Dr. Murphy Research Lab-Research Focus
Bone marrow transplantation (BMT) is currently used for the treatment of a variety of disease states ranging from aplastic anemia to cancer. However, 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, relapse of the tumor. Using both in vivo and in vitro model systems, our laboratory has been examining the immunobiology underlying these obstacles.
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 concerning the nature of these cells and BMC rejection which 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 promoting hematopoietic engraftment and preventing GVHD in mice. We are currently examining the mechanism(s) by 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 focussing 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. We are also examining physiological role of these neuroimmune interactions.
Another problem with BMT is an EBV-induced B-cell lymphoma that can arise in immunodeficient individuals. We have found that stimulation of CD40, a molecule present on B cells critical for their development and function, can promote B-cell recovery after BMT. Using a human/mouse chimera model, we have also found that CD40 stimulation can prevent the occurrence of this EBV-induced B-cell lymphoma in vivo. Thus, CD40 stimulation after BMT may accelerate immune recovery and prevent lymphoma generation. We are currently examining the role of CD40 in hematopoiesis.