Organ transplantation is an incredible medical achievement that, unfortunately, still presents significant unresolved challenges, including rejection by the body’s immune system.
Although the standard regimen for transplant recipients is to take immunosuppressive medications for life, this carries considerable dangers and side effects, including susceptibility to infections and decreased effectiveness of vaccines.
Now, groundbreaking research from a new University of Virginia biomedical engineering professor who recently joined the College of Engineering and Applied Sciences and the School of Medicine is helping to pioneer a new way for the body to accept transplanted organs. without compromising the immune system.
Evan Scott is the Thomas A. Saunders III Family Jefferson Scholars Foundation Distinguished University Professor and the David Goodman Family Bicentennial Professor of Nanomedicine in the Department of Biomedical Engineering, a joint program of the College of Engineering and Applied Sciences and the College of Medicine. from UVA, which he joined after 11 years at Northwestern University.
Scott is co-author of a new article in the journal. Proceedings of the National Academy of Sciences,describing a study in which Scott and his fellow researchers used nanoparticles to make cells from hearts transplanted into mice resistant to attack by their immune system.
“What we are trying to do is modify the immune system in a controlled and therapeutic way, so that one day transplant patients will not have to continually take the immunosuppressive drugs they take today, with all the risks that entails,” explains Scott. saying.
Beyond the area of transplantation, Scott’s new laboratory at UVA will continue this line of research, which could have implications for other areas dealing with immune rejection, such as diabetes, cell therapy and autoimmune disorders. He will also direct UVA’s Institute for Advanced Nanoscale Scientific and Technological Research, or NanoSTAR, as part of the new Paul and Diane Manning Biotechnology Institute.
“Evan’s innovative work with nanoparticles represents the kind of forward-thinking science that can reshape entire medical fields. We are thrilled to have him join our UVA community,” said Jennifer L. West, dean of the College of Engineering and professor of the Saunders family. Engineering.
The dilemma of the immune system: friend or enemy?
About 4,000 heart transplants are performed each year in the United States and the number is increasing. However, in a significant percentage of cases, the body rejects the transplanted organ, misclassifying it as a threat and sending the immune system to attack.
Existing treatments focus on one of two paths: suppressing the immune system from attacking, but leaving the patient’s immune system compromised to viral and bacterial threats, or developing tolerance, which helps the body accept the new organ.
Scott and his lab focus on the second approach; In the new study, he and his co-authors attempted to reconfigure the cellular-level instructions that cause an immune system to attack a new organ, essentially retraining the immune system to tolerate the new cells.
The role of myeloid cells in organ rejection
The body’s immune system uses a wide range of white blood cell types to address a variety of threats and functions, including pathogenic infections, cancer, and wound healing. Myeloid cells circulating in the bloodstream are particularly versatile white blood cells, capable of changing into several different shapes as required by the task at hand. When they detect a threat, myeloid cells called monocytes can transform into inflammatory macrophages: attack cells that deal with intruders.
Targeting HIF-2α: a new therapeutic strategy
Dr. Edward Thorp, a long-term collaborator of Dr. Scott, discovered that these inflammatory macrophages did not always develop in response to the transplanted cells. They found that a particular protein, HIF-2α, influenced this process, as it was present in the hearts of mice that accepted the transplant, but not in those that rejected the new heart.
For the researchers, this meant that the protein could be therapeutically targeted and used to signal to the host’s immune system that the newly transplanted heart cells were fine and did not need to be attacked, preventing monocytes from transforming into inflammatory macrophages.
Therefore, the research team developed nanoparticles that encapsulate the drug Roxadustat, which increases HIF-2α levels in monocytes. Since the spleen serves as a reservoir for monocytes, the nanoparticles were targeted to this organ to modify circulating white blood cells and maximize the effect of the therapy. This strategy ensured that a sufficient number of circulating monocytes were modified to signal the immune system to specifically leave the transplanted heart cells alone, while allowing the immune system to remain fully functional.
In the study, mice that received the treatment showed a significantly increased ability to accept their transplanted hearts.
“We specifically targeted delivery of the drug directly to the spleen, which proved to be very effective. This ability to modify the way circulating monocytes respond to their environment has immense and broad therapeutic potential to treat a variety of different disorders.” Scott stated.