Danny Zipris, PhD
BioResources Core Director
Our lab is focused on understanding how microbial infections and the innate immune system promote the development of type 1 diabetes (T1D). Our recent studies conducted in the BioBreeding Diabetes-Resistant (BBDR) and LEW1.WR1 rat models of Kilham Rat Virus (KRV)-induced disease have led to the hypothesis that the upregulation of proinflammatory pathways shortly after virus infection plays a crucial role in the course of islet destruction. We have identified a number of innate immune modulators, such as steroids, antibiotics, and blockers of IL-1 and histone deacetylases that can protect animals from beta cell destruction and are currently investigating mechanisms involved in disease amelioration. The animal studies have led us to examine the possibility that altered innate immune pathways are associated with disease progression in subjects at risk for disease development.
One other major interest is how the intestinal microbiome and interactions between the gut microbiota and the innate immune system regulate islet autoimmunity. It was recently hypothesized that alterations in the gut bacterial composition may result in a number of autoimmune disorders including T1D. Our recent data from the LEW1.WR1 rat and RIP-B7.1 mouse models of diabetes support this notion and further imply that cross-talk between the innate immune system and the gut microbiota is involved in disease progression. We are testing the possibility that changes in gut bacteria are involved in disease development in genetically-susceptible individuals. It is our hope that these studies will advance the knowledge about early disease mechanisms and lead to anti-inflammatory immune interventions to prevent human diabetes.
Zipris D., Crow A.R., and Delovitch T.L. (1991). Altered thymic and peripheral T-lymphocyte repertoire precede the development of diabetes in NOD mice. Diabetes. 40:429.
Zipris D., Lazarus A.L., Crow A.R. , Hadzija M, and Delovitch T.L. (1991). Defective thymic T cell activation by Con A and anti-CD3 in autoimmune NOD mice. Evidence for thymic T cell anergy that correlates with the onset of insulitis. J. Immunol. 146:3763.
Rapoport M.J., Jaramillo A., Zipris D., Lazarus A.H., Serreze D.V., Leiter E.H., Cyopick P., Danska J.S., and Delovitch T.L. (1993). IL-4 reverses T cell unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice. J. Exp. Med. 178:87.
Levy L., Claes D.E., Zipris D., and Cohen I.R. (1994). Protection of mice against mycobacterial infection by lymphoid cell vaccination. Isr. J. Med. Sci. 30:22.
Zipris D., Greiner D.L., Malkani S., Whalen B., Mordes J.P., and Rossini A.A. (1996). Cytokine gene expression in islets and thyroids of BB rats: Interferon-g and IL-12p40 mRNA increase with age in both diabetic and insulin treated nondiabetic BB rats. J. Immunol. 156:1315.
Zipris D. (1996). Evidence that Th1 lymphocytes predominate in islet inflammation and thyroiditis in the Biobreeding (BB) rat. J. Autoimmun. 9:315.
Kanaitsuka T., Bortell R., Stevens L.A., Moss J., Sardinha D., Rajan T.V., Zipris D., Mordes J.P., Greiner D.L. and Rossini A.A. (1997). Expression in BALB/c and C57BL/6 mice of Rt6-1 and Rt6-2 ADP-ribosyltransferase that differ in enzymatic activity. C57BL/6 Rt6 is a natural transferase knockout. J. Immunol. 159:2741.
Zipris, D., Mordes J.P., Greiner D.L. and Rossini A.A.. (2000). Animal models of type 1 diabetes: concordances,discordances, lessons. In: Di Mario, U, Leonetti, F, Pugliese, G, Sbriglia, M, and Signore, A, eds. Diabetes in the newmillennium. John Wiley & Sons, Chichester, UK, 1-16, 2000.
Zipris D., Leif J., Deluca D., Lin M.Y., Mordes J.P., Rossini A.A., Greiner D.L. and Whalen B.J. (2001). Fetal thymi from diabetes-prone but not diabetes-resistant BB/Wor rats fail to generate mature ART2+ T-cells in organ culture. Cell. Mol. Biol. 47:65.
Zipris D. and Karnieli E. (2002). A single treatment with IL-4 via retrovirally transduced lymphocytes partially protects against diabetes in BioBreeding (BB) rats. J.O.P 2002 3:76.
Zipris D., Hillebrands J.L., Welsh R.M., Rozing J., Xie J.X., Mordes J.P., Greiner D.L. and Rossini A.A. (2003). Infections that induce autoimmune diabetes in BBDR rats modulate CD4+CD25+ T cell populations. J. Immunol. 170:3592.
Zipris D., Lien E., Xie J.X., Greiner D.L., Mordes J.P., Rossini A.A. (2005). TLR activation synergizes with Kilham rat virus infection to induce diabetes in BBDR rats. J. Immunol. 174:131.
