Firdaus Dhabhar - US grants

The overall goal of these studies is to elucidate the mechanisms mediating the recent finding that under certain conditions stress can enhance skin immunity. We initially reported that acute of short-duration stress induces a redistribution of immune cells from the blood to organs such as the skin. Since the skin is the body's first line of defense, we examined the functional consequences of this leukocyte trafficking using the delayed type hypersensitivity (DTH) response as an in vivo assay for skin cell mediated immunity. Studies showed that acute stress experienced immediately before primary ( sensitization phase) or secondary (challenge phase) antigen exposure significantly enhanced skin DTH. In contrast, chronic stress suppressed skin DTH. In agreement with these studies, several investigators have reported stress-induced enhancement of DTH to different antigens administered to different sites of sensitization and challenge. The long- term objective of our research program is to elucidate the neuroendocrine and immune mediators and health consequences of the bi-directional effects of acute versus chronic stress on immune function. The overall goal of the proposed studies is to elucidate the mechanisms mediating the effects of acute stress on leukocyte trafficking and skin immunity. These studies will use wild type and gene knockout mice, immunoneutralization, flow cytometry, immunohistochemistry, in situ hybridization, RT-PCR, and ELISA to conduct analyses at the level of the organism, cell, protein, and gene expression. Three specific aims will be addressed: 1)Identify cell adhesion molecules that mediate the stress-induced redistribution of leukocytes. 2) Identify leukocyte subpopulations that mediate a stress-induced enhancement of the sensitization and challenge phases of DTH. 3) Identify chemokines and cytokines that mediate a stress-induced enhancement of both phases of DTH. These studies are important because stress is suspected to play a role in the etiology of many diseases and we propose to study the effects of stress on two important immune parameters: Leukocyte trafficking, which is crucial for the surveillance and effector functions of the immune system. And DTH, which mediates aspects of immunoprotection (e.g. resistance to infections and cancer and post-vaccination immunity) and immunopathology (e.g. autoimmune, dermatitis, and granulomatous disorders). It is hoped that the elucidation of mechanisms such as those proposed here will facilitate the development of biomedical treatments designed to harness and individual's physiology to selectively enhance (during surgery, wound healing, infections, or cancer) or suppress (during autoimmune or inflammatory disorders) an immune response depending on the clinical needs to the patient.

DESCRIPTION (provided by applicant): The primary goal of the studies proposed here is to examine the effects of acute (skin immunoenhancing) versus chronic (skin immunosuppressive) stress on the emergence, progression or regression of skin cancer. We will use a murine model of ultraviolet B radiation (UVB) induced squamous cell carcinoma (SCC). SCCs afflict over 200,000 Americans per year and cause approximately 2,000 deaths per year. An examination of the effects of stress on SCC is warranted given the rising incidence of skin cancer and the ubiquitous nature of psychological stress. However, no study has examined the relationship between stress and SCC. Five key findings support such an examination: First, acute stress has been shown to enhance skin cell mediated immunity (CMI). A stress-induced trafficking of leukocytes to the skin, and increased pro-inflammatory and Th1 cytokines mediate this immunoenhancement. Second, in contrast to acute stress, chronic stress significantly suppresses skin CMI by decreasing leukocyte mobilization and T cell numbers. Importantly. SCCs are antigenic tumors that are eliminated by anti-tumor T cell immunity and hence may be affected by stressors that modulate CMI. Third, preliminary results suggest that acute stress suppresses the emergence of UVB induced SCC. Acute stress induced trafficking of T cells to skin may mediate this effect. Fourth, preliminary data show that chronic stress increases the emergence & progression of UVB induced SCC. Suppression of IFN-y production and inhibition of tumor infiltration by T cells may mediate susceptibility. Fifth, preliminary data show that baseline anxiety status predicts susceptibility to SCC. In light of these findings, we propose experiments that will accomplish the following specific aims: Aim 1: Elucidate mechanisms by which acute or chronic stress affect tumor emergence, progression or regression following repeated UVB exposure. Aim 2: Elucidate the effects of acute vs. chronic stress on DNA damage & inflammation following single UVB exposure. Aim 3: Determine whether specific phases of UV induced pathology are accompanied by dysregulation of the circadian corticosterone rhythm (such dysregulation increases mortality in cancer patients) and identify potential cytokine mediators of dysregulation. Aim 4: Determine whether differences in anxiety-related behavior can predict susceptibility to SCC and identify potential biological mediators. Our overarching hypothesis is that acute stress may enhance resistance to SCC through increased Th1 cyotkine action & leukocyte infiltration into SCC and sentinel lymph nodes, while chronic stress will increase susceptibility by suppressing leukocyte infiltration and altering the Th2-Th2 balance in favor of Th2 cytokines within and around SCC and in sentinel lymph nodes. These findings are likely to be generalizable to other cancers that are naturally antigenic or induced to be antigenic via tumor immunotherapy. The knowledge gained from these studies may lead to development of clinical treatments using behavioral and/or pharmacological manipulations to enhance endogenous anti-tumor responses or counter factors that favor tumor progression. These studies are important in light of increasing morbidity and mortality associated with skin cancer, the ubiquitous nature of stress, and our preliminary findings on the effects of stress on SCC.

