CHAPTER4 Psychoneuroimmunology

JEFFREY R. STOWELL, LYNANNE McGUIRE, TED ROBLES, RONALD GLASER, AND JANICE K. KIECOLT-GLASER

STRESS-IMMUNE PATHWAYS 75 Social Relationships 82 HPAAxis 75 Close Personal Relationships 83 Sympathetic Nervous System (SNS) 76 PSYCHOLOGICAL INTERVENTIONS 84 ACUTE VERSUS CHRONIC STRESS 76 Classical Conditioning 85 Acute Stress 77 Relaxation and Hypnosis 85 Chronic Stress 78 Emotional Disclosure 85 INDIVIDUAL PSYCHOLOGICAL DIFFERENCES 78 Cancer 86 Negative and Positive Affect 79 HIV 86 Coping 81 CONCLUSIONS 87 Disease Progression 81 REFERENCES 87 SOCIAL RELATIONSHIPS AND PSYCHONEUROIMMUNOLOGY 82

The field of psychoneuroimmunology (PNI) addresses how pituitary to release adrenocorticotropin hormone (ACTH) psychologicalfactors influence the immune system and phys­ into the general circulation. The adrenal cortex then responds ical health through neural and endocrinological pathways. to ACTH by releasing glucocorticoids, predominantly corti­ These relationships are especially relevant to immunologi­ sol in humans. cally mediated health problems, including infectious dis­ Some of cortisol's effects are anti-inflammatory and ease, cancer, autoimmunity, allergy, and wound healing. In immunosuppressive. These immunological effects may be this chapter, we briefly introduce two major physiological adaptive, as they can limit a potentially overactive im­ systems that modulate immune function and then provide ev­ mune response that could result in inflammatory or autoim­ idence for stress-immune relationships. Next, we explore the mune disease (Munck & Guyre, 1991; Munck, Guyre, & psychosocial factors that may be important in moderating Holbrook, 1984; Sternberg, 1997). Although glucocorticoids and mediating these relationships, including negative affect, exert anti-inflammatory and immunosuppressive effects, social support, and interpersonal relationships. Finally, we they have a more complex role in immune modulation than review intervention strategies that may be beneficial in re­ originally thought. For example, glucocorticoids suppress ducing the negative effects of stress on the immune system. cytokines that promote a cell-mediated TH-l type immune For more detailed explanations of immunological terms or response (e.g., interleukin-2 [IL-2]), but they enhance the processes, we recommend the text by Rabin (1999). production of cytokines that promote a humoral TH-2 type immune response (e.g., IL-4; Daynes & Araneo, 1989). Thus, there may be a shift in the type of immune defense toward an STRESS·IMMUNE PATHWAYS antibody-mediated response. This shift mayor may not be adaptive depending on the types of pathogens that are pre­ HPAAxis sent. Additionally, glucocorticoids induce a redistribution of Activation of the hypothalamic-pituitary-adrenal (HPA) axis immune cells from the blood to other organs or tissues by stress results in a predictable cascade of events (see Fig­ (McEwen et al., 1997). Thus, a drop in peripheral blood lym­ ure 4.1). Neurons in the hypothalamus release corticotropin­ phocyte counts may mistakenly be interpreted as immuno­ releasing hormone (CRH), which stimulates the anterior suppression when the cells may simply be migrating to other

75 76 Psychoneuroimmunology

sympathetic nerve terminals release norepinephrine into various effector organs including the adrenal medulla, which Brainstem releases the catecholamines, epinephrine and norepineph­ + 1<------1~ Autonomic rine, into the blood stream; hence the term sympathoad­ '-...... -_.. Centers renomedullary (SAM) axis (see Figure 4.1). Additionally, sympathetic nerve terminals innervate pri­ mary and secondary lymphoid tissue and appose lympho­ Sympathetic Nerves cytes and macrophages in synaptic-like contacts (Felten, Ackerman, Wiegand, & Felten, 1987; Felten et al., 1985; +8 Felten & Olschowka, 1987; Madden, Rajan, Bellinger, Adrenal Medulla Felten, & Felten, 1997). Consequently, catecholamines re­ leased from either the adrenal medulla or local sympathetic nerves may influence immune function. Indeed, lymphocytes +,- +,- @ possess adrenergic receptors that induce a change in the pat­ +,- tern of cytokine production following stimulation. For exam­ IImmune System 14-----' ple, adrenergic agonists