- Prof. Giuseppe Remuzzi, Principal Investigator
- Dr. Marina Noris, Co-Investigator
- Dr. Ariela Benigni, Co-Investigator
- Mario Negri Institute for Pharmacological Research, Bergamo, Italy
- Donor Engineered Dendritic Cells to Generate Tolerogenic Regulatory T Cells for Renal Transplantation
Increasing the acceptance rate of organs is the central goal of transplant medicine. In the past decades transplant immunologists have sought to develop safe and effective approaches to induce transplant tolerance, a condition in which the recipient accepts the foreign transplanted tissue/organ as self, without the need for chronic immunosuppression. In this regards, studies in experimental animals have recently documented that transplantation of allogeneic hematopoietic cells can lead to life-long donor specific chimerism that is linked with permanent tolerance of donor organ or tissue transplants. The above strategy, however, may expose graft recipients to the risk of graft-versus-host disease. In addition, donor MHC-mismatched hematopoietic grafts usually are acutely rejected unless the host is vigorously myeloablated or immunosuppressed.
Dendritic cells are unique professional major antigen-presenting cells (APCs) capable of stimulating naive T lymphocytes in the primary immune response. Recent studies, however, have also revealed the unexpected ability of DCs to inhibit T cell-mediated autoimmune diseases. How do the same DCs that mount primary immune response also inhibit immune activation? Evidence is now available that the ability of DCs to induce immunity or tolerance is related to their state of functional maturation. Immature DCs, lacking enough costimulatory activity, can induce T lymphocyte hyporesponsiveness in vitro and prolong allograft survival in vivo, suggesting their involvement in the induction of graft tolerance.
In preliminary studies we found that rat DCs made stably immature by transfecting specific genes that block maturation, are capable to generate hyporesponsive T lymphocytes with potent regulatory activity on naive T cells. In this project we propose to characterize in vitro phenotypically and functionally regulatory T cells generated by immature engineered DCs and to explore in vivo their capacity to control the effector arm of the immune response and induce tolerance to solid organ graft from the same DC donor.