The intersection of immunity and cardiovascular diseases

Vanderbilt University Medical Center, Nashville TN

Investigators

Abstract

PROJECT SUMMARY The overall goal of the Intersection of Immunity and Cardiovascular Disease (IICD) Program Project Grant is to understand how immune cells are activated and contribute to target organ damage in hypertension and autoimmune diseases. Our overarching hypothesis is that activated immune cells promote renal and vascular dysfunction and damage, promoting vascular and renal disease, blood pressure elevation and worsened autoimmunity. Robust experimental and clinical data indicate that Isolevuglandins (IsoLGs) formed in these conditions alter enzyme and transcription factor function and form antigens that stimulate T cell activation and autoantibody formation. Project 1 director Dr. Harrison has identified specific peptide antigens, and characteristics of class 1 human leukocyte antigens (HLAs) that present these antigens. He will identify T cells and T cell receptors common to experimental hypertension, SLE and psoriasis. The ability of HLAs to present IsoLG-adducted peptides will be evaluated and an unbiased assay will be employed to discover peptides that can activate T cells in human hypertension. In project 2 Dr. Annet Kirabo’s team will examine how salt stimulates IsoLG formation in human salt sensitivity and in the hypertension associated with SLE. She will characterize salt sensitivity using a well-accepted inpatient protocol, and then randomize subjects to a trial of 2-hydroxybenzamine (2-HOBA) for 4 weeks to determine if this improves salt sensitivity and vascular function in these subjects. Dr. Kirabo has developed an innovative animal model involving adoptive transfer of peripheral blood mononuclear cells from humans with SLE to immunodeficient mice, which leads to blood pressure elevations and albuminuria. Preliminary data indicate that salt feeding exacerbates disease in this model, and she will determine if scavenging IsoLGs is protective in these animals and in humans with salt sensitivity. Dr. Michelle Ormseth, the director of Project 3, will conduct a 20-week randomized, placebo-controlled, double-blind, cross-over proof-of- concept phase II study to determine the effect of scavenging IsoLGs with 2-HOBA in humans with SLE. Our early-stage investigator (ESI) and director of Project 4, Dr. Matthew Alexander, has found a marked renal accumulation of granulocytes in a mouse model of psoriasis that is associated with increased cutaneous IL-17A, renal damage and blood pressure elevation. He will define the role of interleukin 17A, IsoLG formation and granulocytes in the hypertension and renal disease observed in these animals using tools employed by other IICD investigators. A major goal of the IICD is to ensure success of our ESI, and we have created a mentoring plan and set aside funding that will enhance his scientific development. The IICD PPG will be supported by an administrative core (Core A), which will also provide biostatistical guidance for all projects, and an Analytical and Biochemical core (Core B) that will provide essential assays and reagents for all projects. Overall, this IICD PPG will provide new understanding of the molecular mechanisms of inflammation in hypertension and autoimmune conditions and identify new therapeutic targets to reduce morbidity and mortality in these devastating illnesses.