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The pathophysiology of the pancreatic beta cell is an area where the Biotech Campus Dresden has created a unique resource. The goal of research is to protect and replace pancreatic islets in order to prevent and cure diabetes, with a focus on immune therapy, transplantation, expansion of beta cell number and function, and in disease pathophysiology.

Immune therapy

Prof. Karsten Kretschmer studies how conventional CD4+ T cells can be converted to regulatory T cells (Tregs) by targeting specific antigens to dendritic cells (Stern, 2010), as well as the mechanisms of Treg development (Vahl, 2014). He has generated novel mouse models able to distinguish thymus-derived from peripherally-derived Tregs, as well as markers to distinguish Treg subpopulations and the influence of these populations on disease models (Petzold et al., 2014).



Prof. Ezio Bonifacio is examining antigen-responsive human Treg profiles to allow their identification in type I diabetics. This is particularly important for monitoring progress of therapies to prevent autoimmunity and beta-cell loss after islet transplantation. In a novel clinical study to prevent insulin autoimmunity (Pre-POINT), the Bonifacio group administered oral insulin to genetically at risk children, in order to assess safety and dosing to achieve engagement of the regulatory arm of the immune system (Bonifacio, 2015). The randomized trial provided mechanistic evidence that a regulatory immune response to insulin can be achieved via oral administration. The study employed innovative single cell transcriptomic methodology developed by the Bonifacio group, including TCR sequencing (Eugster, 2013).

Prof. Triantafyllos Chavakis' group at the Department of Clinical Pathobiochemistry, University Hospital Carl Gustav Carus, Dresden bridges immunity and metabolism and has shown how CD40 signaling in immune cells regulates insulin resistance and adipose tissue inflammation, including accumulation of CD8+ T cells and macrophages (Chatzigeorgiou et al., 2014a). They also showed that absence of B7 costimulation leads to features of non-alcoholic hepatosteatitis via the loss of Treg and identified a therapeutic opportunity for type 2 diabetes related pathology via modulation of B7 co-stimulation (Chatzigeorgiou et al., 2014b).

Expansion of beta-cell number and function

To understand how beta cell number and function are regulated in physiological and pathophysiological conditions, Dr. Stephan Speier utilizes innovative models for in situ and in vivo monitoring of pancreatic islet cell physiology. These include a slice technique, which allows assessment of islet function and morphology within an intact environment (Marciniak et al., 2014), and transplantation of islets into the anterior chamber of the mouse eye for long term in vivo monitoring of islet biology (Speier, 2011).

With the help of these platforms, the Speier group has recently investigated how mouse and human beta cell mass and functional status change during T cell mediated destruction and recovery in a model of type 1 diabetes. The study showed that beta cell de- and regranulation is a key component of onset and remission of type I diabetes and that mouse islets, but not human islets, have a propensity to additionally increase their mass during hyperglycemia (Chmelova 2015).

Restoring functional β-cell mass is a promising therapeutic avenue for normalizing glycemic control in both type 1 and 2 diabetics. Dr. Nikolay Ninov’s goal is to identify new drugs for beta-cell expansion and protection. Using a set of novel transgenic reporter zebrafish lines, he has performed the first in vivo high-content chemical screen for inducers of beta-cell replication, which identified FDA-approved drugs and natural products that expand beta-cell mass. An important challenge is to further validate these compounds using human beta-cells in vitro and to elucidate their mechanisms-of-action with the goal of developing novel effective pharmaceuticals for beta-cell regeneration.

Dr. Ninov also utilizes zebrafish models of diabetes in order to identify factors that promote beta-cell regeneration following near-complete beta-cell destruction.

Dr. Anthony Gavalas is using embryonic stem cells to simulate aspects of embryonic development and beta cell differentiation to reveal new players involved in cell fate decisions and discover markers for tissue specific stem or progenitor cells. The long-term goal is to discover novel pathways for efficient conversion of human pluripotent stem cells into insulin-producing cells and motor-neurons or stimulation of endogenous stem cells.

Transplantation

Dresden is home to the only clinically active islet transplantation program in Germany, a result of synergy between CRTD, the Uniklinikum Dresden, and the Medical Faculty of the Technical University of Dresden. The beta cell transplant program is led by Prof. Stefan Bornstein, Director of the Department of Internal Medicine III, University Hospital Carl Gustav Carus, Dresden, with Dr. Barbara Ludwig and Dr. Andreas Reichel, providing islet facility, regulatory and clinical leadership. The center offers a spectrum of clinical therapeutic options, including whole organ pancreas and islet allotransplantation, and islet auto-transplantation. The program also coordinates a supply of human islets for research.

An innovative aspect of the program has been the pursuit of alternative sources of islets for xenotransplantation and devices that permit beta cell transplantation without immunosuppression (Ludwig et al., 2013). The first ever transplant of its kind provided proof-of-principle that human allo-islets could survive for months within the "Beta O2 chamber" in a patient with type 1 diabetes. Validation studies are now planned in Scandinavia and in the UK.

Transplantation includes the immunology of rejection and, in the context of type 1 diabetes, autoimmunity. Prof. Ezio Bonifacio and Prof. Karsten Kretschmer are studying the effect of IL-7 mediated homeostatic proliferation of T cells on immune function (Heninger et al., 2012) using models of inducible IL-7 hyper-expression, with the aim of seeking therapeutic strategies to improve transplantation outcome.

