NIH – Immune Drivers of Autoimmune Disease (IDAD) (U01 Clinical Trial Not Allowed)

March 4, 2022 by dld5dt@virginia.edu

Purpose:

This Funding Opportunity Announcement (FOA) invites applications to participate in the Immune Drivers of Autoimmune Disease (IDAD) cooperative research program, which will focus on defining the immunologic states and dynamics that drive autoimmune disease. The main objective of this program is to enhance our understanding of the immunologic processes, events, and changes that underlie the clinical manifestations of autoimmune diseases, including disease flare, remission, and progression of established disease, as well as the progression from a state of elevated risk to clinical diagnosis of autoimmune disease.

Background:

While our general understanding of immunology and the mechanisms of many immune-mediated conditions has significantly expanded in recent years, efforts to decipher the underlying mechanisms of autoimmune diseases continue to face distinct challenges. In many diseases the identity of the relevant autoantigens is not certain, and both clinical manifestations and responses to immunomodulatory therapies can vary widely among patients with a given disease. In addition, autoimmune disease in humans is typically characterized by a latent phase between the initial autoimmune activity and the onset of clinical disease, and by an unpredictable course in terms of flare, remission, and progression of disease. Although genome-wide association studies have implicated numerous immune-related genetic loci in various autoimmune diseases and thereby bolstered the hypothesis that immune system activity is driving these diseases, elucidation of the mechanistic details underlying onset, flare, remission, and progression of disease remains a major challenge.

Even though significant gaps remain, progress has been made in understanding immune mechanisms of autoimmune disease. Notable examples of success in defining serological markers of disease progression include studies of systemic lupus erythematosus and rheumatoid arthritis using the Department of Defense (DoD) Serum Repository, and the Diabetes Autoimmunity Study in the Young (DAISY) study of children at genetic risk for development of type 1 diabetes, supported by the National Institute of Diabetes and Digestive and Kidney Diseases. While it remains unclear what some of the serological markers defined in these studies signify in terms of immunopathologic mechanisms, the utility of these markers provides a useful foundation upon which further studies can be based. More recently, the use of gene expression profiling based on peripheral blood samples has yielded provocative suggestions that both systemic lupus erythematosus and Sjogren’s syndrome can be subdivided into distinct molecular endotypes, though again the relationship of these molecular markers to immune mechanisms remains unclear. While molecular markers may eventually provide insights into cellular-level immune functions that drive or modulate the course of autoimmune disease, the role of the cellular component of the autoimmune response in driving disease remains a significant knowledge gap. It also remains to be determined why many autoimmune diseases present a cyclic pattern of flare and remission and how this is driven by immune activity. Therefore, the primary scientific effort of this FOA seeks to address these knowledge gaps by fostering further development of our understanding of the immunologic states and events that drive the progression and clinical course of autoimmune diseases.

Our current understanding of the preclinical period of human autoimmune diseases indicates prolonged autoimmune activity in the years prior to diagnosis, suggesting that molecular signatures such as those that have been characterized in several autoimmune diseases also may be detectable in the preclinical phase. Definition of these signatures or other prognostic markers would be of enormous scientific and clinical benefit, but a number of obstacles stand in the way of observational cohort studies that could accomplish this goal. For example, these studies would require thousands of subjects, frequent sampling, and continuous monitoring for the onset of disease, and methods for performing these tasks at low cost, ideally without the need for clinic visits, remain largely underdeveloped. In addition, the nature of the signal that might be observed in a large cohort study remains to be determined. Recent advances in scRNAseq, CITE-seq and similar technologies have vastly increased the potential information yield from small biospecimens, suggesting potential approaches to elucidating the immunology of the pre-clinical period, but the best means for applying these advances to small samples from large cohorts remains to be determined. Some recent studies in human autoimmune disease (https://www.nejm.org/doi/full/10.1056/NEJMoa2004114) have been designed to take advantage of new devices and approaches that allow self-sampling and self-monitoring by research subjects, thereby obviating the need for expensive and burdensome clinic visits, but extension of these approaches to large studies and single-cell readouts remains a challenge. This FOA will therefore place an emphasis on the use of novel approaches and techniques to probe immune status in autoimmune disease patients and/or those at elevated risk of developing autoimmune disease, with the goal of increasing the feasibility and informational yield of future large-scale studies designed to increase our understanding of how the immune system drives autoimmune diseases in the pre-clinical stage.

Key Dates:

Open Date (Earliest Submission Date): June 01, 2022
Letter of Intent Due Date(s): 30 days prior to the application due date
Applications Due: July 01, 2022

URL for more information:

https://grants.nih.gov/grants/guide/rfa-files/RFA-AI-22-012.html

Filed Under: Funding Opportunities