Proinflammatory cytokines induce NF-kappaB-dependent/NO-independent chemokine gene expression in MIN6 beta cells. J Surg Res 110:295-303
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