Cellular and molecular mechanisms of antigen-specific tolerance and its application in the treatment of graft rejection, autoimmune diseases and cancer
The ability to induce unresponsiveness to our own tissue and transplanted organ grafts while retaining immune responses towards viruses and malignant cells has been a dream of immunologists and clinicians for many years. To achieve this goal requires understanding the cellular and molecular mechanisms that control and regulate immune responses.
Our laboratory's research is focused on two major areas:
1) Dissecting cellular and molecular mechanisms involved in immunity and tolerance and their relevance in graft rejection, graft versus host disease and autoimmune diseases.
The research focus of my laboratory is to understand the cellular and molecular mechanisms governing tolerance and immunity and to translate obtained knowledge into novel therapies for immune related diseases. We study the mechanisms by which regulatory T cells, including NK-CD3+ CD4 and CD8 double negative (DN Tregs) and CD4+Foxp3+ Tregs control immune responses. We are also interested in the regulatory function of myeloid suppressor cells. We have generated various new strains of gene-deficient mice to examine the importance of different molecules on the induction of T cell tolerance or activation.
The mouse disease models that we are studying include:
1. Donor-specific transplantation tolerance
2. Graft-versus-host disease after bone marrow transplantation
3. Autoimmune lymphoproliferative disease
4. Autoimmune encephalomyelitis (EAE)
5. Leukemia and solid tumour models
2) Developing novel adoptive T cell therapy for leukemia and lung cancer.
Human CD3+CD4-CD8-CD56- T cells, termed double negative (DN) T cells, compose a small population of peripheral T cells in human blood. Recently, we have developed a novel protocol by which human DN T cells can be expanded ex vivo in large numbers from peripheral blood of healthy donors as well as patients with leukemia and lung cancer. More importantly, we have demonstrated that these ex vivo propagated human DN T cells have potent anti-tumor function both in vitro and in vivo. We are investigating the mechanisms by which these DN T cells kill cancer cells and exploring the possibility of using DN T cells as a novel adoptive immunotherapy to eliminate residual cancer cells after conventional therapy. We are also studying the ability of DN T cells on eliminating leukemic initiating cells.
- Inaugural Maria H. Bacardi Chair in Transplantation
- Research Director, University of Toronto Transplantation Institute
- Professor, Department of Laboratory Medicine & Pathobiology, University of Toronto
- Professor, Department of Immunology, University of Toronto
- Professor, Institute of Medical Sciences, Faculty of Medicine, University of Toronto