decrease TH-l cytokine production (e.g., IL-2 and IFN-')'), but have no effect on TH-2 cytokine Figure 4.1 Neural and endocrine pathways that may modulate the immune production (e.g., IL-4; Ramer-Quinn, Baker, & Sanders, system. The hypothalamic-pituitary-adrenal (HPA) and sympathoad­ 1997; Sanders et al., 1997). In humans, catecholamine renomedullary (SAM) axes are represented, which influence the immune infusion increases the number of peripheral blood lympho­ system in multiple ways. Abbreviations: cytes, likely due to actions at the [32 adrenergic receptor CRH-corticotropin-releasing hormone, (Schedlowski et al., 1996). Natural killer (NK) cells, thought ACTH-adrenocorticotropin hormone, to be important in the surveillance and elimination of tumor NEPI-norepinephrine, and virus-infected cells, appear to be especially sensitive to EPI-epinephrine, (+) stimulation, (-) inhibition. catecholamines, increasing in number (Crary et al., 1983) and organs or tissues, such as the skin, where they are more likely cytotoxic ability (Nomoto, Karasawa, & Uehara, 1994). to encounter antigens (Dhabhar & McEwen, 1997). This il­ Although the HPA axis and SNS are major pathways by lustrates the complexity of understanding the pattern of which stress can influence immune function, other systems, changes in immune function, particularly when only one such as the opioid system, are also involved (Rabin, 1999). or two measures of immune function are assessed. Thus, the Furthermore, brain-immune communication is bidirectional. term immune dysregulation is probably a more descriptive A growing body of literature acknowledges that the immune term than immune suppression (or enhancement) when dis­ system can modulate brain activity and subsequent behavior cussing general changes in immune function, via the production of cytokines (Dantzer et al., 1998). The Although the HPA axis significantly modulates immune immune system acts as a diffuse sensory organ by providing function, other pathways also exist, as noted when the blasto­ information about antigenic challenges to the brain, which, in genic response to phytohemagglutinin (PHA) was still sup­ turn, regulates behaviors appropriate to deal with these chal­ pressed following stress, despite removal of the adrenal lenges (Maier & Watkins, 1998). glands (Keller, Weiss, Schleifer, Miller, & Stein, 1983). Later studies suggested that the sympathetic nervous system is another important modulator of immune function (Felten, ACUTE VERSUS CHRONIC STRESS Felten, Carlson, Olschowka, & Livnat, 1985; Irwin, 1993). As stress-induced modulations of brain-immune relation­ ships were discovered, multiple types of stressors that varied Sympathetic Nervous System (SNS) in duration, intensity, and controllability were studied. In As with the HPA axis, the hypothalamus is centrally involved comparing the effects of acute and chronic stress on immune in the regulation of autonomic nervous system activity. function, different patterns have emerged depending on the Neurons in the hypothalamus project to autonomic centers model of stress being studied. Using an animal model of in the lower brainstem and spinal cord, including pregan­ stress, Dhabhar and McEwen (1997) operationally defined glionic sympathetic neurons (Luiten, tel' Horst, Karst, & acute stress as restraint for two hours, and chronic stress as Steffens, 1985). During a classical "fight or flight" response, daily restraint for three to five weeks. Exposure of humans to Acute versus Chronic Stress 77

laboratory stressors generally falls within this definition that used laboratory stressors, NKCC was decreased, and stu­ of acute stress, while the chronic stress of long-term events dents who reported the highest levels of loneliness had the such as caregiving may last for years (Heston, Mastri, lowest NKCC (Kiecolt-Glaser et aI., 1984). Compared to the Anderson, & White, 1981). The stress of major academic ex­ less stressful baseline period, examination stress also impaired aminations is often preceded by a period of anxiety that blastogenic responses to the mitogens PHA and concanavalin varies (Bolger, 1990), and therefore, may fall somewhere A (Con A; Glaser, Kiecolt-Glaser, Stout, et aI., 1985).An inhi­ along the