2009 General Immune System Function, New Treatments
2016 B-Cells, New treatments, General Immune System Function
Can improving existing therapies that destroy B cells provide an effective new treatment for lupus?
The study and what it means to patients
“While B cells are considered a major disease-causing cell population in lupus, current therapies to destroy them have — surprisingly — not been any more effective in reducing symptoms than standard drugs used to treat lupus. We aim to identify why eliminating these cells is not effective, and use that information to develop a new, improved therapy with lasting benefits for lupus patients.”
One way lupus is triggered is when B cells go haywire and start producing autoantibodies. Although current therapies that deplete B-cells can eliminate them for six months or longer, a significant number of SLE patients show only temporary and limited improvement.
To improve the effectiveness of this treatment, which does not provide long-term beneficial therapeutic outcomes to many patients, our research aims to: 1) Better understand why many patients do not show greater improvements after B cell depletion, 2) Explain why the disease-causing B cells return after treatment and then use this explanation to, 3) Develop strategies to overcome the current treatment defects to create a novel, more effective treatment for lupus.
B-cell depletion therapy (BCDT) represents a rational approach to treat systemic lupus erythematosus (lupus). Surprisingly, clinical trials indicate that BCDT is not more effective than standard therapies. The mechanisms underlying this unsatisfactory outcome are not known. We propose to test the highly novel hypothesis that BCDT results in near complete loss of spleen marginal zone B cells, which leads to deterioration marginal zone macrophage (MZMs). The MZMs represent a follicular exclusion barrier against the entry of apoptotic blebs into the follicles. Loss of MZMs removes that barrier, converting the normally tolerogenic marginal zone microenvironment into an immunogenic microenvironment that drives the production of type I interferons. In Aim 1, we will determine if BCDT promotes the loss of apoptotic-cell phagocytic MZMs and induction of type I interferons in lupus mice. In Aim 2, we will determine if pharmacologic interventions that can preserve the tolerogenic marginal zone barrier will establish tolerogenic repopulation of B cells in lupus mice. In Aim 3, we will determine if signatures that are associated with marginal zone tolerance defects, which include diminished circulating marginal zone macrophages and elevated type I interferon, can serve as biomarkers for a poor BCDT response in lupus patients. The proposed work will set the stage for development of rational combination therapy for lupus that can be administered during “windows of opportunities” that will be defined in this proposal.
Deletion of lupus autoreactive cells using an anti-hDR5 antibody
In lupus, immune system cells are mistakenly activated, causing attack against otherwise healthy organs and tissues. Would selectively eliminating these activated cells help stop or slow the disease—without causing toxic effects and reducing overall immune system strength?
Dr. Hsu, an expert in using animal models of lupus, reports that activated cells commit suicide when the “TRA-8” antibody binds to “anti-human death receptor 5” (DR5). Few if any scientists have ever studied DR5 as a therapeutic target for accomplishing this—eliminating the specialized cells of the immune system (CD4 and B cells) that lead the charge against foreign pathogens and other invading micro-organisms.
Working with a specialized mouse model, Dr. Hsu and colleagues will test the effectiveness and safety of administering TRA-8 to reduce lupus-causing cells. If successful, she will launch her strategy for rapidly evaluating the approach in humans, through clinical trials.
In an accompanying commentary in JCI, Drs. Claudia Mauri and Madhvi Menon, University College London write that, “The results of this study provide important insight into factors that inhibit AC clearance and promote the development of systemic lupus erythematosus.”
J Clin Invest. 2015 Jul 1;125(7):2877-90. Epub 2015 Jun 22. Interferon-induced mechanosensing defects impede apoptotic cell clearance in lupus. Li H, Fu YX, Wu Q, Zhou Y, Crossman DK, Yang P, Li J, Luo B, Morel LM, Kabarowski JH, Yagita H, Ware CF, Hsu HC, Mountz JD.