Numerous environmental and iatrogenic pro-oxidative stressors ranging from chemotherapy to ultravioletradiation have been demonstrated to induce immunosuppression in preclinical murine models. Thesestressors have also been shown to be potent inducers of the lipid mediator platelet-activating factor (PAF),which exerts immunosuppressive effects in murine models. Ours and other groups have characterized theexact pathways by which PAF-dependent immunosuppression occurs and have identified a major role ofregulatory T cells (Treg). PAF released from injury acts upon the mast cell PAF receptor resulting in theformation of immunosuppressive Tregs. This process is dependent upon the cytokine IL-10 andcyclooxygenase-2 (COX-2) generated prostaglandins. Though high levels of PAF has been shown to begenerated in humans in response to many of the immunosuppressive stressors that induce PAF in animalmodels, studies are needed to define if this PAF?COX-2?Treg pathway is functional in humans. This revisedR21 application is designed to take advantage of our group?s recent findings that topical photodynamic therapy(PDT) is a very potent inducer of PAF in murine skin, and induces systemic immunosuppression only in miceexpressing PAF receptors. PDT is a very common procedure in dermatology which has been shown to exertimmunosuppressive effects in humans. This provides the rationale to test if the PAF?COX-2?Treg pathwayis involved in PDT-induced effects and could be pharmacologically modulated with COX-2 inhibitors to blockthe immunosuppression and potentially improve PDT efficacy in treating precancerous actinic keratoseslesions. We will test if standard PDT performed in dermatology clinics generates: 1) PAF and related oxidizedglycerophosphocholines in skin; 2) systemic isoprostanes in response to reactive oxygen species; and 3)systemic COX-produced prostaglandins. We will also characterize the immunosuppressive effects of PDT inhumans by both skin testing, and assaying Tregs and T cell responses against established and neo-antigens.The ability of short-term post-PDT treatment with the COX-2 inhibitor celecoxib to modulate PDT-mediatedimmunosuppression and clinical effectiveness will also be defined. These translational studies will thus defineif a previously unappreciated immunomodulatory pathway is engaged following PDT which can be exploited toenhance treatment outcomes. If successful, these studies will change the standard of care for how PDT isadministered.
|Effective start/end date||7/1/16 → 3/31/18|
- National Institutes of Health: $195,360.00