The laboratory is engaged in studying the role of angiogenic chemokines in promoting tumor growth and the effect of inhibitors. We demonstrated that a number of pro-inflammatory chemokines including MCP-1 and Eotaxin have angiogenic activities. This is based on our evidence that microvascular tissue endothelial cells actually express a considerable number of chemokine receptors. This enabled us to show in the case of MCP-1, that neutralizing anti-MCP-1 antibodies actually caused tumor regression and a decrease in metastatic spread of human breast cell carcinoma in SCID mice. The antitumor effect of inhibiting MCP-1 is presumably based on interference with vascularization of the tumor. In an effort to evaluate the role of NK cells in transplant rejection, we have tested a method of using donor natural killer (NK) cells to promote engraftment of donor bone marrow and/or tolerance of a donor tissue or organ transplant. The method comprises isolating NK cells from a donor, treating the NK cells ex vivo to interfere with the ability of the inhibitory receptors that are present on the surfaces NK cells to interact with major histocompatibility complex (MHC) molecules of a host, and then adoptively transferring the NK cells to a host simultaneously with or sequentially to, in either order (preferably before), the bone marrow or tissue organ transplant. Fab' antibody fragments, small molecules and soluble MHC molecules are among those agents that can be used to treat the NK cells ex vivo, as well as drugs that block signaling with respect to the inhibitory receptors on the NK cells and enzymes that modify the inhibitory receptors such that they can no longer interact with MHC molecules. The advantages of such a method include the ability to use smaller amounts of NK cells and bone marrow in transplantation, as well as the avoidance of toxicity and immunosuppression.
| Welniak, L A; Tian, Z G; Sun, R et al. (2000) Effects of growth hormone and prolactin on hematopoiesis. Leuk Lymphoma 38:435-45 |
| Raziuddin, A; Bennett, M; Winkler-Pickett, R et al. (2000) Synergistic effects of in vivo depletion of Ly-49A and Ly-49G2 natural killer cell subsets in the rejection of H2(b) bone marrow cell allografts. Blood 95:3840-4 |
| Murphy, W J (2000) Revisiting graft-versus-host disease models of autoimmunity: new insights in immune regulatory processes. J Clin Invest 106:745-7 |
| Murphy, W J; Funakoshi, S; Fanslow, W C et al. (1999) CD40 stimulation promotes human secondary immunoglobulin responses in HuPBL-SCID chimeras. Clin Immunol 90:22-7 |
| Woody, M A; Welniak, L A; Sun, R et al. (1999) Prolactin exerts hematopoietic growth-promoting effects in vivo and partially counteracts myelosuppression by azidothymidine. Exp Hematol 27:811-6 |
| Murphy, W J; Blazar, B R (1999) New strategies for preventing graft-versus-host disease. Curr Opin Immunol 11:509-15 |