continuum of acute and chronic stress (i.e., suba­ bition of the memory immune (blastogenic) response to cute stress). No definitive criterion has been established for Epstein-Barr Virus (EBV) polypeptides was also observed classifying stressors as acute, subacute, or chronic, but the (Glaser et aI., 1993). Production of interferon-gamma (IFN­ general categories of acute and chronic will be used to illus­ "'{), an important antitumor and antiviral cytokine (Bloom, trate the complexity of the different patterns of immunologi­ 1980), was decreased in leukocytes obtained at the time of cal changes that occur in various models of stress. exams (Glaser, Rice, Speicher, Stout, & Kiecolt-Glaser, 1986). Additional studies confirmed examination stress­ Acute Stress induced changes in leukocyte numbers (Maes et aI., 1999), serum immunoglobulin levels (Maes et aI., 1997), and cy­ Laboratory Stress tokine production (Maes et aI., 1998). Exposure to laboratory stressors, such as mental arithmetic Comparison of the delayed type hypersensitivity (DTH) andpublic speaking tasks that generally lasted no longer than response to acute stress in animals and humans adds com­ 20 minutes, were associated with lower CD4+/CD8+ plexity to the domain of acute stress. For example, stress (T helperlT cytotoxic-suppressor) cell ratios, poorer blas­ associated with an academic examination suppressed DTH togenic responses, and increased catecholamine release responses in subjects who reported higher levels of stress (Bachen et aI., 1995; Bachen et aI., 1992; Burleson et aI., (Vedhara & Nott, 1996), while acute restraint stress in 1998; Cacioppo et aI., 1995; Herbert et al., 1994). These rodents during the sensitization or challenge phase enhanced same studies also revealed that peripheral NK cell number DTH responses (Dhabhar & McEwen, 1997; Dhabhar, and cytotoxicity (NKCC) were consistently increased. Satoskar, Bluethmann, David, & McEwen, 2000). In another Furthermore, these stress-induced immune changes were study, socially inhibited individuals showed heightened DTH blocked by an adrenergic receptor blocker (Bachen et aI., responses compared to controls following five weekly ses­ 1995), suggesting that these short-term immune changes sions of high-intensity social engagement (Cole, Kemeny, were largely mediated by sympathetically activated cate­ Weitzman, Schoen, & Anton, 1999). Further research will be cholamine release. required to understand these complex interactions. Studies using laboratory stressors have also revealed im­ The clinical importance of the immunological changes portant individual differences in physiological responses to associated with examination stress is underscored by several stress. For example, subjects who showed the greatest change findings. First, students who reported greater distress during in sympathetic activity to laboratory mental stress also had exams took longer to seroconvert after inoculation with a the greatest change in HPAactivity and immune function, de­ hepatitis B vaccine (Glaser, Kiecolt-Glaser, Bonneau, spite reporting similar levels of stress (Cacioppo et aI., 1995; Malarkey, Kennedy, et al., 1992).They also had lower antibody Herbert et aI., 1994; Matthews et aI., 1995). This suggests ad­ titers to the vaccine six months postinoculation and a less vig­ ditional psychological or genetic factors may be responsible orous virus-specific Tcell response. Furthermore, examination forthe observed differences in physiological reactivity to lab­ stress was associated with reactivation of two latent her­ oratory stressors, and possibly other types of stressors. These pesviruses, EBV and herpes simplex virus type-I (HSV-I; differences may be explained, in part, by psychosocial factors Glaser, Kiecolt-Glaser, Speicher, & Holliday, 1985; Glaser, such as negative affect, social support, and interpersonal Pearl, Kiecolt-Glaser, & Malarkey, 1994). Finally, examina­ relationships. tion stress prolonged the time to heal a standardized oral wound compared to a low stress period (three days or 40% longer to heal); in fact, none of the students healed as fast during exams Academic Examination Stress as they did during vacation (Marucha, Kiecolt-Glaser, & Fav­ Usingacademic examinations as a model of "subacute" stress, agehi, 1998).This delay in wound healing was accompanied by depression and loneliness in first-year medical students in­ a reduction in the production of the proinflammatory cytokine creased during final exams compared to the less stressful base­ IL-II3, which, in addition to ILl-a, is important in the early line period (Kiecolt-Glaser et aI., 1984). In contrast to studies stages of wound healing (Barbul, 1990; Lowry, 1993). 78 Psychoneuroimmunology

