Over the past 20 years the Clinical Research Division of the Fred Hutchinson Cancer Research Center has been involved in a continuing program of marrow transplantation for the treatment of patients with otherwise fatal malignant and nonmalignant hematological diseases. Initially, most transplants were with marrow from genotypically HLA-identical sibling donors. Over the past 5 years more and more grafts are being carried out with marrow from alternative donors including less-well-matched family members and unrelated individuals. Currently, approximately one-third of the transplants done here are from alternative donors. With the increasing use of alternative donors, the spectrum of transplant-related complications has changed. Graft failure and poor graft function have become prominent problems, as have acute graft-versus-host disease (GVHD), more severe and more frequent chronic GVHD, along with an increased incidence of bacterial infections. The current grant will address these complications due to the change in the selection of donors for marrow transplantation. Long-term follow-up, prevention and treatment of chronic GVHD, and infection prophylaxis will be addressed in Project 0002. Project 0011 will evaluate new protocols for immunization to encapsulated bacteria and define defects in production of lymphokines that regulated B-cell function. Project 0012 will analyze the selection process of immunoglobulin gene repertoire in B cells after transplantation. Three projects 0013, 0014, and 0015 will address the problem of graft failure, both in human marrow transplant recipients and in a preclinical canine model. In this context, stromal cell/marrow cell interactions will be investigated as well as the role of CD44 adhesion molecules in engraftment and that of class II antigens in stem cell proliferation and differentiation. Finally, preliminary in vitro studies on tolerance induction to major histocompatibility complex antigens by antibodies to CD3 will be extended in Project 0016 with the aim of developing novel ways for preventing GVHD in the setting of marrow grafts from alternative donors. A core section on information management, statistical, secretarial and administrative support completes the program project grant.
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