Disease pathophysiology

The interplay between immunity, beta-cells and metabolism in diabetes pathogenesis is a special focus of research at CRTD. Prof. Ezio Bonifacio is studying mechanisms of autoreactive T and B cell expansion in type 1 diabetes and islet transplantation, with the aim of preventing beta-cell destruction. The work takes advantage of German cohort studies performed in collaboration with Prof. Anette Ziegler (Helmholtz Zentrum München). The work has provided significant advances in understanding of early type 1 diabetes pathogenesis, in particular the identification of a period of extreme susceptibility to development of islet autoimmunity between the ages of 6 months to 2 years (Ziegler et al., 2012). They have shown that progression to clinical diabetes is linear and almost absolute over a period of 20 years from islet autoantibody seroconversion (Ziegler et al., 2013). The studies have also provided insights into genetic and environmental factors, including infection, that may affect type 1 diabetes risk and these findings will have a major impact on diabetes prevention activities in Germany and internationally.

References
  • Bonifacio E. (2015) Predicting type 1 diabetes using biomarkers. Diabetes Care 6:989-96.
  • Chatzigeorgiou, A., Seijkens, T., Zarzycka, B., Engel, D., Poggi, M., van den Berg, S., van den Berg, S., Soehnlein, O., Winkels, H., Beckers, L., et al. (2014a). Blocking CD40-TRAF6 signaling is a therapeutic target in obesity associated insulin resistance. Proc Natl Acad Sci USA 111:2686-2691.
  • Chatzigeorgiou, A., Chung, K.J., Garcia-Martin, R., Alexaki, V.I., Klotzsche-von Ameln, A., Phieler, J., Sprott, D., Kanczkowski, W., Tzanavari, T., Bdeir, M., et al. (2014b). Dual role of B7 costimulation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation. Hepatology 60:1196-1210.
  • Chmelova H, Cohrs CM, Chouinard JA, Petzold C, Kuhn M, Chen C, Roeder I, Kretschmer K, Speier S. (2015) Distinct roles of β-cell mass and function during type 1 diabetes onset and remission. Diabetes 64:2148-60.
  • Eugster A, Lindner A, Heninger AK, Wilhelm C, Dietz S, Catani M, Ziegler AG, Bonifacio E. (2013) Measuring T cell receptor and T cell gene expression diversity in antigen-responsive human CD4(+) T cells. J Immunol Methods. 400-401:13-22.
  • Heninger, A.K., Theil, A., Wilhelm, C., Petzold, C., Huebel, N., Kretschmer, K., Bonifacio, E., and Monti, P. (2012). IL-7 abrogates suppressive activity of human CD4+CD25+FOXP3+ regulatory T cells and allows expansion of alloreactive and autoreactive T cells. Journal of immunology 189, 5649-5658.
  • Ivanova, A., Kalaidzidis, Y., Dirkx, R., Sarov, M., Gerlach, M., Schroth-Diez, B., Muller, A., Liu, Y., Andree, C., Mulligan, B., et al. (2013). Age-dependent labeling and imaging of insulin secretory granules. Diabetes 62:3687-3696.
  • Ludwig, B., Reichel, A., Steffen, A., Zimerman, B., Schally, A.V., Block, N.L., Colton, C.K., Ludwig, S., Kersting, S., Bonifacio, E., et al. (2013). Transplantation of human islets without immunosuppression. Proc Natl Acad Sci USA 110:19054-19058.
  • Marciniak, A., Cohrs, C.M., Tsata, V., Chouinard, J.A., Selck, C., Stertmann, J., Reichelt, S., Rose, T., Ehehalt, F., Weitz, J., et al. (2014). Using pancreas tissue slices for in situ studies of islet of Langerhans and acinar cell biology. Nature protocols 9:2809-2822.
  • Petzold, C., Steinbronn, N., Gereke, M., Strasser, R.H., Sparwasser, T., Bruder, D., Geffers, R., Schallenberg, S., and Kretschmer, K. (2014). Fluorochrome-based definition of naturally occurring Foxp3 regulatory T cells of intra and extrathymic origin. European Journal of immunology.
  • Speier, S. (2011). Experimental approaches for high-resolution in vivo imaging of islet of Langerhans biology. Current diabetes Reports 11: 420-425.
  • Stern JN, Keskin DB, Kato Z, Waldner H, Schallenberg S, Anderson A, von Boehmer H, Kretschmer K, Strominger JL. (2010). Promoting tolerance to proteolipid protein-induced experimental autoimmune encephalomyelitis through targeting dendritic cells. Proc Natl Acad Sci U S A. 107:17280-5.
  • Sturm, D., Marselli, L., Ehehalt, F., Richter, D., Distler, M., Kersting, S., Grutzmann, R., Bokvist, K., Froguel, P., Liechti, R., et al. (2013). Improved protocol for laser microdissection of human pancreatic islets from surgical specimens. Journal of visualized experiments : JoVE.
  • Vahl J.C., Drees C., Heger K., Heink S., Fischer J.C., Nedjic J., Ohkura N., Morikawa H., Poeck H., Schallenberg S., Rieß D., Hein M.Y., Buch T., Polic B., Schönle A., Zeiser R., Schmitt-Gräff A., Kretschmer K., Klein L., Korn T., Sakaguchi S., Schmidt-Supprian M. Continuous T Cell Receptor Signals Maintain a Functional Regulatory T Cell Pool. 2014. Immunity, 2014. 41:722-736.
  • Ziegler, A.G., Bonifacio, E., and Group, B.-B.S. (2012). Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes. Diabetologia 55:1937-1943.
  • Ziegler, A.G., Rewers, M., Simell, O., Simell, T., Lempainen, J., Steck, A., Winkler, C., Ilonen, J., Veijola, R., Knip, M., et al. (2013). Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children. JAMA 309:2473-2479.