Dixon B. Kaufman, MD, PhD Associate Professor Surgery Immunobiology of Islet Transplant Rejection Curricula: Immunology and Microbial Pathogenesis E-mail:   d-kaufman2@northwestern.edu

Our ultimate goal is to contribute in a meaningful way to the cure of diabetes through islet transplantation. Early loss of transplant islet mass at the implantation site significantly reduces the functional potential of the freshly purified islet preparation. Certain anatomic and immunologic variables impact on the early fate of the implanted cells.

One of the projects will define how the transplant location and the immune responsiveness of the host affect cellular viability and function. We hypothesize that early loss of viable islet mass significantly reduces the functional potential of the freshly purified islet preparation. The primary aim of the project is to develop useful methods of real-time bioluminescent and magnetic resonance imaging as modalities to monitor the fate of transplanted"tagged' islets from transgenic RIP-luciferase donor strain mice. These imaging modalities will permit visualization of "tagged' transplanted islets or beta cells in the living mouse. Through serial post-transplant monitoring it will be possible to define how the fate of the viable islet mass is affected by anatomic and immunologic considerations that directly relate to transplant functional outcome. The project will entail collaboration with Prof. Thomas J. Meade, Department of Departments of Chemistry, Biochemistry and Molecular and Cell Biology, Neurobiology and Physiology, Northwestern University. This project is supported by the NIH.

The other project is aimed at solving the vexing problem of early islet graft failure. Early non-specific host inflammatory responses associated with pro-inflammatory cytokine production are critical effectors of early islet graft injury. Understanding the signal transduction pathways by which specific cytokines effect islet function is critical to solving the problem. Our research approach will ascertain whether protection from the detrimental effects of the cytokine ligands will be conferred by interferring with the signal transduction pathways. A signaling pathway shared by both IL-1 and TNF involves activation of transcriptional factor NF-kB. We have developed a new mouse model which expresses a mutatation that inactivates NF-kB in whole islets. Expression of NF-kB dependent genes in response to IL-1, TNF, or/and IFN will be examined. Studies will also be conducted to determine whether inactivation of NF-kB will protect the islets from primary dysfunction and rejection post-transplant. This project is supported by the Juvenile Diabetes Research Foundation.

Publications:

Wu JJ, Chen J, Cao X-C, Baker MS and Kaufman DB. 2001. Cytokine-induced dysfunction of MIN6 beta cells is nitric oxide independent. J Surg Res 101: 190-5.

Kaufman DB, Baker MS, Chen X, Leventhal JR, and Stuart FP. 2002. Sequential kidney/islet transplantation using prednisone-free immunosuppression. American Jour of Transplantation 2: 674-7.

Baker MS, Chen X, Rotramel, A, Nelson J, Kaufman DB. 2003. Pro-inflammatory Cytokines Induce NF-kB-Dependent/NO-Independent Chemokine Gene Expression in MIN6 beta Cells. J Surg Res 110: 295-303.

Kaufman DB, Lowe W. 2003. Clinical Islet Transplantation, Current Diabetes Reports. 3: 344-350.

Baker MS, Chen X, Rotramel AR, Nelson, JJ, Kaufman DB. 2003. Genetic deletion of chemokine receptor CXCR3 or antibody blockade of its ligand IP-10 modulates effector cell infiltrates and prolongs functional graft survival in pancreatic islet allograft recipients. Surgery. 134:126-33.

Baker MS, Chen X, Rotramel AR, Nelson JJ, Kaufman DB. 2003. Interferon regulatory factor-1 (IRF-1) down-regulates cytokine-induced IP-10 expression in pancreatic islets. Surgery. 134:134-41.