A team of scientists at the University of California, Davis, used whole-body dynamic positron emission tomography (PET) to provide the first image of the human body’s immune response to a COVID-19 infection in recovering patients. Their work, published in Science Advances, may lead to a better understanding of how the body’s immune system responds to viral infections and develops long-term protection against reinfection.
The researchers used the uEXPLORER whole-body PET scanner. It is an innovative imaging technology developed at UC Davis in collaboration with United Imaging Healthcare.
Dynamic PET involves injecting very small amounts of radioactive tracers into the patient, followed by continuous imaging over a period of time. It essentially creates a movie showing the kinetics (distribution over time) of the radiotracer in the body. Mathematical models can then be applied to extract biologically relevant information.
Whole-body PET scanners enable simultaneous dynamic imaging and kinetic modeling in all organs of the body. They have significantly higher sensitivity than conventional PET systems. This results in better image quality while allowing the use of lower radiotracer injection doses.
“Dynamic whole-body PET is currently the only available technology with an acceptable radiation dose that allows non-invasive quantitative measurements of immune cell distribution and trafficking (movement) in all tissues of living humans,” said first author Negar Omidvari, an assistant project scientist at UC Davis, Department of Biomedical Engineering.
Non-invasive technology for studying the body’s immune response
The study represents the first use of dynamic PET and kinetic modeling to measure CD8+ T cell proliferation in humans. CD8+ T cells are specific immune cells with CD8 protein on their surface. During viral infection, naïve (unpersonalized) CD8+ T cells are activated and become cytotoxic. This means they find and kill infected cells. Some of these CD8+ cells develop into antigen-specific memory T cells for long-term protective memory against reinfection.
These cells circulate in the blood, but are mostly found and function in non-blood tissues, especially lymphoid organs, such as the bone marrow, spleen, tonsils, and lymph nodes.
“There is growing interest in studying the critical role of CD8+ T cells in immune response and memory. However, assessment of immunological changes in non-blood tissue is challenging due to the invasive nature of biopsies. In some cases, this is not even practical in certain anatomical areas of living participants, such as the brain, spinal cord, cardiopulmonary tissue and vascular tissue,” Omidvari said. “So the challenge was to find non-invasive quantitative methods to measure the distribution and trafficking of CD8+ T cells in the body that were safe to use in healthy people as well.”
For the study, the researchers enrolled three healthy subjects and five patients recovering from a COVID-19 infection. Recovering patients had mild or moderate symptoms and were not hospitalized.
The team injected participants with a small amount of radioactive liquid that included a radioactive immunoPET tracer (89Zr-Df-Crefmirlimab) that targets human CD8. For each participant, the team performed a dynamic 90-minute scan, a 60-minute scan at six hours, and a 60-minute scan at 48 hours after the injection. The recovering patients also had the same set of scans four months later.
The researchers measured the activity of the radioactive tracer in blood and non-blood tissue on PET images. They did kinetic modeling to isolate the effect of blood circulation on tissues. This allowed them to measure the uptake of a radioactive tracer in the tissues, regardless of when the image was taken and differences in each participant’s blood.
With whole-body PET, researchers can make noninvasive measurements of T cell distribution with remarkable image quality throughout the body, in all tissue types. Their study showed a high uptake of CD8+ T cells in the lymphoid organs of all participants. The highest uptake is in the spleen, followed by the bone marrow, liver, tonsils, and lymph nodes.
The most significant finding was the increased concentration of CD8+ T cells in the bone marrow of recovering COVID patients compared to healthy controls. In follow-up images (acquired 6 months post-infection), these concentrations in the recovering patients were slightly higher than those obtained at about 2 months post-infection (baseline) in all bone marrow regions.
“Bone marrow has been identified as a major pool and preferred site for proliferation of memory CD8+ T cells following viral infection. This trafficking of memory T cells to certain tissues such as the bone marrow is crucial for the development of immune memory after viral infection,” explained Omidvari.
Less radiation, better results
The specificity of the immunoPET indicator, combined with the high detection sensitivity of whole-body PET, provides a new platform for scientists to study the immune response and memory in all organs long-term in a non-invasive manner.
“What is fundamentally important about this study is that it demonstrated the potential of whole-body PET to assess T-cell distribution throughout the human body, with the image quality required for detailed modeling and with a radiation dose that is low enough to allow its widespread application to study the immune response in humans,” said Simon R. Cherry, UC Davis physicist and distinguished professor emeritus of biomedical engineering and radiology. “In our case, we were able to characterize the dynamics of this immunoPET indicator in healthy control subjects and in patients with an infectious disease (COVID-19), which is an important first.”
The team pointed to many potential applications for this method. It can be used to study the immune response during viral infection, immune memory after viral infection, and to assess the response to treatment in cancer patients. It can also be extended to studies of infectious diseases, autoimmune diseases and transplants, and can be used for prediction as well as therapeutic and vaccine development.
The UC Davis study was co-authored by Terry Jones, April L. Ferre, Jacqueline Lu, Yasser AbdelHafez, Fatma Sen, Stuart Cohen, Ramsey D. Badawi and Barbara Shacklet. The other co-authors are Ian Wilson and Kristin Schmiedehausen of ImaginAb Inc. and Pat M. Price of Imperial College.
This work was supported by grants from the National Institutes of Health (NIH) (R01CA206187, R35CA197608), the NIH National Cancer Institute (NCI) (P30 CA0933730), and the NIH National Center for Research Resources (NCRR) (S10 RR12964, S10 RR026825, S10 OD018223-01A1). It was also supported by the James B. Pendleton Charitable Trust and ImaginAb Inc.