- Dr Hao Wang, Principal Investigator
- Dr Wei-Ping Min, Collaborator
- Dr Bertha Garcia, Collaborator
- University of Western Ontario, London, Canada
- Induction of Transplant Tolerance in Sensitized Recipients
Although immunosuppressive drugs have increased graft survival and made transplantation a clinical reality, these treatments require life-long administration and are associated with adverse effects, such as cancers and infections. Therefore, induction of immunologic tolerance is an important clinical goal in transplantation. A tolerant patient is someone who accepts the transplanted organ yet is capable of mounting an effective immune response against vaccines and microbial pathogens. Although several immunomodulatory strategies have been successfully used to induce tolerance in rodents, the same strategies have failed in non-human primates and in humans who are constantly exposed to bacteria and viruses or have received a prior stimulus via blood transfusion, previous transplant, or pregnancy. This type of stimulus creates the presence of memory T cells (Tmem). Tmem not only endanger graft survival by causing both acute and chronic rejection but also impede tolerance induction. Using a potent protocol, we have successfully induced stable murine cardiac allograft tolerance through formation of tolerogenic dendritic cells (Tol-DC) and regulatory T cells (Treg), which are responsible for initiating and maintaining immunological tolerance. However, this same therapy failed to induce tolerance in presensitized mice, in a model designed to mimic sensitized patients, owing to significantly increased Tmem.
In this study, we will investigate the interactions among Tol-DC, Treg and Tmem. We will identify an effective strategy to inhibit Tmem-mediated rejection by functionally blocking the activation pathway that is unique for the recall of Tmem. This will restore tolerance, which had been induced by currently available tolerant protocol, through the generation of Tol-DC and Treg. This study will provide insight into understanding the role of Tmem in tolerance induction. Its findings can potentially be translated into improved therapies for preclinical primate studies and eventually sensitized transplant patients, thereby increasing the success of organ transplantation and improving the quality of life for transplant recipients.