DESCRIPTION (provided by applicant): This R13 meeting proposal requests support to continue an annual training and mentoring program for 25 pre- and post-doctoral trainees at the 2010 meeting of the PsychoNeuroImmunology Research Society (PNIRS) to be held at Trinity College, Dublin, Ireland, June 2-5, 2010. Opportunities for advanced, interdisciplinary training of younger scientists interested in the basic science aspects of behavioral and neuroimmune interactions and their translational relevance for disease prevention and treatment are often limited at the university level. Since 1999, the PNIRS conference has received NIH support to provide formal didactic instruction and constructive career guidance for over 200 fellows. The primary goal is to create pedagogical opportunities and offer supportive mentoring at this formative stage in the trainee's career in order to enhance their research potential and trajectory for success. Psychoneuroimmunology (PNI)-related research has shown that psychological factors and life style can impact immune competence and influence disease susceptibility and progression. In addition to the relevance for infectious illness and autoimmunity, the findings are germane to cancer and help to account for variations in cancer morbidity and mortality as well as quality of life. PNI also offers unique assessment strategies and outcome measures for evaluating the efficacy of nontraditional and complementary medicine approaches. Based on an enriched understanding of brain-immune interactions, PNI has also provided novel insights into the potential contributions of the immune system to neuropsychiatric disorders, mental health, and aging. The PNIRS is the primary professional organization representing the many diverse scientific disciplines involved in these types of inquiry. The Society has approximately 300 regular members, including 40% at the early career stage. A Trainee Scholars Advisory Committee oversees the Society's commitment to the mentoring program and ensures its quality. The committee is comprised of Society officers and meeting organizers, and benefits from at least 10 Senior Faculty Mentors who volunteer to participate in the training colloquium each year. Selection of the 25 Trainee Scholars (including 5 Diversity Trainees) is based on an open competition, and is determined by evaluation of a submitted abstract, research excellence and career promise. The impact of this program has been amply documented by the productivity of former awardees and their success in obtaining tenure-track faculty positions. A testament to the success of trainee program is the fact that the applicant of this R13 grant (Dr. Firdaus Dhabhar, Stanford University) and the local organizer of the 2010 meeting in Dublin (Dr. Thomas Connor, Trinity College Dublin) are both previous recipients of trainee awards. In addition to the exposure to cutting edge science, plenary lectures, and symposia offered by leading scientists, the trainees participate in an Educational Short Course, a mentoring colloquium with Senior Faculty, and two workshops with Junior Faculty and NIH program staff, who provide advice on career building, grant writing and funding opportunities. There are also luncheon roundtable discussions and a trainee dinner to nurture the establishment of enduring, collaborative and professional relationships. This training and mentoring program is congruent with a primary aim of the NIH roadmap, which is to ensure the successful creation and productivity of the future scientific workforce of the United States.