Jan A. Moynihan - US grants

The goal of the proposed research is to better understand the physiological consequences of stress or handling as these are reflected in alterations of different parameters of antibody and cell-I mediated immune responses to levels of antigenic stimulation that are more characteristic of the stimulation that occurs under natural conditions. To this end, we have proposed descriptive parametric studies to examine the development of secondary (memory) immune responses generated following low dose antigen priming in footshock stressed, handled, and control mice. We will also determine whether there are differential effects of stress on primary and secondary antibody responses in normal versus immunologically compromised (i.e., immunosuppressed) mice. Further studies, predicated on these data, will determine whether the animal's ability to predict or control the stressor alters its immunomodulatory effects and whether stress-induced changes in immunity can be conditioned. The effects of handling and footshock stress (and the degree to which the animal is capable of coping with stress) on the metastatic spread of the Line I tumor will also be studied in relation to the immunologic changes induced by these forms of stimulation. Using both in vitro and in vivo protocols, several possible mechanisms that might underlie the immunomodulatory effects of handling and footshock that have already been observed and that will be uncovered in the proposed studies will also be explored. Data from our proposed studies may be clinically relevant in situations where patients are immunosuppressive by human immunodeficiency disease (HIV) or receive immunosuppressive drugs as part of a chemotherapeutic protocol or in association with organ transplantation. These basic studies will also meet the defined need to characterize the range and parameters of immune function that are subject to the influence of environmental (e.g ., "stress") conditions and will enable a more focused approach to the neuroendocrine and immunologic mechanisms underlying the effects of stress on immunity.

Teacher/scientist partnerships will be developed between scientists from the University of Rochester School of Medicine and Dentistry and teachers from the Rochester City School District. These contacts will provide opportunities for teachers in grades 5-12 to develop programs within their individual schools, and will allow scientists to promote current outreach programs and develop additional programs. Partnerships with inner city schools will aim to increase the numbers of underrepresented minorities in the sciences. Science outreach programs, including a school-year mentoring program, and lecture series, as well as a summer program, will foster student's interest in science by allowing them to learn science through hands-on inquiry-based activities. A combination of structured and exploratory learning methods will be used. Curriculum development between teachers and scientists will aim to bring hands-on activities into the classrooms during the school year. The use of technology, including computers, the internet, and videos, will aid students in increasing their level of science literacy. Students will learn how to use current technology to gather information as well as to disseminate information that they have learned.

DESCRIPTION: A large literature unequivocally reveals that exposure of humans and experimental animals to psychological and physical stressors can be immunomodulatory. Very few studies, however, support the popular notion that this immunomodulation typically and causally relates to a clinically significant increase in the incidence and/or severity of infectious disease. We hypothesize that although the immune system in healthy individuals may be modulated by stressor exposure, the resulting changes in immune function may not be of sufficient magnitude or duration to render that individual clinically immunodeficient in terms of the ability to effectively combat opportunistic pathogens. Further, if the immune system is compromised either naturally or artificially (e.g., by immunosuppressive drug therapy), this lower "immune system set point" now puts the organism at a greater relative health risk when exposed to an immunomodulatory stressor. Many pharmacologically immunosuppressed transplant and other patients perceive significant levels of stress, and become ill with potentially lethal opportunistic viral infections. As for the fate of a transplant, however, we hypothesize that immunosuppression induced by stressors should interact with drug treatment to increase allograft survival. The overall goal of our proposed research is to understand the impact of a stressor in an organism whose immune response capacity has already been lowered by deliberate pharmacological immunosuppression. We are particularly interested in understanding whether stressors in mice subjected to immunosuppressive regimens can result in increased graft survival. We are also interested in determining if stress and drug-induced immunosuppression interact to adversely affect the number of, and/or recovery from, opportunistic infections. Initial studies will be performed with the broadly immunosuppressive reagent cyclophosphamide (CY) to test our hypothesis. Later studies will employ the targeted reagent cyclosporin A (CsA), to establish the principle or generality of the finding and to begin to determine mechanisms. The administration of a stressor to an immunocompromised animal will increase the magnitude of immunosuppression. In turn, this will result in prolonged allograft survival. In contrast, the immunocompromised animal will have poorer immune responses to an opportunistic pathogen (HSV-1).

