Torrey Pines Institute for Molecular Studies science image
Torrey Pines Institute for
Molecular Studies
3550 General Atomics Court, 2-129
San Diego, CA 92121-1122
USA
Scientists
Joanna D. Davies, D.Phil.
Director of Scientific Affairs
Member
Immunology

858.597.3877 - phone
858.597.3804 - fax
contact by email

Biography

Dr. Joanna Davies received a D.Phil. from Oxford University, UK. in Immunology in 1986. She completed post-doctoral fellowships at The Medical Biology Institute, La Jolla, and Cambridge University, UK. before becoming an Assistant Professor at The Scripps Research Institute, La Jolla, in 1998. In 2001 she moved her laboratory to the Torrey Pines Institute for Molecular Studies in La Jolla where she is now a Member.

Research Focus - Immune Regulation

The overall interest of the laboratory is to understand the role of the immune system in preventing tissue pathology including, autoimmunity, transplant rejection and severe muscle wasting. Most of our research is dedicated to understanding the mechanism of immune regulation in protection from transplantation rejection and autoimmunity, specifically, type I diabetes. We also have developed an active research interest in the potential role for CD4+ T cells in the control of muscle wasting in type I diabetes and cancer. In the long term it is hoped that this program will shed light on novel targets that might be exploited in the design of new therapeutic strategies.

The following is a summary of our ongoing research interests.

1. Monoclonal antibody (mAb)-induced tolerance in transplantation and autoimmunity.

One of the main goals of our research group over the past 20 years has been to identify mechanisms that result in antigen-specific tolerance to self and foreign antigens in the hope that they might be exploited to prevent and reverse autoimmunity, and prevent transplant rejection. Most recently our research has focused on the role of CD8 blockade in promoting antigen-specific CD4+ T cell-mediated tolerance and immune regulation. The research is based on the findings that, although co-stimulation and accessory molecule blockade with monoclonal antibodies (mAbs) specific for either CD40L, or CD28, or CD4+, results in antigen-specific transplantation tolerance, long-term survival is only achieved by including a co-treatment that also targets CD8+ cells. While CD8 blockade clearly plays a role in blocking CD8+ T cell-mediated effector mechanisms, we have tested the hypothesis that CD8 blockade also plays a role in enhancing tolerance and immune regulation. Using a cocktail of non-depleting CD8-specific and CD4-specific mAb to induce tolerance to ovalbumin in a mouse model system, we have recently shown that CD8 blockade enhances both antigen-specific tolerance and CD4+ T cell-mediated immune regulation (selected publication #4). In this model CD8 blockade promotes proliferation of antigen-specific CD4+ T cells with regulatory activity (selected publication #3). These data suggest that CD8 blockade does play a role in the development of long-term tolerance and CD4+ T cell-mediated immune regulation. We are currently investigating the mechanism induced by CD8 blockade to promote antigen-specific CD4+ T cell regulation in transplantation and Type I Diabetes.

2. The role of CD4+ T cells in controlling cachexia.

Cachexia is the dramatic weight loss and muscle atrophy seen in chronic disease states including autoimmunity, cancer and infection, and is often associated with lymphopenia. Lymphopenia and cachexia are associated with reduced responsiveness to therapy and poor prognosis. Several years ago we began a series of experiments to test the hypothesis that lymphopenia plays a role in the development of cachexia, We have shown that CD4+ T cells that express the lowest density of CD44 (CD4+ CD44v.low) are significantly reduced in diabetic NOD mice that are cachexic compared to diabetic mice that are not cachexic (selected publication #5).In order to validate our findings, we are in the process of conducting clinical studies to determine whether the CD4+ CD44v.low cells are also lost in patients with TID as the disease progresses. In transfer assays we have shown that highly purified CD4+ CD44v.low cells, but not CD4+ cells depleted of CD44v.low cells, delay the onset of wasting when infused into either diabetic or pre-diabetic NOD recipients. In a mouse model of cancer cachexia, the same cell subset significantly reduces muscle atrophy, and inhibits muscle protein loss, and DNA loss, even when given after the onset of cachexia. Protection from wasting and muscle atrophy by CD4+ CD44v.low cells is associated with protection from lymphopenia (selected publication #6). These data suggest, for the first time, a role for an immune cell subset in protection from cachexia, and further suggest that the mechanism of protection is independent of protection from autoimmunity.

