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Dr. David Wagner's Laboratory

Investigating Autoimmunity
 
Front (L-R): Michael Olmstead, David H. Wagner, PhD, Dan Waid
Back:: Jessica Carter, Gisela Vaitaitis.

Our research seeks to determine how auto-aggressive or "self reactive" T cells cause autoimmune diseases such as Type 1 (juvenile) Diabetes and Multiple Sclerosis (MS). 

T cells normally respond to foreign antigens such as bacteria, virus, fungus or parasitic infections even tumors. T cells recognize antigens through their T cell receptor (TCR) molecules which are specifically expressed so that one T cell for example recognizes an antigen from influenza and another T cell recognizes antigen from Streptococcus B. However, during an autoimmune disease, T cells incorrectly identify self-tissue as being foreign and therefore respond. This response results in inflammation that is persistent and ultimately destroys the normal tissue. In the case of type 1 diabetes (T1D), T cells recognize the islet cells of the pancreas (the cells that produce insulin) and destroy them, thus preventing insulin production which leads to high blood sugar. 

Our laboratory is focused on three research areas: 1) Generation of auto-aggressive T cells; 2) A means of controlling auto-aggressive T cells and 3) The role of T cells as culprits in a multitude of diseases such as MS, Chronic Obstructive Pulmonary Disease, Lupus, T1D and other diseases. 

At the Webb-Waring Center, we identified the T cells that are responsible for causing T1D. We found a biomarker, CD40, which identifies pathogenic T cells and showed that these T cells specifically attack the islet cells of the pancreas and lead to destruction of insulin producing cells. 

Additionally, we are exploring the way that the CD40-positive T cells (Th40 cells) develop in diabetes and other autoimmune diseases. We have determined that Th40 cells can alter the expression of their T cell receptor, in other words the way they recognize antigens. We are determining how to change Th40 cells so that they no longer cause disease. These findings will lead to better treatments for auto-immune disease; however, we will need to control the T cells that damage the normal system, without destroying the overall immune system. 

We have discovered that Th40 cells are radically expanded in human T1D and MS subjects. This finding suggests that these T cells are involved in the disease process. We have confirmed that Th40 cells from T1D and MS subjects respond to known self antigens suggesting that these T cells cause disease. 

Statistics from the Centers for Disease Control and Prevention show that more than 32 million Americans are afflicted by some form of Arthritis which affects 125 of every 1000 people under the age of 45, and almost half of the people aged 45 to 64. Diabetes was responsible for 63,000 deaths in 1997 making it the seventh leading cause of death in people 18 to 64 years.

Juvenile Diabetes Research Foundation

 

American Diabetes Association

National Institutes of Health

Robert Kleberg and Helen Kleberg Foundation

TTO State Funding

Peter Gottlieb, MD. Barbara Davis Diabetes Center

Kathryn Haskin, PhD.  National Jewish Hospital, Denver, Colorado

John Corboy, MD. Rocky Mountain Multiple Sclerosis Center

Michael Edwards, PhD. Pulmonology, University of Colorado, Denver

David Bleich, MD. Chief, Division of Endocrinology, Diabetes and Metabolism Associate Professor of Medicine, New Jersey Medical School.

