Alexander Chervonsky, MD, PhD - The University of Chicago Kovler Diabetes Center

Alexander Chervonsky, MD, PhD

My laboratory addresses a number of issues concerning the development, treatment and prevention of Type 1 Diabetes (T1D). One of the projects investigates the dual role of the pro-apoptotic molecule Fas (Apo-1, CD95) in regulation of autoimmune responses and in destraction of pancreatic beta cells producing insulin. Using tissue-specific elimination of Fas expression, we have shown that the lack of Fas expression by antigen-presenting cells (dendritic cells and B lymphocytes) led to systemic autoimmune reactions. Contrary to the accepted paradigm that loss of Fas expression by T cells is the key to lupus-like disease in animals and humans caused by Fas deficiency, our results revealed a new mechanism protecting against autoimmunity—Fas-mediated killing of antigen presenting cells by activated T cells. We now are set to test whether this mechanism also controls organ-specific autoimmunity such as T1D. On the other hand, Fas, as a death-inducing molecule, has been implicated into destruction of beta cells. To test the actual contribution of Fas and other death-inducing signals (perforin/garnzyme B, TNF and others) in B cell death, we produced a number of genetically manipulated mice either lacking expression of receptors or corresponding ligand molecules. The genetic approach will help us to delineate the role of Fas (and other factors) in beta cell death.

The other area of our interest relevant to diabetes development is the understanding of routes that T cells take to home to the pancreatic islets. This process of homing appears to be very complex, but tightly regulated by a number of signaling mechanisms that involve T cell receptor, chemokine receptors and adhesion molecules of different types. Lately, we concentrate on real-time imaging of T cells penetration of the islets using an intravital microscopy approach that we have developed. A titanium device termed “abdominal window” allows one to observe live pancreatic tissue without sacrificing an animal. This approach is complemental to genetic approach that we also take to study T cell homing. Currently we are investigating the genetic resistance of some mouse strains to the activated CD8+ T cells with specificity to insulin, a major pancreatic autoantigen.

Finally, we are also interested in role of microorganisms in the initiation phase of organ-specific autoimmunity. We have established that microbe-free mice that are genetically susceptible to diabetes, develop the disease as do mice housed in conventional facilities. However, mice lacking a signaling adaptor involved in several innate immunity pathways, termed MyD88, were only susceptible to diabetes when microbe-free. Thus, we have to search for normal intestinal bacteria that can prevent diabetes development by signaling through receptors that are MyD88-independent, and for such receptors. The finding, however, makes an important prediction that T1D development can be prevented by manipulation of intestinal flora or vaccination with microbial products.