Allergic diseases occur when an immune response is mounted against a seemingly innocuous environmental agent. The prevalence of these diseases has steadily increased within industrialized countries over the last 50 years. To date there are no therapeutics that effectively cure these diseases. The immune response that occurs to allergens is a type 2 (Th2) response, characterized by the physiologic and immunologic response to the cytokines interleukin (IL) 4, IL-5, and IL-13. Mounting evidence suggests that drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX) enzymes acting in the arachidonic acid (AA) metabolism pathway, may contribute toward the growing allergy epidemic. Excitingly, our laboratory has shown in recent years that prostaglandin I2 (PGI2), a lipid product formed from AA metabolism, restrains Th2 immune responses. We have demonstrated that PGI2 acts to directly inhibit the functionality of both dendritic cells and CD4+ Th1 and Th2 cells. However, its impact on the functionality of T regulatory (Treg) cells is unknown. Treg are a subtype of T cells that are important for suppression/resolution of immune responses. I have preliminary data which suggests that PGI2 promotes the function of Treg; Treg isolated from mice deficient in the receptor for PGI2, IP (IP KO), are less able to suppress effector T cell proliferation than wild- type (WT) Treg in vitro and in vivo. Additionally, I have shown that IP KO Treg express less of the canonical transcription factor, forkhead box p3 (Foxp3) compared to WT Treg and IP KO nave T cells are unable to differentiate into Treg in culture as well as WT nave T cells. Moreover, I have shown that the PGI2 analog cicaprost is able to promote WT Treg production of IL-10. Importantly, Treg are also present in the lungs during Th2 immune responses and impaired development of Foxp3+ Treg has been linked to the development of allergies. Furthermore, Chen et al. recently described the contribution of dysfunctional and reprogrammed pathogenic Treg to allergic disease. Thus, these recent studies and my preliminary data lead me to hypothesize that PGI2 promotes Treg stabilization and functionality, and prevents their conversion to pathogenic Treg that produce Th2 cytokines during allergic disease. The experiments described in this proposal are paradigm-shifting in that there are no FDA approved pharmacologic agents which promote Treg function and our preliminary data suggests that PGI2 may be the first. Furthermore, the proposed studies are clinically relevant in that PGI2 may be a therapeutic for inflammatory diseases, such as asthma, which occur as a result of aberrant inflammatory responses. Finally, these proposed studies will advance the field by generating a more thorough understanding of how a prostaglandin regulates Treg function in allergic disease.
The prevalence of allergic diseases has been steadily increasing in developed countries in recent years. Dysfunctional T regulatory cells have been shown to contribute to allergic disease pathogenesis. Our studies aim to determine if PGI2 promotes T regulatory cell function in models of allergy, thereby identifying PGI2 as a potential therapeutic for the treatment of allergic inflammation.