Bone marrow transplantation (BMT) is currently used for the treatment of various diseases yet significant obstacles still remain. These obstacles include: graft-versus-host disease (GVHD), rejection of the marrow graft by the host, and a period of immune deficiency following the BMT leaving the patient susceptible to opportunistic infections. Our work has focussed on finding ways to abrogate the host's ability to reject the marrow graft and to accelerate immune reconstitution following BMT. We have found that NK cells activated with IL-2 in vitro can produce a variety of cytokines including: TGF-beta, TNF-alpha, GM-CSF, IL-1beta, and a potentially novel hematopoietic growth factor as determined through RNA analysis and protein analysis of their supernatants. These NK cells could then be adoptively transferred in vivo during allogeneic BMT in mice. We found that transfer of activated NK cells syngeneic with the donor could promote marrow engraftment in allogeneic recipients. The use of these NK cells also resulted in faster immune reconstitution in the recipients and no GVHD occurred. We found that these NK cells neutralized the host effector cells and prevented rejection. We are now utilizing rhGH in conjunction with other cytokines (IL-2, IL-7) in the human/mouse chimera model to determine effects on engraftment and potential antitumor effects in mice given a human colon carcinoma. Another approach was with the use of neuroendocrine hormones to accelerate reconstitution. Utilizing a model in which human lymphocytes are transferred into immunodeficient mice, we found that recombinant human growth hormone (rhGH) promoted human T-cell engraftment in these mice. Surprisingly, rhGH treatment also allowed for the entry of human cells into the mouse thymus. We have used rhGH in other murine model systems and found that rhGH exerts profound effects on T-cell reconstitution and development. We also observed that rhGH exerts significant effects on hematopoietic proliferation and engraftment following BMT.