DESCRIPTION (applicant's abstract): The sense of smell is highly developed in rodents, and odors provide a critical set of stimuli that are necessary for reproduction, neuroendocrine responses and recognition of conspecifics, predators, and prey. We have shown that olfactory cues can also alter type 2 cytokine and antibody production following immunization with a protein antigen. This effect appears to be mediated by endogenous opioid production. The following specific aims have been designed to explore the role of endogenous opioids on immune function in our unique aNd naturalistic stress pheromone model. The central hypothesis is: Stress odor exposure (SOE) induces an endogenous opioid response that is immunomodulatory. Specific Aim 1: To test the hypothesis that type 2 cytokine production and immune effector functions in BALB/c mice immunized with KLH are preferentially altered by SOE via endogenous opioids. Specific Aim 2a: To test the hypothesis that the immunomodulatory effects of SOE may depend upon the antigen used to elicit the immune response. Specific Aim 2b: To test the hypothesis that administration of the opioid receptor antagonist naltrexone will abrogate SOE-induced changes in anti-HSV immunity. Specific Aim 3a: To determine whether endogenous opioid-induced changes in immune function are mediated centrally, resulting in an indirect effect on peripheral immune function, and/or peripherally, thereby directly affecting the immune system. Specific Aim 3b: To determine the specific class(es) of opioid receptors that are involved in stress odor-induced immune changes. Specific Aim 4: To determine if C57B1/6 mice, which do not have altered immune responses to KLH following stress odor exposure, have evidence of elevated endogenous opioids following odor exposure.

DESCRIPTION (provided by applicant): This proposal will focus on disseminating science education programming, developed as part of our Phase I SEPA project, through the development of a science inquiry center for hands-on science activities. The Life Sciences Learning Center (LSLC), at the University of Rochester Medical Center (URMC), will focus on activities for teachers and students in grades six through twelve. The purpose of this Phase II program will be: To facilitate the continued development of collaborative linkages among University of Rochester biomedical scientists, and local science teachers and students. To continue to develop innovative programming for students emphasizing hands- on, inquiry-based learning. Programs emphasizing grade-appropriate topics will be offered throughout the school year and summer. Student programs and activities will align with national and New York State science education standards. To enhance current knowledge of life sciences as well as to develop the process of inquiry in teachers via teacher professional development workshops and summer programs. Teacher workshops and a Summer Science Teacher Academy will focus on activities with current science education standards. Teachers will have use of a "lending library" of science equipment and supplies to perform activities in their classrooms.

DESCRIPTION (provided by applicant): Given the public health and policy challenges posed by the aging of the large population born after World War II, research aimed at understanding the myriad influences on health and immune function of middle aged-older adults is vital. The process of aging includes declining bodily system function and immunosenescence. The rate of loss of function is dictated, in large part, by genetic makeup. An emerging picture from the literature is that, among the aging-related changes in health, there is a chronic, low level inflammatory response that we hypothesize to be a function of personality, and repeated exposures to what are perceived to be stressful life events. It is in middle aged-older individuals, then, that the interplay of these factors is most likely to be elucidated. The interaction among aging, individual differences and environmental factors is the "stuff1 of the Rochester Center for Mind-Body Research. In the RCMBR, we capitalize on our considerable strengths in clinical science, aging research, developmental psychobiology and psychoneuroimmunology. We bring together scientists from multiple disciplines to create cross-disciplinary research teams that partner with clinicians, community activists and agencies to address human aging from our unique perspective. In this renewal, we blend in our strong program of animal research, which allows us to examine biopsychosocial interactions across the life course, beginning with the perinatal period. Our human research is premised on the notion that age and individual differences moderate the effects of socioenvironmental circumstances on immune function and other health outcomes. The effects of early life experiences may become magnified in older adult humans and animals experiencing declines in immune and central nervous system function. RCMBR studies among older adult humans will be complemented by longitudinal studies in rodents that will address the effects of individual differences and early life experiences on immunity and health across the lifespan. Since its inception in August 2004, the RCMBR has built a portfolio of pilot studies and NIH funded grants. In the next three years, investigators in the Human Aging and Developmental Animal Research Cores and their collaborators will continue to pursue cutting-edge research consonant with our scientific mission. We will also expand our recruitment and research initiatives from the clinics to the community. The Community Relations and Recruitment Core will educate and advise investigators on effective community outreach and important aspects of community-based participatory research. All RCMBR investigators will be supported by the Administrative Core, the Biological and Behavioral Assessment Core, the Biostatistics Core, and the Training, Assessment, and Risk Management Core.

