(CLOSED) Immune Drivers of Autoimmune Disease (IDAD) (U01 Clinical Trial Not Allowed) (RFA-AI-22-012)

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 improve our understanding of the immunologic processes and events that drive not only the course of autoimmune disease but also the preclinical phase and the transition from subclinical autoimmunity to diagnosed autoimmune disease. A secondary objective is to establish innovative approaches that will facilitate further studies by enhancing feasibility of large-scale studies and reducing both financial costs and the burden to subjects.

Research Objectives and Scope:

The objective of the IDAD program is to improve our mechanistic understanding of the immunologic processes underlying the initiation, progression, and clinical course of autoimmune diseases in humans. Research projects proposed in response to this FOA should test hypotheses related to this objective and must adhere to the following parameters:

• All studies must be performed using human subjects and/or materials
• Some portion of the project must involve subjects at elevated risk of developing one or more autoimmune diseases (i.e., at greater risk than healthy subjects from the general population)
• Studies may also involve subjects already diagnosed with autoimmune disease
• Studies may focus on the development of additional autoimmune disease(s) in subjects previously diagnosed with an autoimmune disease

Although these studies should be designed to be self-standing, collaboration among members of the research group will be encouraged. Areas of interest include, but are not limited to:

• Mechanisms by which genetic variants influence the course, progression, or clinical features of one or more autoimmune diseases;
• Biomarkers for flare, remission, or progression of autoimmune disease;
• Evolution and regulation of immune responses during disease progression or flare;
• Refinement of molecular-level markers of autoimmune diseases into mechanistic understanding of cellular and/or humoral immune dysfunction in those diseases;
• Elucidation of immunologically distinct endotypes within autoimmune diseases;
• Mechanisms by which environmental or microbial influences modulate immune responses to result in flare, remission, or progression of disease;
• Improving the ability to define relative risks for development of autoimmune disease among clinically healthy individuals or among individuals already diagnosed with one autoimmune disease;
• Analyses of pre-existing specimens to determine the nature of molecular profiles or other biomarkers that are likely to be both obtainable and informative in terms of predicting the ultimate course of human autoimmunity.

Applicants are highly encouraged to incorporate and test novel approaches or combinations of approaches that hold promise to reduce the cost and clinical burden of longitudinal cohort studies. These approaches include, but are not limited to:

• Determining the relative advantages of using peripheral blood and other biospecimens for obtaining immunologically valuable data;
• Devices, approaches, and techniques for long-term, low-cost, non-invasive or minimally invasive monitoring of subjects for the onset of autoimmune disease;
• Devices, approaches, and techniques for procuring frequent biospecimens from subjects in a manner that minimizes burden to subjects and financial costs (e.g., at-home self-sampling);
• Analytic approaches that will enable extraction from small biospecimens of immunologic data pertinent to understanding the immunologic events that drive clinically relevant changes in autoimmune disease;
• Comparisons of bulk or single-cell RNA sequencing, measurement of soluble mediators, cellular phenotypic analysis, or a combination of approaches as the optimal readout for a prospective observational study of the preclinical phase of human autoimmune disease.

Applications proposing any of the following will be deemed non-responsive and will not be reviewed:

• Clinical trials; however clinical research using specimens obtained from human subjects in clinical trials funded through other mechanisms is allowed
• Projects focused on primary immune deficiency/inborn errors of immunity, autoinflammatory diseases or syndromes
• Projects focused on cancer
• Studies of autoimmune disease arising after immune checkpoint inhibitor therapy or other clinical interventions
• Projects focused on HIV/AIDS/SIV
• Studies employing animal models
• Genome-wide association studies
• Projects that do not focus on autoimmune disease in humans.