Loma Linda University

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Denise Bellinger, PhD
Assoc Res Prof, Pathology and Human Anatomy
School of Medicine

Psychoneuroimmunology (PNI) investigates the bidirectional communication between the central nervous system and the immune system.  This network of connections permits the CNS to regulate the immune system through both neuroendocrine and neuronal pathways. In turn, the immune system signals the CNS through neuronal and humoral routes, via immune mediators and cytokines. This regulatory system plays an important role in susceptibility and resistance to cancer, autoimmune, inflammatory, infectious and allergic diseases. Studies in my laboratory investigate a number of interesting research questions under the umbrella of PNI.

Sympathetic Modulation of the Immune System in Aging.  My laboratory is interested in understanding how the relationship between the sympathetic nervous system (SNS) and the immune system changes with advancing age. Previous work has revealed different patterns of sympathetic aging in secondary lymphoid organs in rodents that is strain-specific. Current research focuses on better understanding: (1) the mechanisms responsible for the age-related changes in sympathetic innervation of immune organs; (2) the functional consequences of altered sympathetic neurotransmission on immunity under normal and pathological conditions that increase with aging (infectious disease, autoimmunity and cancer); (3) determining whether a causal relationship exists between altered sympathetic activity in aging and the decline in cell-mediated immunity with advancing age; and (4) examining male and female differences in aging of neural-immune interactions.

Neural-Immune Interactions in the Pathophysiology of Inflammatory Autoimmune Diseases. Studies in my laboratory investigate the role of the SNS in the development and progression of rheumatoid arthritis (RA) using adjuvant-induced arthritis in a susceptible rat strain as a model. Current research is focused on determining the mechanisms through which a- and b-adrenergic drugs interact with immune cells to affect joint destruction and bone loss, and how RA alters signaling via specific adrenergic receptors.  A second related project examines immune-to-brain signaling changes RA, with the aim of gaining a better understanding of pathophysiological mechanisms responsible for dysregulation of stress pathways (sympathetic and hypothalamo-pituitary adrenal outflow) in RA that secondarily contributes to disease development, progression and severity.   

Mechanisms of Psychosocial Influences on Prostate Cancer. Cancer research has focused largely on understanding tumor biology, assuming that tumor characteristics mostly determine disease course.  However, it is clear that host defense and psychophysiological mechanisms that influence host defense also play an important role in disease outcome.  Host defense against cancer is modulated by the central nervous system, via behavior, innervation of immune organs, especially by the SNS, and neuroendocrine outflow. In my laboratory, we study how these hardwired and chemical networks mediate psychosocially-induced changes in prostate cancer growth and metastases using the RM-9 mouse reconstitution model. Since, prostate cancer is a disease of elderly men, and striking dysregulation of SNS, neuroendocrine, and immune functions occurs with aging, my research investigates how aging affects the ability of these systems to affect tumor growth in old mice subjected to isolation and restraint stress.  Data from these studies will lead to the development of a psychosocial stress model for prostate cancer in aged mice to study: (1) mechanisms through which the SNS, HPA, and hypothalamo-pituitary gonadal axis interact to influence host defense against prostate cancer under conditions of social stress; and (2) neural-immune mechanisms that influence current treatment strategies in this disease.  Research examining how psychophysiological interactions affect prostate cancer may eventually provide a better understanding of variance in disease outcome, and aid in the development of efficacious treatments for patients with advanced disease.

Routes for Bidirectional Communication between the Nervous and Immune Systems. Previously, we have shown that administration of IL-2 in physiological and pharmacological concentration induces the expression of corticotrophin releasing hormones (CRH) in nerves that distribute to the spleen and thymus. Current studies are focused on (1) determining the origin of these nerve fibers; (2) investigating the mechanism(s) IL-2 induced CRH expression in nerves that do not constitutively express CRH; and (3) study the physiological relevance of CRH a novel neurotransmitters in nerves that supply primary and secondary lymphoid organs.  The clinical relevance of this research lies in the current use of IL-2 in the treatment of cancer and HIV to boost cell mediated immunity.

Biological and Psychosocial Manifestations of Religion. This collaborative prospective study complements the LLU’s Adventist Health Study-2 (AHS-2), currently funded by NCI and enrolling 1250,000 participants from across the United States. Whereas AHS-2 focuses on diet and its effects on cancer incidence, our research with a subset of the AHS-2 participants explores how religious beliefs and practices may affect not only cause-specific mortality but also quality of life. My laboratory participates in the clinical arm of this study, which is designed to assess biological and physiological mediators that may mediate religious effects on quality of life and mortality in 500 members of the proposed study, ages 60-95+, who live in the Loma Linda vicinity.  This study should further current understanding of how various manifestations of religion positively and negatively affect physical and mental health.