DESCRIPTION (provided by applicant): Demographic trends underscore the public health significance of research to decrease morbidity and mortality in adults 65 years of age and older. Societal and economic costs of diseases of old age will increase exponentially as the population ages. Because the immune response is a major factor in determining longevity, the development of novel, low-cost interventions to slow the rate of immunosenescence could lead to reduced morbidity, as well as substantial cost-savings. In the proposed randomized clinical trial (RCT), 200 older adults (65 years of age or older) will be randomly assigned to either an experimental intervention, Mindfulness Based Stress Reduction (MBSR), or a Living Well control condition. Effects on immunological, psychological, and physical outcomes will be examined. A primary outcome measure for this study is immune function. We will capitalize on the antibody response to a novel, benign antigen to which subjects will be immunologically naive. The use of a novel antigen will circumvent the real possibility that higher baseline antibody liters to, e.g., a booster vaccination will be associated with less new antibody production. This strategy will also allow us to define differences between treatment groups in the magnitude of the antibody response across multiple antigen doses, from suboptimal to optimal. The proposed study will examine two additional critical questions. The first concerns treatment moderators, and asks who among the elderly will benefit from MBSR. The second addresses behavioral, psychological, and physiological mediators of change, including behavioral adherence to meditative practice, increases in mindfulness, decreases in stress, and changes in brain electrical activity, as measured by electroencephalography (EEG). The Specific Aims are to examine: 1. The effects of Mindfulness Based Stress Reduction (MBSR) on immunological outcomes, perceived health, and psychological well-being in a sample of seniors 65 years of age and older. 2. Whether treatment effects are moderated by age, personality traits, physical health status, or depression. 3. The effects of behavioral, psychological, and physiological mediators of immune outcome. The findings of this RCT will have implications for the conceptualization, refinement, and dissemination of psychosocial interventions aimed at slowing the rate of immunosenescence.

DESCRIPTION (provided by applicant): Psoriasis is a chronic inflammatory disease of the skin that affects between 2-3% of Americans. It is characterized by erythematous, scaling, infiltrated plaques and histology that shows a markedly hyperproliferative epithelium (acanthosis) with infiltration of neutrophils and CD4+ (helper) and CD8+ (cytotoxic/suppressor) lymphocytes, as well as growth and dilation of blood vessels in the papillary dermis with CD4+ lymphocytes. Cytokines (small molecular weight messenger proteins) produced by T helper (Th)1 and Th17 lymphocytes, antigen presenting cells, and leukocytes have been implicated as being critical to the development of lesions. The condition is chronic, persistent and difficult to treat. Although not fatal, psoriasis can involve almost the whole body surface, typically requiring lifelong treatment and, on occasion, may be a source of significant morbidity. A growing literature suggests that the disease also is associated with higher rates of cardiovascular disease and metabolic syndrome, suggesting that inflammation is not only localized to skin. In many patients, psychological or life stress precedes onset of disease flares. Other literature suggests that stress is associated with increased production of many of the proinflammatory cytokines involved in psoriasis, including interleukin (IL)-6 and tumor necrosis factor (TNF)-1. Psoriasis patients commonly report significant reductions in quality of life, as well as social stigmatization, increased rates of anxiety and depression, and increased thoughts of suicide. The increased psychological distress associated with this skin disease may well be amplified by the process of inflammation itself, as proinflammatory cytokines are currently hypothesized to induce depression and anxiety. Thus, psoriasis appears to have a strong psychoneuroimmunological component to it, such that signals from the brain may exacerbate disease, and the disease itself may induce psychological distress. Psoriasis patients may well benefit from low-cost, adjunctive psychological interventions that are intended to decrease psychological distress, but which may also ameliorate the skin disease and inflammatory processes by interrupting the feedback loop between the stress response and psoriatic flares. In the proposed randomized clinical trial, we will examine the effects of Mindfulness Based Stress Reduction (MBSR) versus a psychoeducational treatment called Living Well on immunological markers of inflammation and keratinocyte proliferation, psoriasis severity, and psychological well-being in a population of patients reporting high stress levels who suffer from mild-moderate psoriasis. Our immunological markers include examination of relevant cells and cytokines in both lesional and normal skin biopsies, as well as monitoring blood cytokine levels. PUBLIC HEALTH RELEVANCE: Psoriasis is an inflammatory skin disease, and may also be a systemic condition associated with increased prevalence of metabolic syndrome; it affects millions of individuals in the US and is associated with significant heath care costs estimated at approximately $4.3 billion/year. Stress is frequently associated with flares in disease activity, and psoriasis patients commonly suffer from high rates of psychological distress, including depression, anxiety, and social isolation. In the proposed randomized control trial, we will examine the low cost, adjunctive intervention Mindfulness Based Stress Reduction (MBSR) for patients reporting high stress levels; outcomes include changes in inflammatory processes in the skin; cytokine levels in blood; disease severity; and psychological well-being.

