Brain infiltrating T lymphocytes are found in a variety of neurological disorders, including multiple sclerosis (MS), autoimmune encephalomyelitis, traumatic brain injury, Parkinson's disease, and tauopathies. Brain infiltrating CD4 T lymphocytes have a clear, causative role in the pathology of MS and autoimmune encephalomyelitis and have been suggested to contribute to other diseases. As such, these cells represent an important therapeutic target in the treatment of neurological disorders. Yet despite all of this, there remains no non-invasive method for visualizing and quantifying these cells in vivo. Current imaging modalities, such as MRI, can only indirectly measure the effects of inflammation and cannot directly image T lymphocytes. This makes it challenging to further validate the contribution of these cells to human disease and to identify whether therapies meant to target these cells are effective in patients. There is a clear clinical need for new methods to image brain infiltrating T lymphocytes. We hypothesize that the radiotracer 18F-FAC will selectively accumulate in brain infiltrating T lymphocytes and that PET imaging with 18F-FAC can be used to quantify and visualize brain infiltrating T lymphocytes. We propose to test our hypothesis in a preclinical mouse model of experimental autoimmune encephalomyelitis (EAE). We envision that the successful completion of this proposal would provide important pilot data for testing this approach in patients. Successful implementation of this approach in the clinic could provide clinicians with a non-invasive method for quantifying brain infiltrating T lymphocytes in patients with neurological diseases and for monitoring treatments developed to suppress these T lymphocytes. We have significant preliminary data to support the feasibility of and our ability to accomplish the proposed studies. We propose to test our hypothesis through the following three Specific Aims:
Specific Aim 1. To quantify 18F-FAC brain accumulation across multiple time points during the induction and progression of EAE in a mouse model Specific Aim 2. To determine whether 18F-FAC PET can be used as a functional biomarker of immunosuppressant drug efficacy in the brains of EAE mice Specific Aim 3. To identify the leukocyte type that causes increased 18F-FAC accumulation in EAE mouse brains using autoradiography, immunohistochemistry, in vivo blocking, and ex vivo accumulation assays
Brain infiltrating T lymphocytes represent an important pathology in a variety of neurological conditions, including multiple sclerosis and autoimmune encephalomyelitis. Despite the importance of brain infiltrating T lymphocytes as causal agents and potential therapeutic targets in these diseases, there remains no non-invasive method for visualizing and quantifying these cells in vivo in patients. Here we propose to test whether PET imaging could be used to image brain infiltrating T lymphocytes in a mouse model of experimental autoimmune encephalomyelitis.
