?Systemic lupus erythematosus (SLE) is a chronic multisystem autoimmune disease with poorly understood etiology and pathogenesis and for which adequate treatment options are limited. Although dysregulated production of autoantibodies and immune complex deposition are considered hallmarks of SLE, considerable evidence supports the hypothesis that auto reactive lymphocytes are implicated in disease. SLE patients have several T cell defects including aberrant signaling, suboptimal IL-2 production, lower regulatory T cell frequencies, high CD4-/CD8- Th17 T cells, and sustained abnormally high intracellular calcium. Effector memory T cells (TEMs) decrease in circulation and increase in the kidneys and urine of lupus nephritis patients, suggesting that renal infiltration of this T ell subtype contributes to disease. Activation and inflammatory cytokine production by effector memory T cells requires expression of Kv1.3, a potassium channel needed for sustained intracellular calcium levels in effector memory T cells that have been found to be autoreactive and pathogenic in several autoimmune diseases. Here we propose to evaluate the levels of expression of Kv1.3 in SLE T cells in peripheral blood of inactive and active SLE patients compared to normal healthy controls, and test the functional effect of blocking the Kv1.3 channels in these cells with Kineta's drug candidate Kv1.3 specific peptide blocker ShK-186 (dalazatide) in terms of calcium flux and cytokine production ex vivo. In addition, we will evaluate Kv1.3 expression in kidney biopsies from patients with lupus nephritis and correlate expression to disease activity. This study will inform our hypothesis that Kv1.3 expressing T cells are pathogenic in SLE and may support considering evaluation of ShK- 186 in SLE patient populations in clinical trials.
Public Health Relevance Statement: Public Health Relevance: Lupus is an autoimmune disease that predominantly affects females early in life. There is no cure, and the uncontrolled inflammation of lupus can cause life-threatening organ failure, requiring chronic and intensive therapy. Current therapies suppressing the immune system leave the patient open to severe side effects, including infection and malignancy. The proposed study will identify whether a protein channel required for the activation of immune cells that mount responses against self (autoimmunity) is expressed in cells in the kidney of lupus nephritis patients and will also test a novel therapeutic agent targeting this protein to evaluate if it can block the autoreactive inflammatory nature of these cells. The results could have implications for the prevention and treatment of lupus, as well as other autoimmune diseases.
Project Terms: Adverse effects; Affect; Animal Model; Antibodies; Antigen-Antibody Complex; Atopic Dermatitis; Atypical lymphocyte; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; autoreactive T cell; base; Biological Assay; Biopsy; Blood Circulation; Blood specimen; Calcium; CD28 gene; CD3 Antigens; CD8B1 gene; Cells; chemokine; Chronic; Clinical Trials; Complication; cytokine; Data; Defect; Dependence; Deposition; Disease; drug candidate; Etiology; Evaluation; Female; Flow Cytometry; Frequencies; Generic Drugs; Glomerulonephritis; Goals; Human; Immune Cell Activation; Immune response; Immune system; Immunohistochemistry; Infection; Infiltration; Inflammation; Inflammatory; inhibitor/antagonist; Interleukin-2; Intestines; Ion Channel; Ionophores; Kidney; Left; Life; Lupus; Lupus Nephritis; macrophage; Malignant Neoplasms; Measurement; Mononuclear; Names; Nature; novel; novel therapeutics; Organ; Organ failure; Pathogenesis; patient population; Patients; Pattern; pediatric lupus; Peptides; peripheral blood; Peripheral Blood Mononuclear Cell; Personal Communication; Play; Potassium Channel; pre-clinical; Prevention; Production; Proteins; Protocols documentation; Psoriasis; Psoriatic Arthritis; public health relevance; Regulatory T-Lymphocyte; release of sequestered calcium ion into cytoplasm; response; Role; Signal Transduction; Staining method; Stains; Systemic Lupus Erythematosus; T memory cell; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; targeted biomarker; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Urine
