Proteomic analysis of hydroxychloroquine prevention trials in T1D, RA and SLE

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Principal Investigator: Jane Hoyt Buckner
Organization: BENAROYA RESEARCH INST AT VIRGINIA MASON
Fiscal Year: 2024
Award: $365,178
Funding agency: National Institute of Allergy and Infectious Diseases

SUMMARY
This is a request for an Administrative Supplement for the Immune Drivers of Autoimmune Disease (IDAD)
project U01 AI176320 “T cells promoting transitions toward autoimmunity”. The proposed studies for the
Administrative Supplement are within the scope of the active parent grant, focused on understanding the immune
mechanisms underlying the transition from sub-clinical autoimmunity to autoimmune disease. Our objective in
this administrative supplement is to test the hypothesis that the transition from high-risk autoantibody positivity
to clinical disease will have shared features across these diseases. The proposed studies will leverage existing
longitudinal serum samples from three clinical trials evaluating the ability of hydroxychloroquine (HCQ) to prevent
progression from sub-clinical autoimmunity with the presence of autoantibodies to clinical diagnosis of
autoimmune disease. The three clinical trials are: the TN22 trial focused on prevention of type 1 diabetes (T1D);
the SMILE trial focused on prevention of systemic lupus erythematosus (SLE); and the StopRA trial focused on
prevention of rheumatoid arthritis (RA). The proposed studies will profile the serum proteome in individuals from
these trials using the Olink Explore HT platform to measure 5400 serum proteins. We will select samples from
baseline, 6 months, and samples drawn near disease transitions when available. The samples will be run at
OMRF leveraging their expertise with Olink and ensuring that the same platform is used for all samples. For data
analysis, we will compare placebo versus HCQ within each trial but also compare across trials to identify both
disease-specific biomarkers and biomarkers present in all three diseases. We will use approaches that support
integration of these datasets with other datasets that have already been generated for each of these trials.
Specific Aim 1 will assess the change in serum protein expression from baseline to 6 months on HCQ using
samples from the treatment arm of each trial. Specific Aim 2 will assess the change in serum protein expression
at baseline, prior to disease transition and after transition selecting samples from individuals in the placebo group
who progress to clinical disease. Specific Aim 3 will compare serum protein expression between patient types at
baseline and upon disease transition. The proposed project brings together IDAD researchers at BRI, UT
Southwestern and OMRF and will include additional research groups in the field including UC Denver. It also
expands the IDAD disease focus to include individuals at risk for rheumatoid arthritis.

Terms: <Administrative Supplement><Atrophic Arthritis><Autoantibodies><Autoimmune Diseases><Autoimmune Status><Autoimmunity><Biological Markers><Blood Serum><Brittle Diabetes Mellitus><Clinical><Clinical Trials><Data Analyses><Data Analysis><Data Set><Disease><Disorder><Ensure><Hydroxychlorochin><Hydroxychloroquine><IDDM><Immune><Immunes><Individual><Insulin-Dependent Diabetes Mellitus><Investigators><Juvenile-Onset Diabetes Mellitus><Ketosis-Prone Diabetes Mellitus><Lupus Erythematosus Disseminatus><Measures><Oxychlorochin><Oxychloroquine><Patients><Placebos><Prevention><Prevention trial><Proteome><Proteomics><Public Health><Research><Research Personnel><Researchers><Rheumatoid Arthritis><Risk><Running><SLE><Sampling><Serum><Serum Proteins><Sham Treatment><Sudden-Onset Diabetes Mellitus><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><T-Cells><T-Lymphocyte><T1 DM><T1 diabetes><T1D><T1DM><Testing><Type 1 Diabetes Mellitus><Type 1 diabetes><Type I Diabetes Mellitus><autoimmune antibody><autoimmune condition><autoimmune disorder><autoimmunity disease><autoreactive antibody><bio-markers><biologic marker><biomarker><clinical diagnosis><data integration><data interpretation><disseminated lupus erythematosus><high risk><insulin dependent diabetes><insulin dependent type 1><intervention arm><juvenile diabetes><juvenile diabetes mellitus><ketosis prone diabetes><parent grant><placebo group><prevent><preventing><protein expression><rheumatic arthritis><self reactive antibody><sham group><sham therapy><specific biomarkers><systemic lupus erythematosis><thymus derived lymphocyte><treatment arm><type I diabetes><type one diabetes>