Mesenchymal Stem Cell Therapy and Gene Therapy in Organ Transplantation

Research Leader: Dr Ravi Krishnan

The focus of this laboratory is on the molecular and cellular mechanisms of rejection of transplanted organs and the development of novel gene and cellular therapy approaches to treat rejection in organ transplantation.

Dendritic cells:

The dendritic cell from the donor organ is the major cell that initiates the rejection response by providing activation signals to the responding T cells from the recipient. The activation signals are provided by costimulatory molecules on dendritic cells, which interact with their appropriate ligands/receptors on T cells. The blockade of signals between these cells produce T cell unresponsiveness that facilitates organ transplant acceptance. Our studies involve the genetic modification of dendritic cells using adenoviral gene therapy vectors to deliver immunomodulatory molecules that belong to the immunoglobulin-like supergene family and the TNF-receptorlike supergene family members. Upon expression of these negative regulatory molecules in dendritic cells the effects on rejection responses and organ transplant acceptance will be studied in experimental models of transplantation.

Mesenchymal stem cells:

Adult mesenchymal stem cells are cells derived from bone marrow that can facilitate tissue repair of damaged or diseased tissue. Furthermore, these cells have the distinct property of differentiating into bone, cartilage and adipose tissues, and intriguingly under appropriate culture conditions can transdifferentiate into insulin producing cells. Pancreatic islet transplantation is currently a clinical treatment for insulin replacement therapy in type 1 diabetics, however, the shortage of donor pancreases is a limitation of this important treatment. Thus MSCs offer an expandable and readily available source of insulin producing cells.

Research Priorities:

• Characterise the immunomodulatory and regenerative properties of adult mesenchymal stem cells for the treatment of transplant rejection and the treatment of diabetes using cellular, molecular and gene therapy strategies
• Evaluate the efficacy of cell therapy (mesenchymal stem cells and dendritic cells) in the treatment of organ transplant rejection and to assess the translational potential in preclinical experimental models