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.
Associate Member
Transplantation

858.455.3751 - phone
858.909.5117 - fax

Biography

  • 1986-1990, Postdoctoral Fellow, Division of Immunology,
    Medical Biology Institute, La Jolla, CA
  • 1990-1995, Postdoctoral Research Associate, Division of Immunology, Department of Pathology, Cambridge University, England U.K.
  • 1995-1996, Assistant Research Scientist, Department of Biology,
    University of California, San Diego, CA
  • 1996-1998, Senior Research Associate, Department of Immunology,
    The Scripps Research Institute, La Jolla, CA
  • 1998-2001, Assistant Professor, Department of Immunology,
    The Scripps Research Institute, La Jolla, CA
  • 2001-Present, Associate Member, Department of Immunology,
    Torrey Pines Institute for Molecular Studies, San Diego, CA

Immune regulation and transplantation tolerance

The main interest of our research program is to understand the cellular and molecular basis for transplantation tolerance. 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.

Background and goals

Organ transplantation is the only therapy available for end stage organ failure. In the absence of immunosuppressive drugs transplanted tissues are typically rejected in a matter of days by a mechanism of acute rejection.

Immunosuppressive drugs have allowed renal, pancreas, heart, liver and lung transplants to survive with a short term (1 year) success rate of 90%, 80%, 70%, 50% and 40%, respectively. However, none of the drugs tested thus far have proven capable of promoting indefinite graft survival, either clinically or in animal models. The end result is always chronic rejection.

In addition the current therapies result in non-specific immunosuppression leaving the recipient vulnerable to opportunistic infection and susceptible to cancer. An ideal therapy would be one that inactivates only the immune response that is specific for the graft (antigen-specific tolerance), leaving the recipient capable of combating pathogens. The long-term goal is to identify new targets and novel strategies to inhibit chronic graft rejection in a manner that is compatible with the simultaneous inhibition of acute rejection.

Approach, major findings and future goals

We are currently using two strategies for the induction of transplantation tolerance as described below:

Strategy #1 - Monoclonal antibody-induced islet transplantation tolerance.

It has been previously demonstrated that treatment with CD4- and CD8-specific monoclonal antibodies promotes tolerance to a transplanted graft for the lifetime of the host. The mechanism of tolerance has been shown to require the presence of regulatory CD4+ T cells. We have shown that these regulatory cells can prevent non-tolerant cells from rejecting the graft as long as the antigen recognized by the regulatory and non-tolerant cells is presented by the same antigen-presenting cell. This concept has been termed ‘linked recognition of suppression’. This unique characteristic is potentially very powerful with respect to its application to transplantation tolerance and we are in the process of testing the limitations and mechanisms of tolerance by 'linked recognition'.

Strategy #2 - Transplantation tolerance induced during a transplantation rejection episode.

Using a model system of pancreas transplantation rejection we have successfully developed a strategy that stops ongoing pancreas graft rejection by inducing transplantation-specific tolerance. This model is particularly interesting for two reasons.

i) Not only is ongoing rejection of the pancreas transplant inhibited but the transplant also undergoes re-modeling returning it to a form indistinguishable from a graft that has never experienced rejection. This indicates that the treatment both protects the graft from further damage and reverses the effects of rejection.

ii) Protection of the graft is graft antigen-specific, leaving the recipient still capable of responding to pathogens. The ultimate goal is to define the minimal requirements for tolerance induction and graft recovery at the molecular level thereby opening new therapeutic approaches allowing indefinite transplant survival.

In summary, the overall goal of our laboratory is to further understand the cellular and molecular mechanisms of transplantation tolerance using cellular, molecular and genetic approaches. The long-term goal is that the information gained from these studies will be useful in the design of novel therapeutic strategies for the inhibition of organ transplantation rejection.

Selected publications. 1-6

  1. Davies, J. D., Cobbold, S. P., and Waldmann, H. Strain variation in susceptibility to monoclonal antibody-induced transplantation tolerance. 1997. Transplantation 63:1570.
  2. Davies, J. D., O'Connor, E., Hall, D, Krahl, T, Trotter, J and Sarvetnick, N. CD4+ CD45RB low-density cells from untreated mice prevent acute allograft rejection. J. Immunol. 1999. 163:5353–5357.
  3. O'Connor, E. Roberts, E, and Davies, J. D. Amplification of cytokine-specific ELISAs increases the sensitivity of detection to 5 – 20 picograms per milliliter. J. Imm. Methods.1999. 229:155–160.
  4. Hall, D., Roberts, E. and Davies, J. Allograft rejection results from a failed attempt by the immune system to protect foreign tissue. Immunologic Research. 2000. 21:177-183.
  5. Roberts, E.M., Hall, D. S., Ferguson, S., and Davies, J. IL-4 expression delays eosinophil-independent vasculopathy and fibrosis during allograft rejection in the mouse. J. Clinical Immunology. 2003. 23:120-132.
  6. Hall, D., Roberts, E. M., Ferguson, S., Wang., and Davies, J. Increasing transplant mass results in long-term allograft survival and recovery from transplant vasculopathy. J. Clinical Immunology. 2003. 23:162-174.

Publications

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. Davies, J.D., Cobbold, S.P., Waldmann, H. Strain variation in susceptibility to monoclonal antibody-induced transplantation tolerance. Transplantation 63:1570-1573, 1997.
  13. 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.
  14. Cobbold, S.P., Adams, E., Marshall, S., Davies, J.D., Waldmann, H. Mechanisms of Peripheral Tolerance. Immunological Reviews 149:5-33, 1996.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. Qin, S., Cobbold, S.P., Pope, H., Elliott, J., Kioussis, D., Davies, J.D., Waldmann, H. Infectious transplantation tolerance. Science 259:974-977, 1993.
  20. 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. 
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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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