Dr. Alegre is a basic immunology researcher who focuses on the mechanisms that induce or maintain tolerance in T cells, as well as on the environmental signals that can prevent or break this tolerance. This interest spans the development of T cells in the thymus, the upregulation of surface molecules that terminate T cell activation, the biology of regulatory T cells that can suppress responses by effector T cells, and the consequences of bacterial infections on these specific pathways of tolerance. The biological significance of these events is tested in mouse models of autoimmunity and transplantation as well as in clinical samples obtained from transplant recipients and infected patients. Dr. Alegre was born in Madrid, Spain. She received her MD degree from the Universite Libre de Bruxelles in Belgium and her PhD in Immunology from the University of Chicago. She completed her clinical training in Internal Medicine and Intensive Care prior to focusing completely on research. Dr. Alegre was a post-doctoral scholar in the laboratory of Craig Thompson when he directed the Knapp Center for Lupus and Immunology Research. She has been principal investigator of her research laboratory at the University of Chicago, in the Section of Rheumatology since 1999. She is currently an Associate Professor.
Type I diabetes (T1D) is an autoimmune disease in which T cells, activated by peptides derived from β cells, invade and destroy pancreatic islets resulting in low insulin secretion and hyperglycemia. Mice on the NOD (non obese diabetic) background develop spontaneous T1D, similarly to diabetic patients. My laboratory is interested in the biochemical pathways in T cells necessary for triggering T1D. T cell stimulation results in activation of several transcription factors, including AP-1, NFAT and NF-κB. In collaboration with Mark Boothby from Vanderbilt University, we have sought to determine whether activation of NF-κB in T cells is necessary for the development of T1D. To this end, NOD mice were crossed with mice that have reduced NF-κB activity selectively in T cells (IκB∝ΔN transgenic mice, see Figure 1). The resulting mice failed to develop T1D, demonstrating the essential role of NF-κB in T cells for T1D in vivo. In addition to investigating the mechanisms by which T1D is prevented in these mice, our laboratory is currently developing high throughput methods to identify small molecule inhibitors that can prevent NF-κB activation selectively in T cells. These drugs will be tested in different models of T1D to evaluate their efficacy at preventing or treating recent onset autoimmune diabetes.
Figure 1. Schematic representation of how NF-κB activation is reduced in T cells from I?B??N transgenic mice. IκB∝ΔN-Tg mice express a superrepressor IκB∝(IκB∝ΔN) transgene selectively in T cells (Lck promoter/CD2 locus control). This transgene cannot be phosphorylated and degraded upon TCR stimulation and therefore retains NF-κB dimmers in the cytoplasm, preventing gene transcription.
The only available cure for type 1 diabetes (T1D) currently is the transplantation of a pancreas or of pancreatic islets. However, transplanted tissues must survive numerous insults to successfully produce insulin long term in the host. First, the process of ischemia/reoxygenation/inflammation inherent to all transplantation procedures results in substantial cell death. Second, the cells that survive this insult are also exposed to autoimmune and alloimmune T cells that would invariably destroy the transplant in the absence of immunosuppression. Therefore, transplant recipients must take numerous immunosuppressive drugs for the rest of their lives to prevent graft destruction. Our laboratory in interested in the biochemical pathways in T cells necessary for mounting autoimmune and alloreactive responses. T cell stimulation results in activation of several transcription factors, including AP-1, NFAT and NF-κB. In collaboration with Mark Boothby from Vanderbilt University, we have shown that mice with selective inhibition of NF-κB in T cells (IκB∝ΔN-Tg mice) display significantly prolonged survival of transplanted pancreatic islets (see Figure 2), indicating that NF-κB in T cells plays an important role in islet allograft rejection. Because rejection is not prevented in all animals, we are also investigating the mechanisms of death of pancreatic ? cells after transplantation. Our focus is on determining whether β-cell-NF-κB is necessary for resistance of these cells to ischemic or inflammatory signals as well as to damage by autoimmune and alloreactive T cells in vitro and in vivo. The long term goal is to modify β cells prior to transplantation by gene therapy to make them resistant to cell death after transplantation.
Figure 2. Reduction of NF-κB activity in T cells results in prolongation of pancreatic islet allograft survival in mice. BALB/c islets (H-2d) were transplanted under the left kidney capsule of C57BL/6 (H-2b) wildtype (WT) or IκB∝ΔN transgenic mice previously made diabetic by an injection of streptozotocin. Blood glucose levels were followed daily. Two consecutive measurements of less than 250 mg/dl were considered recurrence of diabetes because of allograft rejection. 50% of IκB∝ΔN transgenic mice accepted pancreatic islets allografts long-term. Prevention of T cell death by overexpression of the anti-apoptotic factor Bcl-xL (IκB∝ΔN/Bcl-xL transgenic mice) restored allograft rejection suggesting that transplant acceptance in IκB∝ΔN transgenic mice is due to T cell death.