Localized Immunosuppression via Optogenetically Controlled Regulatory T Cells
Abstract
Overview: Vascularized composite allografts (VCAs) are transplants of heterogeneous tissues, such as hands, arms, faces, and feet. VCAs have an extraordinary potential to return function and dignity of life for individuals who have suffered devastating injuries. VCAs are similar to organ transplantation where recipients must take a number of different drugs to suppress their immune system, which would otherwise destroy the grafted tissue. These drugs, however, have serious toxic side effects and risks, such as kidney dysfunction, risk for infections, and the development of cancers. Patients on these drugs must also be frequently monitored by clinicians to maintain sufficient immunosuppression while not causing dysfunction to other tissues. Improvements are needed in immunosuppressive therapy that aren’t as damaging or risky for the patient, but that are still strong enough to prevent long-term rejection of the tissue and enabling long-term use of the transplanted VCA. Proposed Solution: We are proposing a way to localize immunosuppression just in the area of the VCA by implantation of cells that can be controlled by administration of light on the outside of the recipients’ body. Near-infrared wavelength (NIRW) light is mostly outside of the spectrum that the human eye can see, ranging from about 700 nanometers to 900 nanometers. Light of this wavelength is low energy in that it is does not cause burns, such as ultraviolet light, but NIRW light additionally penetrates through several centimeters of skin, bone, and muscle. One example of NIRW light is an LED. We have developed a genetic circuit that, when implanted into cells, makes the cells able to be controlled via NIRW light. This means that by placing a NIRW light source near the skin, it may be possible to control cells within the body that contain this genetic circuit. We propose to apply this system of external control of internal cells to a cell type that can suppress the immune response. The mature therapy would involve sampling some of the patients’ blood cells, growing the cells outside of the body, modifying them with the genetic circuit, and implanting them back into the patient. The patient would then place a NIRW light source next to their VCA, which would stimulate activation of the implanted cells that would then suppress the immune response in the patient, but only where the NIRW light was applied. NIRW light could be administered to the VCA at home during rest or watching TV for potentially minutes during the day. The patients would have an improved quality of life as the rest of their immune system would remain intact and they would not be at risk for infections or cancer throughout their body. This has the potential to replace or supplement standard immunosuppressive therapies given to patient recipients of VCAs. Plan of Research: We propose to first test and develop this idea in rats. Our plan of research seeks to accomplish the three major goals: (1) Develop NIRW-responsive circuits to control immunosuppressive cell types. (2) Confirm in experiments in cell culture that the cells with the genetic circuits are indeed more immunosuppressive in response to NIRW light. (3) Implant NIRW responsive cells into a live rat and expose the rat to NIRW light, confirming that the cells proliferate and become more immunosuppressive in the area where the NIRW light was administered. Successful completion of these experiments will position the work to next be carried out in an animal model of a VCA and to be positioned for clinical trials in humans.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710402
Entities
People
- Jared Bushman
Organizations
- United States Army
- University of Wyoming