Dixon Kaufman

Credentials: MD, PhD

Position title: Ray D. Owen Professor of Surgery

Email: kaufman@surgery.wisc.edu

My research has had a focus on islet transplantation. Early research projects demonstrated that cellular transplants, such as islets, were exquisitely susceptible to injury by an early host non- specific inflammatory immune response that was primarily mediated by macrophages, and later found to be associated with cytokine production composed primarily of IL-1 and TNF-a. These studies were extended into large animals making the novel advance that the combination of anti-lymphocyte globulin, a powerful T-cell depleting induction agent, deoxyspergualin, a potent anti-macrophage agent, and corticosteroid avoidance, a toxic agent to islets, should be combined to improve outcomes. These approaches were later translated into important immunosuppression protocols for human phase 2 and 3 clinical trials that became a cornerstone in the NIH-supported Clinical Islet Transplant (CIT) consortium. A second area of my research involved study of the early host non-specific (innate) inflammatory responses associated with macrophage-generated pro- inflammatory cytokine production found to be critical effectors of early islet graft injury. By defining the specific cytokine ligand-receptor interactions that governed host immune-mediated islet injury and correlating to common signal transduction pathways, new strategies were designed to deliver siRNA-functionalized gold nanoparticles to inhibit intra-islet IKKb that would inhibit cytokine-activation of nuclear binding protein, NFkB, to abrogate cytokine-mediated beta cell injury. A third area of my islet transplant research showed that in vivo real-time imaging modalities could be applied to monitor transplanted islet mass in the living animal. The novel use of bioluminescent imaging modalities demonstrated proof-of-concept of its potential for following the course of clinical transplants beyond reliance of just metabolic information. Another area of my research involved tissue engineering advances to create an islet graft delivery scaffold generating a favorable microenvironment to enhance islet engraftment at sites other than the intraportal hepatic location. This may important implications on the future prospects of beta cell replacement therapies using insulin-producing cell lines that may be generated from embryonic or iPS cell derivatives.