- Dr Jacques Thibodeau, Principal Investigator
- Dr Abdelaziz Amrani, Co-Investigator
- Dr Viktor Steimle, Co-Investigator
- University Montreal, Montreal, Canada
- New Immunological Avenues to Improve Allograft Survival
A major challenge in organ transplantation is to specifically prevent immune rejection of the foreign tissues without compromising global responses against pathogens and cancers. Dendritic cells (DCs) play a key role in the control of immune responses. Host DCs efficiently capture foreign material, including transplant antigens, and then display them on molecules capable of activating the immune system, specifically T lymphocytes. It has recently been recognized that DCs not only activate the immune response, but may also induce immune tolerance against foreign antigens. As an alternative to non-specific immunosuppressive drugs, it was proposed to engineer ex vivo tolerogenic DCs from the host and / or donors to prevent the attack against transplants or even to avoid the original auto-immune attack, for example, in diabetes-prone individuals.
We have recently shown in humans that an E3 ubiquitin ligase called MARCH1 plays a key role in the immunosuppressive activity of the IL-10 cytokine. Its ability to down-modulate key players in the activation of the immune system confirms its strong potential for achieving tolerance. Our preliminary results strongly suggest that MARCH1 is indeed part of the arsenal of tolerogenic DCs.
We propose experiments to explore the prophylactic and therapeutic potential of MARCH1 in mouse models of autoimmunity and transplantation of pancreatic islets. The regulation of MARCH1 expression by various cytokines will be monitored. The immunomodulatory potential of MARCH1 will be exploited by overexpression in DCs conditioned with various regimens. We will test the ability of adoptively transferred MARCH1-expressing DCs to prevent diabetes and to prolong engraftment between MHC-incompatible mice.
Given the recent advances in the field of immunotherapy, the knowledge obtained from this study could be easily transposed to the clinic in the next few years and could be applicable to all types of organ transplants relying on cadaveric or live donors.