Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects a staggering 1 out of 1,000 individuals, 90% of which are women. Unfortunately, treatment options for this debilitating disease remain limited. Most strategies involve overt immunosuppression which increases susceptibility to infection and often has off-target effects. Given the complex nature of this disease, developing effective therapeutic strategies is challenging, with new therapies emerging slowly and often times proving ineffective. Although SLE is largely thought of as an antibody-mediated disease, potentiation of the B cell response via interaction with CD4+ T helper cells is critical to autoantibody production. Central to this CD4+ T cell/B cell cooperation is their physical interaction at what has been termed the immune synapse, an area of concentrated signaling and interaction located at the point where the membranes of the CD4+ T cell and antigen presenting cell (APC) make physical contact. There are two main objectives for this R03 grant. The first is to test the hypothesis that specific inhibition of the immune synapse between T cells and APCs is a therapeutic option for SLE. The second is to develop new nanotechnology that may be used to study autoimmunity and accelerate development of future therapies for autoimmunity and other T cell-mediated diseases. This application proposes the novel approach to target the immune synapse between T and B cells to decrease autoimmune inflammation. This will be accomplished by using a newly discovered small molecule, eggmanone (Egm), which is predicted to disrupt the immune synapse between T cells and APCs. To specifically target CD4+ T cells, Egm will be loaded into polymer nanoparticles, or micelles, conjugated with the Fab fragment of a monoclonal antibody specific for CD4, a surface receptor known to be internalized upon ligation. Specific inhibition of activated CD4+ T cells will prevent T cell help to B cells and, ultimately, the production of autoantibodies that cause tissue damage and death in SLE. This research has high potential to identify an innovative therapy to specifically target CD4+ T cells in SLE. Future studies will use Egm to elucidate the molecular mechanisms involved in dysregulation of T cell activation and autoimmune inflammation.

Public Health Relevance

An autoimmune disease is characterized by the immune system attacking self-proteins, causing persistent inflammation and organ damage. Systemic lupus erythematosus (SLE) is one such autoimmune disease and those that suffer from SLE have increased risk for heart disease, kidney disease and arthritis. This proposal will test the hypothesis that inhibiting the ability of T cells to help the B cells make autoantibodies would prevent the damaging effects of this debilitating disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Research Grants (R03)
Project #
5R03AI124190-02
Application #
9406059
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Johnson, David R
Project Start
2017-01-01
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Rhoads, Jillian P; Major, Amy S; Rathmell, Jeffrey C (2017) Fine tuning of immunometabolism for the treatment of rheumatic diseases. Nat Rev Rheumatol 13:313-320