Injectable scaffolds for early detection of immune dysregulation and monitoring response to immunotherapies

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Abstract

Undesired immune responses are central to many chronic diseases, with these immune responses either responsible for disease and its progression (e.g., cancer) or limiting therapies (e.g., transplant rejection). However, a significant challenge with these chronic diseases is that they develop over time and often go undetected until the disease has reached a substantial burden such as tissue or organ failure, after which therapeutic efficacy is limited. We propose a living sentinel based on an injectable material for i) monitoring of the immune system to identify disease at the earliest stages and ii) monitoring of the response to immunotherapy. Type 1 diabetes mellitus (T1D) will be used as a model system, as patients, typically children and young adults, present acutely ill due to symptoms of hyperglycemia (polydipsia, polyuria, nocturia, and weight loss) or diabetic ketoacidosis, which occurs because of destruction of the insulin-producing -cells of the pancreatic islets. The system is based on employing an injectable scaffold that functions as an “immunological niche" (IN) to which immune cells home and contains many of the cell types found in the diseased tissue during progression, including neutrophils, inflammatory monocytes, macrophages, B, and T cells. INs have been used to monitor these cell populations during disease progression in cancer, and herein we are proposing to develop them for T1D. We propose that the IN can be used for longitudinal surveillance of systemic immune responses and can monitor for the initiation of diabetes and the response to immunotherapy. Teplizumab has emerged as an immunotherapy with the potential to delay T1D onset if applied at the appropriate time, and emerging immunotherapies such as those by the industry partner Cour Pharmaceutical can transform diabetes treatment. The proposed studies are captured in the following aims. Aim 1 will develop the design parameters for an injectable IN to non-invasively monitor alterations in immune responses in the onset of T1D. The injectable IN allows for easy delivery, as well as analysis of cells with a fine needle aspirate (FNA). We will analyze the gene expression dynamics at the IN, with comparison to the native pancreas, and will develop a gene expression signature from the IN to predict disease onset and progression. The IN will also be analyzed histologically comparison to the pancreas. Aim 2 will employ injectable INs modified with disease antigens to monitor response to immunotherapy and for surveillance of recurrence. INs are modified with disease antigens will enable the analysis of disease specific T cells. These studies will employ teplizumab and nanoparticles, that latter being developed for clinical trials in autoimmune disease. The assembled research team has expertise in biomaterials, T1D, and immunology that will contribute to the success of the project. This system offers the opportunity to treat autoimmune disease prior to tissue destruction and potentially avoid the lifelong mangament of disease that is often associated with severe macrovascular and microvascular complications (e.g., coronary artery disease, stroke, retinopathy, neuropathy, nephropathy).