Icahn School of Medicine at Mount Sinai Researchers Awarded $15.1 Million Grant to Explore Immune Rejection of Transplanted Organs
Researchers target a part of the immune system previously unexplored in transplantation
Striving to improve organ transplant survival rates, internationally renowned researchers in immunology and bioengineering at the Icahn School of Medicine at Mount Sinai have received $15.1 million from the National Institute of Allergy and Infectious Diseases (NIAID) to lead a novel, five-year multi-center research program that will explore trained immunity—the innate immune system’s ability to remember infections and other insults—as a target for preventing organ transplant rejection.
Each year, more than 40,000 organ transplants are performed nationwide, but an estimated 30 percent of transplants are lost due to transplant rejection within the first five years. Researchers have traditionally focused on controlling the so-called adaptive branch of the immune system to prevent transplant rejection. This branch uses T cells—a type of white blood cell—to mount a sustained and targeted response against perceived threats, including foreign tissue. As a result, controlling the adaptive immune system’s T cell response using immunosuppressants can promote transplant survival. However, such therapies have suboptimal success rates, and their chronic use is associated with significant side effects, including an increased risk of infection, metabolic toxicity, and cancer.
Meanwhile, there is growing evidence that the innate branch of the immune system—which mounts a rapid but non-specific defense against threats—also plays a crucial role in organ transplantation. Icahn Mount Sinai researchers have found that transplantation effectively trains cells of the innate immune system to become more inflammatory and better capable of sustaining the adaptive immune response (as reported in Immunity in 2018 by Braza et al). This training of innate immune cells has been termed “trained immunity” and plays a role in various conditions but has not yet been studied in the context of transplantation (as reported in Nat. Rev. Immunol., in 2020 by Netea et al). Based on their findings, the researchers hypothesize that trained immunity promotes transplant rejection by amplifying the innate and adaptive rejection response, and thus represents a compelling therapeutic target for prolonging transplant survival.
“We believe that inhibiting trained immunity, and thereby limiting activation of the innate and adaptive immune system, is a promising strategy for preventing transplant rejection. With a relatively short and effective course of treatment that does not carry the risks of the current standard of care, we may save and improve countless lives of people experiencing organ failure,” said co-Principal Investigator Zahi Fayad, PhD, Director of the Biomedical Engineering and Imaging Institute (BMEII), and holder of the Lucy G. Moses Professorship in Medical Imaging and Bioengineering at Icahn Mount Sinai. “We are grateful to NIAID for recognizing this potential and making this research program possible.”
The program will engage a multidisciplinary team of scientists and clinicians at Mount Sinai, Massachusetts General Hospital, and Radboud University Medical Center in Nijmegen, the Netherlands, to achieve two goals: exploring how trained immunity drives transplant rejection and developing tools for diagnosing and regulating trained immunity in transplantation.
These goals will be pursued through three independent projects:
- Elucidating the role of trained immunity in kidney transplant patients, led by Willem J. Mulder, PhD, Professor of Precision Medicine, Eindhoven University of Technology and Radboud University Medical Center.
- Studying and regulating trained immunity in mouse transplant models, led by Abraham J. P. Teunissen, PhD, Assistant Professor of Diagnostic, Molecular and Interventional Radiology at BMEII at Icahn Mount Sinai.
- Using trained immunity-inhibiting nanobiologics to achieve heart transplantation survival in non-human primates, led by Joren Madsen, PhD, MD, Professor of Surgery at Mass General and the Paul S. Russell/Warner-Lambert Professor of Surgery at Harvard Medical School.
These projects will be supported by three Cores:
- Administrative Core, led by Dr. Fayad
- Bioengineering Core, also led by Dr. Fayad
- Mechanistic analysis and Bioinformatics Core, led by Jordi Ochando, PhD, Assistant Professor of Oncological Sciences and Director of the Flow Cytometry Core at Icahn Mount Sinai
“The number of organs available for transplantation is limited and we must find new ways to ensure that transplantations are sustainable,” said Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean of Icahn Mount Sinai and President for Academic Affairs of the Mount Sinai Health System. “This program has the potential to generate new therapeutic strategies that result in more effective prevention of rejection and achieve immune intolerance. That would not just be game-changing for the field of transplantation, but also could have benefits in the fields of bone marrow transplantation and autoimmune disease. Mount Sinai is excited to be leading this effort, which we believe will be transformational both for the communities we serve and for millions of patients around the world.”
The BioMedical Engineering and Imaging Institute is a state-of-the-art research facility housed in 20,000 square feet in the Hess Center for Science and Medicine on Mount Sinai’s Upper East Side campus. BMEII comprises more than 60 faculty, staff, and trainees with expertise in all aspects of translational imaging research. The faculty consists of chemical, biomedical, and electrical engineers; radiologists; cardiologists; immunologists; and data scientists, who are leading experts in neuroimaging, cardiovascular imaging, body/cancer imaging, and nanomedicine. Co-directed by Drs. Fayad and Teunissen, the nanomedicine lab combines expertise in radiochemistry, imaging, and immunology to create nanomaterials for studying and treating diverse medical conditions, including cancer, cardiovascular disease, and organ transplant rejection. BMEII researchers will build upon the advancements the nanomedicine lab has made in nanotherapeutics and imaging probe development to lead this interdisciplinary research effort.
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The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight- member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population.
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Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 43,000 employees working across eight hospitals, over 400 outpatient practices, nearly 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time — discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.
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