  1. Vaitaitis, GM, Waid, DM and Wagner, Jr., DH. 2010. “The expanding role of TNF-Receptor Super Family member CD40 (tnfrsf5) in Autoimmune Disease: Focus on Th40 cells.
  2. Wagner, D. H., Jr. 2009. The co-evolution of our understanding of CD40 and inflammation. Diabetologia 52:997-999.
  3. Vaitaitis, G. M., and D. H. Wagner, Jr. 2008. High distribution of CD40 and TRAF2 in Th40 T cell rafts leads to preferential survival of this auto-aggressive population in autoimmunity. PLoS ONE 3:e2076.
  4. Baker, R. L., D. H. Wagner, Jr., and K. Haskins. 2008. CD40 on NOD CD4 T cells contributes to their activation and pathogenicity. J Autoimmun 31:385-392.
  5. Waid, D. M., G. M. Vaitaitis, N. D. Pennock, and D. H. Wagner, Jr. 2008. Disruption of the homeostatic balance between autoaggressive (CD4+CD40+) and regulatory (CD4+CD25+FoxP3+) T cells promotes diabetes. J Leukoc Biol 84:431-439.
  6. Siebert, J. C., M. Inokuma, D. M. Waid, N. D. Pennock, G. M. Vaitaitis, M. L. Disis, J. F. Dunne, D. H. Wagner, Jr., and H. T. Maecker. 2008. An analytical workflow for investigating cytokine profiles. Cytometry A 73:289-298.
  7. Waid, DM, Wagner, BA, Putnam, Vaitaitis, GM, Pennock, ND, Calverley, DC, Gottlieb, PA, Wagner Jr., DH. 2007 “A unique T cell subset described as CD4loCD40+ (TCD40) in human type 1 diabetes” Aug; 124(2):138-148. Epub June 8, 2007
  8. Wagner, Jr., D. H. 2007. “Reshaping the T cell repertoire: TCR editing and TCR revision for Good and for Bad.” Clin. Immunol Apr 123 (1): 1-6.
  9. Waid, DM, Vaitaitis, GM, and Wagner Jr., D.H. 2004. Peripheral CD4loCD40+ Auto-Aggressive T Cell Expansion During Insulin-Dependent Diabetes Mellitus. Eur. J. Immunol 34:1488-1497.
  10. Vaitaitis, GM, Poullin, M., Sanderson, RJ, Haskins, KJ, and Wagner, Jr., DH. 2003. CD40 Induced Expression of Recombinase Activating Gene (RAG) 1 and RAG 2: A Mechanism for The Generation of Autoaggressive T Cells in The Periphery. Cutting Edge, J. Immunol. 170:3455-3459.
  11. Wagner, DH, Jr., G. Vaitaitis, R. Sanderson, M. Poulin, C. Dobbs, and K. Haskins. 2002. Expression of CD40 identifies a unique pathogenic T cell population in type 1 diabetes. Proc Natl Acad Sci U S A 99:3782-3788.
  12. Wagner, Jr., DH, E. Newell, R. Sanderson, J.H. Freed, and M.K. Newell. “Increased expression of CD40 on thymocytes and peripheral T cells in autoimmunity: A mechanism for acquiring changes in the peripheral T cell repertoire.”1999. Intr. J. Mol. Med. 4:231-242.
  13. Huber SA., DH, Wagner Jr., J.E. Stone, J. Kupperman, L. Pfeiffer, C. David, R L. O’Brein, G. S. Davis, and M.K. Newell. 1998. “+ T cells regulate MHC class II (IA and IE)-dependent susceptibility to coxsackievirus B3-induced autoimmune ocarditis.” J. Virol. 73:5630-5636.
  14. Poe J.C., Wagner Jr., DH, Miller, R.W., Stout, R.D., and Suttles, J. 1997. " Role of protein tyrosine kinase activity in CD40 signaling of NFB activation and interleukin-1B synthesis in monocytes: modulation by interleukin-4 and interleukin-10." J. Immunol. 159 (2):846-852.
  15. Jonathan C. Poe, David H. Wagner, Jr., Robert W. Miller, Robert D. Stout, and Jill Suttles, 1997. "IL-4 and IL-10 Modulation of CD40-Mediated Signaling of Monocyte IL-1 Beta Synthesis and Rescue from Apoptosis." 1997 American Assoc. of Immunol.  0022: 846-852.
  16. Wagner Jr, DH, J. Hagman, P.S. Linsley, W.H. Hodsdon, J.H. Freed, and M.K. Newell. 1996. "Rescue of thymocytes from glucocorticoid-induced cell death mediated by CD28/CTLA-4 costimulatory interactions with B7-1/B7-2." J. Exp. Med. 184:1631-1638.
  17. Wagner Jr., DH, R.D. Stout, and J. Suttles. 1994. “Role of the CD40-CD40 ligand interaction in CD4+ T cell contact-dependent activation of monocyte interleukin-1 synthesis. Eur. J. Immunol. 24:3148-3154-3164.
  18. Wagner Jr., DH, and Suttles J. 1993." Cognate T cell signaling of monocyte inflammatory cytokine production. "J. Immunol. 150:135.
  19. (Submitted)  Vaitaitis, GM and Wagner Jr., DH. The signaling impact on glycosylation status - CD40 glycoforms and TNF-receptors 1 and 2 in the formation of CD40 receptor(s) on Th40 cells".

David Wagner's CV