Understanding and eliminating major barriers to successful
allogeneic hematopoietic stem cell transplantation
The Program in Transplantation Biology combines basic and translational research directed at understanding and eliminating major barriers to successful allogeneic hematopoietic stem cell transplantation; these include host-versus-graft reactions, graft failure, acute and chronic graft-versus-host disease (GVHD), regimen-related toxicities, and induction of graft-versus-tumor reactions. The program’s goal has been to use stem cell transplantation to treat patients with malignant and nonmalignant hematologic diseases.
Specific research goals include:
- Developing novel conditioning regimens to better destroy the patients’ underlying diseases and prevent relapse;
- Controlling alloreactivities to prevent rejection and GVHD;
- Understanding the genetic basis of alloreactivities;
- Directing alloreactivities against desired tumor targets, including leukemias, lymphomas, and solid tumors;
- Identifying regulatory components required for both hematopoietic and immune reconstitution; and
- Developing strategies for interventions for late complications of transplantation.
A new direction includes investigations of the “plasticity” of stem cells which might be used to regenerate epithelial and muscle cells. For the latter studies, a canine model of Duchenne’s muscular dystrophy has been developed. The program’s preclinical studies are done in a canine model which has proven to be reliable for quick extrapolation to humans. The choice of this model has necessitated the development of canine molecular immunogenetics and the cloning of many canine genes to produce reagents analogous to those used in humans, e.g. CD34 monoclonal antibodies, hematopoietic growth factors, anti-T and -B cell reagents, microsatellite polymorphism markers, and so forth. This effort to optimize the canine model has allowed the program to play a leading role in canine “genome” and disease gene mapping projects.
Finally, our experience in hematopoietic stem cell transplantation has prompted increased referrals of human patients with genetic and other nonmalignant diseases. This has led to research in gene therapy.