3. Insulin-secreting islet growth and regeneration.

The number of pancreas donors available is insufficient to meet the needs of the diabetic patients awaiting pancreas and islet transplantation. A theoretical alternative to using cadaver pancreas tissue as a source of insulin secreting tissue is to either, grow insulin-secreting islet beta-cells in culture, or to stimulate an increase in insulin-secreting islet beta cell mass in situ. In collaboration with Dr. Richard Houghten (Torrey Pines Institute for Molecular Studies), we are screening peptide and small molecule libraries (made in the Houghten laboratory) for their ability to promote beta cell insulin secretion using an in vitro islet culture assay. We are in the process of deconvoluting candidate libraries to identify single compounds with significant activity in vitro and, ultimately, in vivo.

Selected publications. 1-6

  1. Roberts, E. M., Hall, D. S., Ferguson, S., Minson, S. and Davies, J. D. IL-4 expression delays eosinophil-independent vasculopathy and fibrosis during allograft rejection in the mouse. J Clinical Immunol. 23:120-132, 2003.
  2. Hall, D. S., Roberts, E. M., Ferguson, S., Wang, Z., and Davies, J. D. Increasing transplant mass results in long-term allograft survival and recovery from transplant vasculopathy. J Clinical Immunol. 23:162-174, 2003.
  3. Wang, Z., and Davies, J. D. CD8 blockade promotes the expansion of antigen-specific CD4+ FOXP3+ regulatory cells in vivo. Int. Immunopharmacology. 7:249-265. 2006.
  4. Wang, Z., and Davies, J. D. CD8 blockade promotes antigen responsiveness to non-tolerizing antigen in tolerant mice by inhibiting apoptosis of CD4+ T cells. J. Immunol.  178:6148-6157, 2007.
  5. Zhao, C., Wang, Z., Robertson, M. W., and Davies, J. D. Cachexia in the non obese diabetic mouse is associated with CD4+ T cell lymphopenia. Immunology. 125:48-58, 2008.
  6. Wang, Z., Zhao, C., Moya, R., Davies, J. D. A novel role for CD4+ T cells in the control of cachexia. J. Immunol. 181:4676-4684, 2008.