DESCRIPTION (provided by applicant): Many studies demonstrate that stress exposure in childhood is associated with multiple kinds of illnesses in adulthood. The mechanisms underlying these associations are not yet clear, but there is consideration speculation that inflammation and, more broadly, alteration of the immune system from early stress exposure has an etiological role. What has not been established is the extent to which, and the mechanisms by which, early stress exposure has childhood onset effects on the immune system. Research is now needed to translate adult and a sizable experimental animal literature to pediatric samples; results from these studies would fundamentally shape public and clinical health approaches. The proposed study makes use of the Family Life Project (FLP), an ongoing prospective longitudinal study of 1292 children who were selected using epidemiological methods to oversample stress-exposed children. Indicators of innate and adaptive immune function will be collected from detailed developmental visits when the children are approximately 9 years of age and linked with measures of stress, behavior and psychosocial context data dating back to 2 months of age. Several features of the proposed study provide particular leverage for advancing this field of research, including a) a large epidemiologically-derived sample of pre-adolescent children at elevated psychosocial risk who have been carefully studied since infancy, b) detailed study of the innate and adaptive immune systems, and c) detailed assessment of socio-demographic and proximal family stress across the first decade of life that provide leverage for testing hypotheses about the type and timing of stress exposure, and d) examination of glucocorticoid resistance as a mediating mechanism. The research aims are to 1) test alternative hypotheses for a link between stress exposures and components of the innate immune system; 2) examine the association between early stress exposure and adaptive immunity, indexed by T cell responses to latent/persistent virus; and 3) determine the associations between behavioral/emotional and somatic symptoms and immune function in stress-exposed children. We also add a fourth exploratory aim: to examine the links between family and socio-demographic risk and illness and functional outcomes. The proposed study will add significant new information to our understanding of if and how stress exposure is associated with childhood onset dysregulated immune outcomes and the mechanisms involved. Findings from the study will provide a much-needed empirical foundation for developmental and clinical models of the interplay between stress and health in children.

? DESCRIPTION (provided by applicant): Influenza infection results in 41,000 deaths every year in the US and is the seventh leading cause of death. Strikingly, older adults, and especially those at risk for chronic medical disorders, account for approximately 90% of these deaths. Studies comparing influenza vaccine responses of older adults with those of young adults show that immune responses are significantly decreased in older adults. It is estimated that influenza vaccine efficacy is approximately 30-50% in older adults, compared to 70-90% in young-middle aged adults. Compounding this age-related decline in response to vaccination are findings that depression and chronic stress further impair older adults' immune responses to influenza vaccination. Caregiving for a family member with dementia is a robust stressor, and is associated with poor responses to influenza vaccination in older adults, as well as increased levels of proinflammatory biomarkers, which mediate many of the chronic diseases of aging. In this proposal, we consider the immunological consequences of the significant psychological distress experienced by older adult caregivers of family members with dementia. A wide variety of psychosocial interventions can lessen the psychological burden of family or spousal dementia caregiving; Mindfulness Based Stress Reduction (MBSR) in particular has psychological benefit for caregivers, yet its biological effects for these burdened caregivers remain unknown. Here we propose a randomized controlled trial (RCT) of MBSR for older adult caregivers of family dementia patients. Notably, no RCT to-date has done all of what we propose to do: focus on older adult family dementia caregivers who experience significant psychological distress; have as the primary outcome measure adaptive humoral and cellular immune response to influenza vaccine; include surveillance for influenza-like disease during flu season; include evaluation of proinflammatory biomarkers associated with morbidity and mortality in older adults; consider changes in mindfulness and stress as mediators of MBSR's effects on immune function; and include a long-term follow-up of MBSR practice activities. Our aims are to: Aim 1. Identify the effects of MBSR training and practice on adaptive immune responses to influenza vaccination as well as outcomes following influenza infection in stressed older adult family dementia caregivers. Aim 2. Identify the effects of MBSR training and practice on circulating levels of the proinflammatory biomarkers IL-6, tumor necrosis factor (TNF)-?, IL-17 and the acute phase reactant C-reactive protein (CRP), which are elevated in older adults and associated with many chronic diseases of aging. Exploratory Aim 3. Examine relationships among improved adaptive immunity, inflammation and flu outcomes following naturally-acquired influenza infection using a full mediation model. Overall, this research will illuminate whether MBSR can slow the age-related changes in immunity known as immunosenescence, which is accelerated by chronic stress.