Beaudette-Zlatanova B.C., Whalen B.J., Zipris D., Yagita H., Rozing J., Benjamin C.D., Hunig T., Drexhage H.A., Amari M.J., Leif J., Mordes J.P., Greiner D.L., Sayegh M.H. and Rossini A.A. (2005). Costimulation and Autoimmune Diabetes in BB Rats. Am. J. Transplant. 6(5 Pt 1):894.
Zipris D., Lien E., Xie J.X., Nair A., Greiner D.L., Mordes J.P. and Rossini A.A. (2007). TLR-9 signaling pathways are involved in Kilham Rat Virus-induced autoimmune diabetes in the BBDR rat. J. Immunol. 178:693.
Anjali N., Wolter T.R., Meyers A.J., and Zipris D. (2008) Innate Immune Pathways in Virus-Induced Autoimmune Diabetes. Ann N Y Acad Sci. 1150:139.
Zipris D. Innate Immunity and its role in type 1 diabetes. (2008). Current Opinion in Endocrinology, Diabetes, and Obesity. 15:326.
Bortell R., Pino S.C., Greiner D.L., and Zipris D., and Rossini A.A. The circle between the bedside and the bench: toll-Like receptors in models of viral induced diabetes (2008). Ann N Y Acad Sci. 1150:112.
Wolter T.R., Wong R., Sarkar S.A., and Zipris D. (2009). DNA Microarray analysis for the identification of innate immune pathways implicated in virus-induced autoimmune diabetes. Clin. Immunol. 132(1):103.
Zipris D. (2009) Epidemiology of type 1 diabetes and what animal models teach us about the role of viruses in disease mechanisms. Clinical Immunology 131:11.
Lien E. and Zipris D. (2009). The role of toll-like receptor signaling pathways in type 1 diabetes. Curr Mol Med. 9(1):52.
Londono P., Komura A., Hara N., and Zipris D. (2010). Brief dexamethasone treatment during acute infection prevents virus-induced autoimmune diabetes, Clin. Immunol. 135:401.
Meyers A.J., Shah R.., Gottlieb P.A., and Zipris D. (2010). Altered Toll-like receptor signaling pathways in human type 1 diabetes. J. Mol. Med. 88:1221.
Zipris D. (2010). Toll-like receptors and type 1 diabetes. In: The Islets of Langerhans, Advances in Experimental Medicine and Biology 654:585.
Zipris D. (2010). Virus-induced diabetes in the rat. In: Immunoendocrinology: Scientific and Clinical Aspects. Ed. G.S. Eisenbarth, Springer, NY, NY.
Zipris D. Innate immunity and type 1 diabetes. (2011). Diabetes and Metabolism Reviews. In Press.
Mordes J.P., Zipris D., Liu Z., and Blankenhorn E.P. (2011). Viruses and autoimmune diabetes in rats. In: Diabetes and Viruses. Eds. Taylor K.W., Hyöty H., Toniolo A., and Zuckerman A.J., Springer, NY
Alkanani A.K., Rewers M., Dong F., Waugh K., Gottlieb P.A., and Zipris D. (2012). Dysregulated TLR-induced IL-1b and IL-6 responses in subjects at risk for the development of type 1 diabetes. Diabetes 61:2525.
Hara N, Alkanani A.K., Ir D., Robertson C.E., Wagner B.D., Frank D.N., and Zipris D. (2012). Prevention of virus-induced type 1 diabetes with antibiotic therapy. J. Immunol. 189:3805.
Hara N., Alkanani A.K., Ir D., Robertson C.E., Wagner B.D., Frank D.N., and Zipris D. (2013). The role of the intestinal microbiota in type 1 diabetes. Clin. Immunol. 146:112.
Zipris D. (2013). The interplay between the gut microbiota and the immune system in the mechanism of T1D. Current Opinion in Endocrinology, Diabetes, and Obesity. doi: 10.1097/MED.0b013e3283628569
Hara N., Alkanani A.K., Dinarello C.A., and Zipris D. (2013). Modulation of Virus-Induced Innate Immunity and Type 1 Diabetes by IL-1 Blockade. Innate Immunity (In Press). Published ahead of print.
Hara N., Alkanani A.K., Dinarello C.A., and Zipris D. (2013). Histone Deacetylase Inhibitor Suppresses Virus-Induced Proinflammatory Responses and Type 1 Diabetes. J. Mol. Med. (In Press). Published ahead of print.
Alkanani A.K., Hara N., Lien E., Ir D., Kotter C.V., Robertson C.E., Wagner B.D., Frank D.N., and Zipris
D. (2013). Induction of diabetes in the RIP-B7.1 mouse model is critically dependent on TLR3 and
MyD88 pathways and is associated with alterations in the intestinal microbiome. Diabetes (In Press).
To access a more complete listing of publications, please go to PubMed http://www.ncbi.nlm.nih.gov/PubMed/
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