Organ transplantation is a remarkable achievement in medicine, yet it still faces major challenges, particularly the rejection of organs by the immune system.
Typically, transplant recipients must take immune-suppressing drugs for the rest of their lives, but this can lead to serious risks and side effects, including a higher chance of infections and reduced vaccine effectiveness.
Recent groundbreaking research led by a newly appointed biomedical engineering professor at the University of Virginia is opening doors to a novel approach that enables the body to accept transplanted organs without compromising its immune defenses.
Evan Scott is the Thomas A. Saunders III Family Jefferson Scholars Foundation Distinguished University Professor and David Goodman Family Bicentennial Professor of Nanomedicine in the biomedical engineering department. This position is part of a joint program within UVA’s School of Engineering and Applied Science and School of Medicine, where he brings 11 years of experience from Northwestern University.
In a recent publication in the journal Proceedings of the National Academy of Science, Scott and his research team explored the use of nanoparticles to help transplanted hearts in mice evade attacks from the immune system.
“Our goal is to modify the immune system in a safe and controlled manner, aiming for a future where transplant patients no longer need lifelong immunosuppressive drugs, along with the accompanying risks,” Scott explained.
In addition to organ transplants, Scott’s new lab at UVA will further this line of inquiry, potentially impacting other fields susceptible to immune rejection, such as diabetes, cell therapy, and autoimmune diseases. He will also take charge of UVA’s Institute for Nanoscale Scientific and Technological Advanced Research, or NanoSTAR, as part of the new Paul and Diane Manning Institute of Biotechnology.
“Evan’s groundbreaking work with nanoparticles exemplifies innovative science that could transform entire medical fields. We are excited to welcome him to our UVA community,” remarked Jennifer L. West, Dean of the School of Engineering and Saunders Family Professor of Engineering.
The Immune System’s Dilemma: Friend or Foe?
Annually, approximately 4,000 heart transplants take place in the United States, and this number is steadily increasing. However, a significant portion of these transplants are rejected by the body, which mistakenly identifies them as threats and activates the immune system to attack.
Current treatment options generally take one of two approaches: either suppressing the immune system to prevent it from launching an attack—at the risk of leaving the patient vulnerable to viral and bacterial infections—or building tolerance to help the body accept the new organ.
Scott and his lab are concentrating on the latter approach. In their study, they aimed to reprogram the immune system’s cellular instructions that trigger an attack on transplanted organs, effectively training the immune system to accept the new cells.
The Role of Myeloid Cells in Organ Rejection
The immune system employs various kinds of white blood cells to tackle threats such as infections, cancer, and healing wounds. Among these, myeloid cells are particularly adaptable and can transform into different forms as needed. When they sense danger, monocytes, a type of myeloid cell, can evolve into inflammatory macrophages—cells specialized in combating threats.
Targeting HIF-2α: A New Therapeutic Strategy
Dr. Scott’s long-time collaborator, Dr. Edward Thorp, found that these inflammatory macrophages don’t always form in response to transplanted cells. Their research indicated that a specific protein, HIF-2α, plays a critical role in this process, being present in the hearts of accepting mice but absent in those that rejected the transplanted organ.
This discovery suggested that the protein could be targeted for therapeutic intervention, signaling the host’s immune system that the transplanted heart cells are harmless and do not require an attack, thereby preventing the transformation of monocytes into inflammatory macrophages.
Consequently, the research team created nanoparticles that deliver the drug Roxadustat, which boosts HIF-2α levels in monocytes. Since the spleen acts as a reservoir for monocytes, the nanoparticles were directed to this organ to alter circulating white blood cells optimally. This method ensured a sufficient number of monocytes would signal the immune system to spare the transplanted heart cells, while keeping the immune system fully operational for other tasks.
Mice treated with this approach demonstrated a significantly enhanced ability to accept their transplanted hearts.
“We focused on the precise delivery of the drug to the spleen, which proved to be highly effective. Our capability to influence how circulating monocytes react to their surroundings holds great promise for treating various disorders,” stated Scott.