Importantly, glucocorticoids modulate processes involved nuclear reactor meltdown at Three Mile Island (TMI) in in wound healing. For example, exogenously administered 1979, psychological assessments revealed that local TMI res­ glucocorticoids suppressed the production of several proin­ idents reported more symptoms of distress and intrusive flammatory cytokines, delaying wound healing (Hubner thoughts and continued to have higher blood pressure, heart et al., 1996). Furthermore, restraint stress in mice increased rate, norepinephrine, and cortisol levels than control subjects corticosterone levels and prolonged wound healing, which who lived 80 miles away, up to five years after the accident was normalized when a glucocorticoid receptor antagonist (Davidson & Baum, 1986). TMI residents also had fewer B was administered (Padgett, Marucha, & Sheridan, 1998). In a lymphocytes, T-suppressor/cytotoxic lymphocytes and NK related human study, perceived stress was associated with in­ cells, as well as evidence for reactivation of latent HSV creased salivary cortisol production and decreased mRNA (McKinnon, Weisse, Reynolds, Bowles, & Baum, 1989). In levels of the cytokine IL-Ia in peripheral blood leucocytes the aftermath of the Northridge earthquake, local residents (Glaser, Kiecolt-Glaser, et al., 1999). Thus, the HPA axis ap­ similarly showed a decrease in T cell numbers, blastogenic pears to be an important factor in the stress-induced delay of responses, and NKCC (Solomon, Segerstrom, Grohr, wound healing, likely via regulation of cytokine production. Kemeny, & Fahey, 1997). Chronic stress can have significant clinical consequences. Chronic Stress As previously mentioned, caregivers and TMI residents showed evidence for reactivation of latent herpes viruses To explore the question ofwhether stress-induced immunolog­ (Glaser & Kiecolt-Glaser, 1997; McKinnon et al., 1989). Fol­ ical changes adapt over time and perhaps eventually return to lowing influenza vaccination, caregivers were less likely to prestress values, we studied a sample of chronically stressed achieve a four-fold increase in antibody titers than controls caregivers of family members with progressive dementia disor­ (Kiecolt-Glaser, Glaser, et al., 1996; Vedhara et al., 1999), ders, primarily Alzheimer's disease (AD). Following disease which suggests greater susceptibility or more serious illness onset, modal survival time for patients with AD is about eight in the event of exposure to influenza virus. Caregivers also years (Heston et al., 1981). Caregivers report greater distress took 24% longer to heal a standardized punch biopsy wound and depression and reduced social support compared to noncar­ (Kiecolt-Glaser, Marucha, Malarkey, Mercado, & Glaser, egivers (Bodnar & Kiecolt-Glaser, 1994; D. Cohen & Eisdorfer, 1995) and reported a greater number and duration of illness 1988; Dura, Stukenberg, & Kiecolt-Glaser, 1990; Kiecolt­ episodes, with more physician visits than control subjects Glaser, Dura, Speicher, Trask, & Glaser, 1991; Redinbaugh, (Kiecolt-Glaser & Glaser, 1991) MacCallum, & Kiecolt-Glaser, 1995). Thus, caregiving has The immune dysregulation associated with caregiving may been conceptualized as a model ofchronic stress. be especially relevant for older adults, as cellular immunity As with short-term stress, chronic stress has significant declines with age (Bender, Nagel, Adler, & Andres, 1986; effects on immune function. For example, caregiving was Murasko, Weiner, & Kaye, 1987), and is associated with associated with lower percentages of T helper and total greater morbidity and mortality, especially due to infectious dis­ T cells and poorer cellular immunity against latent EBV eases (Murasko, Gold, Hessen, & Kaye, 