Study co-authors, from left: Zahi Fayad, PhD, Director of the Translational and Molecular Imaging Institute; and Willem J.M. Mulder, PhD, Professor of Radiology, and Oncological Sciences.
The nearly 35,000 individuals who receive organ transplants each year in the United States face a harsh reality: the immunosuppressive drugs they must take to maintain organ survival also weaken the immune system, breaking down the body’s critical defenses against cancer, infection, and more. Researchers at the Icahn School of Medicine at Mount Sinai recently developed an innovative type of immunotherapy based on nanotechnology that they hope will address this conundrum. Their findings, published in the November 6, 2018, issue of Immunity, have demonstrated the technology’s feasibility of long-term organ acceptance in mice.
“This is a whole new approach to programming the immune system, not just another small molecule drug that’s going to help with organ transplantation,” says Zahi Fayad, PhD, Director of the Icahn School of Medicine at Mount Sinai’s Translational and Molecular Imaging Institute, which conducted the work. Dr. Fayad is also Professor of Diagnostic, Molecular, and Interventional Radiology, and Medicine (Cardiology). “Because of the many problems this approach addresses—the risk of rejection, the shortage of organs for transplant, the cost of these procedures—we believe it can be transformative for the organ transplant field.”
Jordi Ochando, PhD
The immunotherapy works by regulating innate immune memory, or trained immunity, which the investigators found to play a central role in organ rejection. In trained immunity, immune cells known as myeloid cells initiate the body’s immune system response by activating T cells, which then attack the transplanted organ.
“By inhibiting trained immunity, we prevent activation of the myeloid cells and their subsequent activation of T cells,” says Jordi Ochando, PhD, the study’s co-senior author, who is Assistant Professor of Medicine (Nephrology), Oncological Sciences, and Pathology at the Icahn School of Medicine. “This novel technology preserves the normal function of the T cells, which is to protect the body against cancer and infections.”
Identifying trained immunity as a target enabled the Mount Sinai scientists to focus on a signaling pathway known as mammalian target of rapamycin (mTOR), which regulates immune cell metabolism. The team developed an injectable nanoimmunotherapy based on high-density lipoprotein (HDL) nanomaterials and the existing mTOR inhibitor rapamycin.
“These nanomaterials essentially deliver the rapamycin to the myeloid cells, and that changes the metabolic state of the cells and prevents their activation,” says co-senior author Willem J.M. Mulder, PhD, Professor of Radiology, and Oncological Sciences at Icahn School of Medicine, and Director of the Nanomedicine Program. The absence of myeloid cell and T cell activation, Dr. Mulder points out, could drastically reduce the need for transplant patients to take lifelong immunosuppressive medicines to prevent graft rejection.