Organ transplantation is often a life-saving intervention whose success is mediated by the host's immune system. Immune-mediated rejection of an organ transplant destroys the transplanted organ or tissue and can be fatal.
While immunosuppressants are routinely used to mitigate host graft rejection, nonspecific inhibition of the immune system is associated with serious adverse side effects. Specific immunomodulatory therapies using Treg and Breg cells have induced immune tolerance in transplanted organs, but with limited success.
Now, a multidisciplinary team of researchers led by Jayachandran Kizhakkedathu at the University of British Columbia (UBC) and Jonathan Choy at Simon Fraser University (SFU) along with collaborators from Northwestern University have found a way to reduce organ rejection following transplant by using a special polymer to coat blood vessels on the organ to be transplanted.
The polymer, developed by Kizhakkedathu and his team at UBC, substantially diminished rejection of transplants in mice when tested by collaborators at SFU and Northwestern University. The team published their findings on August 9, 2021, in Nature Biomedical Engineering.
Kizhakkedathu is professor of Pathology and Laboratory Medicine at UBC where his team develops blood-compatible multivalent polymer glycoconjugates and surfaces for cell targeting purposes. Jonathan Choy is an associate professor at SFU, where he studies T-cell biology and nitric oxide signaling.
The endothelium is the first point of contact between the graft recipient and the transplanted organ. In the organs, the endothelium is protected with a coating of a special sugar (glycocalyx) that suppresses the immune system's reaction. However, in the process of procuring organs for transplantation, there is breakdown of the glycocalyx and loss of endothelial integrity, leading to release of inflammatory molecules like chemokines.
Kizhakkedathu and his team sought to minimize organ rejection by rebuilding and rescuing the functional glycocalyx barrier via a cell-surface engineering (CSE) approach.
The team at UBC attached functionalized polymers to the endothelial surface through a chemo-enzymatic "Q-tag" conjugation strategy using guinea pig liver tissue transglutaminase.
The polymer scaffold was made with linear polyglycerol (LPG) which was found to be highly hydrophilic, biocompatible and nonimmunogenic. A glycocalyx mimic was made by functionalizing the Q-tagged LPG with sialyl lactose to increase the immunosuppressive action of the engineered polymer.
Speaking to Bioworld Science, Choy said that "We were amazed by the ability of this new technology to prevent rejection in our studies. To be honest, the level of protection was unexpected."
The engineered glycocalyx was successfully able to provide both vascular protection as well as localized immune suppression. This early inhibition of inflammation via localized immune suppression during the cold storage of the organ is long-lasting, and according to Choy, "it can potentially prevent acute and chronic rejection post-transplantation."
Choy further explained that the best part about the CSE technology is that "we can apply it during organ procurement and preservation ex vivo under current clinical protocols (for both static and perfusion-based organ storage conditions) without the need for systemic exposure in the actual patient. Moreover, this is a simple protocol and, as such, should be easily used in a clinical setting."
Choy, however, warns that several other studies would be required before a workable technology for clinical use is developed. For example, Choy points out that the human population is expected to show "much more heterogeneity in the immune system and any such heterogeneity is expected to affect efficacy at a population level. Further, our mice models lack the memory cells present in the human system that play an important role in tolerance induction and allograft rejection".
However, the fact that the engineered glycocalyx was also effective at reducing organ failure in more complex models, such as in a mouse model of kidney ischemia reperfusion injury as well as in allogeneic kidney transplantation, increases confidence about the "success of this technology in humans," added Choy.
Choy indicated that his team would next work on elucidating the mechanism of the immunosuppressive effect exerted by the engineered glycocalyx. He concluded by saying that the study was a testament to the collaborative interdisciplinary work that spanned across multiple groups in different institutions and was completed under "challenging conditions during the pandemic."