General Aspects of the Research Program
Dr. Lee's research program is based in the Transplantation and Immunology Research laboratory, where Dr. Lee is the Director of Research. This is a modern immunology laboratory using molecular and cell biology techniques to understand the basis of disease and to develop novel therapies. The laboratory was recently upgraded with a 1.5$ million CFI grant. That upgrade has enhanced our molecular component such as Real-Time PCR and DNA array facilities.

Dr. Lee's research is highly collaborative and disease focused. He makes an effort to work extensively with clinical colleagues to maximize relevance of his basic research to patient care. In addition, Dr Lee has extensive links with industry and usually has between two and four basic research contracts ongoing in his laboratory at any given time. Dr. Lee has diverse industrial experience having worked with start-up biomedicals, multi-national Pharma and everything in between.

Transplantation

Dr. Lee has been collaborating with clinical colleagues for the last ten years to address a variety of aspects of solid organ transplant rejection.

In a major project in acute rejection of kidneys, Dr. Lee, working with Dr. Ronald Carr and Dr. Juan Zhou, discovered that oral exposure of alloantigen leads to the development of T regulatory cells that appear in the mesenteric lymph node and spleen of the transplant recipient as well as in the transplanted kidney. These Treg cells markedly delay kidney transplant rejection in the recipient. Treg cells harvested from the kidneys of these recipient animals can transfer graft prolongation to naive graft recipients. This graft infiltrating cell population which is capable of transferring graft prolongation is characterized by a dramatic increase in IL-4 transcription as compared to infiltrating cells in kidneys of control animals undergoing rejection. This suggests that the oral exposure may have produced type 2 Treg cells in this model.

Dr. Lee's major area of research interest is in the immuno-pathological mechanisms responsible for graft vasculopathy. Graft vasculopathy is currently the major cause of late transplant rejection of hearts and is involved in late transplant rejection of kidneys. This pathology has proved resistant to immunosuppression. In recent years Dr. Lee and his co-workers, along with other researchers in the field, have demonstrated that the accepted paradigm to explain this pathology is incorrect. Much of the work ongoing in this project deals with the immune processes that initiate and maintain this pathology and the aberrant tissue repair mechanisms that result in the pathological expression of the disease. Dr. Lee and colleagues have implicated CD8+ T cells as the cells that escape immunosuppression and mediate to this response. Ongoing research is directed at revealing the process by which these CD8+ T cells mediate the pathology.

In a separate project Dr. Lee and colleagues have demonstrated that antibody is not essential for AV but can contribute to disease.

Dr. Lee and colleagues have also demonstrated that pre-existing vascular disease in the coronary arteries of donor organ likely has a dramatic impact on the developing graft vasculopathy. In animal models, pre-existing disease contributes markedly to lumenal narrowing in diseased vessels.

In his research in allograft vasculopathy, Dr. Lee works in close collaboration with Dr. Greg Hirsch, Head of the Division of Cardiac Surgery in the Department of Surgery.

Novel Immunomodulatory Therapies
Recently, Dr. Lee has been exploring products extracted from plants and fungi for their ability to modulate the innate immune response in such a manner as to contribute to resolution of metastatic breast cancer.

In a study of Cordyceps sinensis, a fungal product, we have demonstrated that this product can be used to limit the growth of breast cancer metastases. We have shown that the agent can be given at the time of mastectomy, thus mimicking the human condition. The agent acts by activating innate immune cells to limit the growth of breast cancer metastases. Ongoing experimentation involves basic molecular mechanistic studies as well as product development studies for clinical trials.