Publications

  1. Wang, Z., Zhao, C., Moya, R., Davies, J.D. A novel role for CD4+ T cells in the control of cachexia. J. Immunol. 181:4676-4684, 2008.
  2. Zhao, C., Wang, Z., and Davies, J. Antigen driven CD4+ Foxp3+ CD25+ memory cell expansion in tolerant mice is enhanced by CD8 blockade. J.Immunol. 181(7):4676-84, 2008
  3. Zhao, C., Wang, Z., Robertson, M.W. and Davies, J.D. Cachexia in the non obese diabetic mouse is associated with CD4+ T cell lymphopenia. Immunology 125(1):48-58, 2008.
  4. Wang, Z. and Davies, J.D. CD8 blockade promotes antigen responsiveness to non-tolerogenic antigen in tolerant mice by inhibiting apoptosis of CD4+ T cells. J. Immunol. 178: 6148-6157, 2007.
  5. Wang, Z., and Davies, J.D. CD8 blockade promotes the expansion of antigen-specific CD4+ FOXP3+ regulatory T cells in vivo. Intl. Immunopharmacology 7:249-265, 2007.
  6. Hall, D.S., Roberts, E.M., Ferguson, S., Wang, Z., Davies, J.D. Increasing transplant mass results in long-term allograft survival and recovery from transplant vasculopathy. J. Clin. Immunol. 23:162-174, 2003.
  7. Roberts, E.M., Hall, D.S., Ferguson, S., Minson, S., Davies, J.D. IL-4 expression delays eosinophil-independent vasculopathy and fibrosis during allograft rejection in the mouse. J. Clin. Immunol. 23:119-131, 2003.
  8. Hall, D., Roberts, E., Davies, J. Allograft rejection results from a failed attempt by the immune system to protect foreign tissue. Immunologic Res. 21:177-183, 2000.
  9. Davies, J.D., Mueller, R., Minson, S., O'Connor, E., Krahl, T., Sarvetnick, N. Interleukin-4 secretion by the allograft fails to affect the allograft-specific interleukin-4 response in vitro. Transplantation 67:1583-1589, 1999.
  10. Davies, J.D., O'Connor, E., Hall, D., Krahl, T., Trotter, J., Sarvetnick, N. CD4+ CD45RB low-density cells from untreated mice prevent acute allograft rejection. J. Immunol. 163:5353-5357, 1999.
  11. Gallichan, W.S., Balasa, B., Davies, J.D., Sarvetnick, N. Pancreatic IL-4 expression results in islet-reactive Th2 cells that inhibit diabetogenic lymphocytes in the nonobese diabetic mouse. J. Immunol. 163:1696-1703, 1999.
  12. O'Connor, E., Roberts, E.M., Davies, J.D. Amplification of cytokine-specific ELISAs increases the sensitivity of detection to 5-20 picograms per milliliter. J. Immunol. Methods 229:155-160, 1999.
  13. Balasa, B., Davies, J.D., Lee, J., Good, A., Yeung, B.T., Sarvetnick, N. IL-10 impacts autoimmune diabetes via a CD8+ T cell pathway circumventing the requirement for CD4+ T and B lymphocytes. J. Immunol. 161:4420-4427, 1998.
  14. King, C., Davies, J.D., Mueller, R., Lee, M.-S., Krahl, T., Yeung, B., O'Connor, E., Sarvetnick, N. TGF-β1 alters APC preference, polarizing islet antigen responses to Th2. Immunity 8:601-613, 1998.
  15. Davies, J.D., Cobbold, S.P., Waldmann, H. Strain variation in susceptibility to monoclonal antibody-induced transplantation tolerance. Transplantation 63:1570-1573, 1997.
  16. Mueller, R., Davies, J.D., Krahl, T., Sarvetnick, N. IL-4 expression by grafts from transgenic mice fails to prevent allograft rejection. J. Immunol. 159:1599-1603, 1997.
  17. Cobbold, S.P., Adams, E., Marshall, S., Davies, J.D., Waldmann, H. Mechanisms of Peripheral Tolerance. Immunological Reviews 149:5-33, 1996.
  18. Davies, J.D., Leong, L.Y.W., Mellor, A., Cobbold, S.P., Waldmann, H. T cell suppression in transplantation tolerance through linked recognition. J. Immunol. 156:3602-3607, 1996.
  19. Davies, J.D., Martin, G., Phillips, J., Marshall, S.E., Cobbold, S.P., Waldmann, H. T cell regulation in adult transplantation tolerance. J. Immunol. 157:529-533, 1996.
  20. Marshall, S.E., Cobbold, S.P., Davies, J.D., Martin, G., Phillips, J., Waldmann, H. Tolerance and suppression in a primed immune system. Transplantation. 62:1614-1621, 1996.
  21. Davies, J.D., Waldmann, H. Monoclonal Antibodies in Transplantation. In: Immunology of Heart and Lung Transplantation (Rose, M.L., Yacoub, M.H., Eds.) Edward Arnold Publishers, Chapter 7, pp. 93-116, 1993.
  22. Qin, S., Cobbold, S.P., Pope, H., Elliott, J., Kioussis, D., Davies, J.D., Waldmann, H. Infectious transplantation tolerance. Science 259:974-977, 1993.
  23. Davies, J.D., Silvers, W.K., Wilson, D.B. A transplantation antigen, possibly of mitochondrial origin, that elicits rejection of parental strain skin grafts by F1 rats. Transplantation 54:730-731, 1992. 
  24. Davies, J.D., Wilson, D.H., Butcher, G.A., Wilson, D.B. Generation of T cells with lytic specificity for atypical antigens. II. A novel antigen system in the rat dependent on homozygous expression of major histocompatibility complex genes of the class I-like RT1C region. J. Exp. Med. 173:833, 1991.
  25. Davies, J.D., Wilson, D.H., Hermel, E., Fischer Lindahl, K., Butcher, G.A., Wilson, D.B. Generation of T cells with lytic specificity for atypical antigens. I. A mitochondrial antigen in the rat. J. Exp. Med. 173:823, 1991.
  26. Davies, J.D., Wilson, D.H., Wilson, D.B. Generation of T cells with lytic specificity for atypical antigens. III. Priming F1 animals with antigen-bearing cells also having reactivity for host alloantigens allows for potent lytic T cell responses. J. Exp. Med. 173:841, 1991.
  27. Davies, J.D., Mueller, D., Wilson, D.B., Gold, D.P. Nucleotide sequence of a cDNA encoding the rat T3 delta chain. Nucleic Acids Res. 18:4617, 1990.
  28. Davies, J.D., Wilson, D.H., Hermel, E., Fischer Lindahl, K., Butcher, G.A., Wilson, D.B. A maternally-transmitted antigen system in the rat. Transplantation Proc. 22:2547-2548, 1990. 
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