Research Interests: Immunobiology of Bone Marrow Transplantation

Our laboratory is interested in examining issues in bone marrow transplantation (BMT) and its use for the treatment of cancer and other disease states.  BMT, both allogeneic and autologous, is currently used for the treatment of a variety of disease states ranging from aplastic anemia to cancer, but significant obstacles limit the efficacy of this procedure–these include marrow graft failure, graft-versus-host disease (GVHD), immune deficiency following the transplant, and, when used for the treatment of cancer, recurrence of the tumor.  Natural killer (NK) cells have been demonstrated to be responsible for mediating the specific rejection of bone marrow cell (BMC) allografts in lethally irradiated mice.  However, little is known about the nature of these cells and BMC rejection that leads to marrow graft failure.  We have found that NK cell subsets exist that are responsible for mediating the specific rejection of BMC from mice bearing the appropriate MHC molecules.  In addition, these NK subsets also play an important role in the normal homeostasis of hematopoiesis, suggesting that it is one of their normal physiologic functions.  We are currently examining the differentiation of these various subsets.  We are also using activated NK cells as a means of providing additional antitumor effects when BMT is used with tumor-bearing mice.  We found that adoptive transfer of NK cells can provide significant antitumor effects while at the same time promote hematopoietic engraftment and prevent GVHD in mice.  We are currently examining the mechanism(s) underlying these effects.

Our laboratory has also been examining means to accelerate immune and hematopoietic reconstitution following BMT.  This would also be of use in other instances where immune recovery is desirable, such as in AIDS.  We have been focusing on the use of neuroendocrine hormones such as growth hormone (GH) and prolactin.  They are attractive since they are relatively nontoxic when given systemically and can exert pleiotropic effects.  We have found that GH can exert significant hematopoietic growth-promoting effects after in vivo administration.  GH can also accelerate immune and hematopoietic reconstitution after BMT in mice.  Using a human/mouse chimera model, we have found that these hormones can improve human T cell trafficking and function in vivo.  Based on our studies, clinical trials are currently underway evaluating these hormones in patients with AIDS.  We are also examining the physiological role of these neuroimmune interactions.

CD40, a member of the TNF receptor family of molecules, has been shown to play a critical role in dendritic cell development as well as being a co-stimulatory molecule in T and B cell responses.  The ligand for CD40 (CD40L) is present on activated T and NK cells.  CD40-CD40L interactions have been demonstrated to be critical for optimal T cell responses and the impairment of these interactions has been shown to foster a tolerogenic state.  CD40 stimulation is also capable of inducing production of numerous inflammatory cytokines by monocytes and dendritic cells.  Thus, CD40 represents an important molecular target for initiating and/or amplifying nascent immune responses against tumors.  We speculated that the enhanced differentiation and function of dendritic cells through CD40 engagement, combined with IL2 administration to stimulate T cell expansion, would act coordinately to enhance both the antigen-presenting and T cell components of the adaptive immune response against cancer.  To this end, we have developed a treatment protocol using CD40 agonist antibody and IL2 to promote anti-tumor activity in mice.  We are currently exploring the mechanisms involved in this response as well as investigating other potential uses for this immunotherapy.

Selected Publications
1. Kozel, T. R., Murphy, W. J., Brandt, S., Blazar, B. R., Lovchik, J. A., Thorkildson, P., Percival, A., and Lyons, C. R.: Monoclonal antibodies to Bacillus anthracis capsular antigen for immunoprotection in anthrax and detection of antigenemia. Proc. Natl. Acad. Sci. U.S.A. 101 (14): 5042-5047, 2004.

2. Sun, K., Welniak, L. A., Panoskaltsis-Mortari, A., O'Shaughnessy, M. J., Liu, H., Barao, I., Riordan, W., Sitcheran, R., Wysocki, C., Serody, J. S., Blazar, B. R., Sayers, T. J., and Murphy, W. J.: Inhibition of Acute Graft-Versus-Host Disease with Promotion of Anti-Tumor Effects by the Proteasome Inhibitor, Bortezomib. Proc. Natl. Acad. Sci. USA 101 (21): 8120-8125, 2004.

3. Sun, K., Wilkins, D .E. C., Anver, M. R., Sayers, T. J., Panoskaltsis- Mortari, A., Blazar, B. R., Welniak, L. A., and Murphy, W. J.: Proteasome Inhibition by Bortezomib Exerts Differential Effects on the Prevention versus Treatment of Acute Graft-Versus-Host Disease. Blood 106(9):3293-9, 2005.

4. Welniak, L. A., Kuprash, D. V., Tumanov, A. V., Panoskaltsis-Mortari, A., Blazar, B. R., Sun. K., Nedospasov, S. A. and Murphy, W. J.: Peyer’s Patches are not Required for Acute Graft-Versus-Host Disease after Myeloabalative Conditioning and Murine Allogeneic Bone Marrow Transplantation. Blood 107(1):410-2, 2006.

5. Brooks, A. D., Ramirez, T., Toh, U., Onksen, J., Elliott, P. J., Murphy, W. J., and Sayers, T. J.: The proteasome inhibitor bortezomib (Velcade) sensitizes some human tumor cells to Apo2L/TRAIL-mediated apoptosis. Ann. NY Acad. Sci. 1059:160-7, 2005.

6. Barao, I., Hanash, A. M., Welniak, L. A., Sun, K., Blazar, B. R., Levy, R. B., and Murphy, W. J.: Suppression of NK cell-mediated bone marrow cell rejection by CD4+CD25+ regulatory T cells: linkage of adaptive to innate responses. Proc. Natl. Acad. Sci. USA., 103: 5460-5, 2006.

7. Welniak, L. A., Blazar, B. R., and Murphy, W. J.: Immunobiology of Allogeneic HSCT. Ann Rev Immunol. Apr 23; 25:139-170, 2007.

8. Berner, V., Liu, H., Zhou, Q., Alderson, K.L., Sun, K., Weiss, J. M., Back, T. C., Longo, D. L., Blazar, B. R., Wiltrout, R. H., Welniak, L. A., Redelman, D., and Murphy, W. J. Interferon-gamma Mediated CD4+ T cell Apoptosis and Impaired Secondary Anti-Tumor Responses after Successful Initial Immunotherapy. Nat. Med. Mar; 13(3):354-60, 2007.