The adaptive immune system is critical in the response to viral, bacterial and parasitic infections. While it can perform this essential protectie function, it also causes disease. Examples of this include autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS), where an immune response is inappropriately generated against self. In addition, unwanted immune responses during organ rejection, graft versus host disease (GVHD) and allergies are major clinical problems. What all of these diseases have in common is that T cells must become activated, proliferate and perform their effector functions for pathology to occur. Although drugs are used in the clinic to treat autoimmune syndromes or prevent organ rejection, they have deleterious side effects including hypertension, hyperlipidemia, increased herpesvirus infection, and renal nephropathy. Thus there is a pressing medical need to develop more effective and safer therapeutics to suppress T cells in a multitude of human diseases. While we desperately need new treatments, developing small molecule drugs is a long and costly endeavor. In the United States the average cost is between 500 million to 2 billion USD over 10 to 15 years. Yet most drugs will fail in development typically due to toxicity effects in humans. Instead of developing new drugs, an emerging alternative is to repurpose FDA-approved drugs for new purposes. As we document in the preliminary studies section, we have harnessed the power of """"""""repurposing"""""""" and determined that adapalene, flubendazole, fluspirilene, and oxibendazole inhibit murine T cell proliferation and cytokine production from healthy and MRL-lpr/lpr mice. We hypothesize that these compounds will inhibit the activation, proliferation and cytokine production of human T cells and have efficacy in a preclinical model of systemic lupus erythematosus (SLE).
Specific Aim 1 will determine if adapalene, flubendazole, fluspirilene, and oxibendazole inhibit the activation, proliferation and cytokine production of human CD4+ and CD8+ T cells. In this aim we will isolate CD4+ and CD8+ T cells from the blood of healthy donors and determine whether our compounds can inhibit their activation and proliferation. We will generate polarized Th1, Th2, Th17, Tc1, and Tc2 effector cells in vitro from each donor and determine whether the production of cytokines can be inhibited by our compounds.
Specific Aim 2 will determine if adapalene, flubendazole, fluspirilene, and oxibendazole can prevent autoimmune disease in the MRL-lpr/lpr mouse model. In this aim we will determine the efficacy of these compounds in the prevention of autoimmune disease in vivo using the MRL-lpr/lpr model. At the conclusion of these studies we will have determined which of our compounds are able to inhibit the activation, proliferation and cytokine production of human T cells. Furthermore, we will have determined which compounds are capable of preventing autoimmune disease in a murine model. This will put us in a strong position to begin clinical testing of these compounds for use in multiple immunologic diseases including allergies, transplantation and SLE.
|McIver, Zachariah A; Kryman, Mark W; Choi, Young et al. (2016) Selective photodepletion of malignant T cells in extracorporeal photopheresis with selenorhodamine photosensitizers. Bioorg Med Chem 24:3918-3931|