1990; Wayne, Rhyne, (Kiecolt-Glaser, Glaser, et al., 1987). In a longitudinal study Garry, & Goodwin, 1990). However, even in younger popula­ of spousal caregivers and community matched controls, care­ tions, longer term stress (greater than one month) has been givers showed greater decrements in cellular immunity over associated with immune dysregulation and increased suscepti­ time as measured by decreased blastogenic responses to PHA bility to infection by a common cold virus (Cohen et al., 1998). and Con A (Kiecolt-Glaser et al., 1991). Additional studies The studies mentioned support the argument that immuno­ have confirmed that caregiving is associated with reduced logical dysregulation associated with chronic stress does not blastogenic responses (Castle, Wilkins, Heck, Tanzy, & necessarily undergo habituation over time. Rather, these ef­ Fahey, 1995; Glaser & Kiecolt-Glaser, 1997), decreased fects appear to be present for the duration of the stressor, and virus-specific-induced cytokine production (Kiecolt-Glaser, in some cases, persist even after the stressor is no longer pre­ Glaser, Gravenstein, Malarkey, & Sheridan, 1996), inhibition sent (Esterling, Kiecolt-Glaser, Bodnar, & Glaser, 1994). of the NK cell response to recombinant IL-2 (rlL-2) and rIFN-')' (Esterling, Kiecolt-Glaser, & Glaser, 1996), and re­ duced sensitivity of lymphocytes to certain effects of gluco­ INDIVIDUAL PSYCHOLOGICAL DIFFERENCES corticoids (Bauer et al., 2000). Other studies have confirmed that chronic stress may have Negative emotions are related to a range of diseases whose behavioral and immunological consequences. Following the onset and course may be influenced by the immune system, Individual Psychological Differences 79

particularly by inflammation resulting from the production of associated with higher levels of basal NKCC and with proinflammatory cytokines (Kiecolt-Glaser, McGuire, Robles, smaller declines in NKCC from a nonstress baseline to a final & Glaser, 2002). Individual differences in emotional and cop­ exam period that occurred six weeks later. ingresponses may account for some of the variation in neuro­ Although optimism has been related to positive physical endocrine and immunological changes associated with stress. health outcomes in surgery patients (Scheier et al., 1999), its Currently, research is aimed at identifying the relationships association with immune function has been inconsistent among these changes and emotional traits and states, daily among prospective studies of naturalistic stressors. These in­ subclinical fluctuations in mood, bereavement, clinical disor­ consistencies might be due tu different methodology in defin­ ders of major depression and anxiety, and coping strategies. ing optimism, different periods of follow-up for immune measures, and differences in the presence and definition of acute and chronic stress. Segerstrom, Taylor, Kemeny, and Negative and Positive Affect Fahey (1998) examined optimism and immune function in Negative affect is defined as general subjective distress and first-year law students before entry into the law school pro­ includes a range of negative mood states, such as depression, gram and again at midsemester, two months before students' anxiety, and hostility (Watson & Pennebaker, 1989). Cohen first examination period. Dispositional optimism was not re­ and colleagues demonstrated an association between nega­ lated to immune measures but to higher situational optimism tive affect and rates of respiratory infection and clinical colds (defined as positive expectations specific to academic perfor­ following intentional exposure to five different respiratory mance) and was associated with higher NKCC. This associa­ viruses (S. Cohen, Tyrrell, & Smith, 1991). A dose-response tion was partially mediated by lower levels of perceived relationship was found between rates of respiratory infection/ stress. In another study, healthy women were followed for clinical colds and increased levels uf a composite measure of three months, using daily self-reports uf stressful events. In psychological stress that included negative affect, major this case, dispositional optimism was associated with a stressful life events, and perceived ability to cope with cur­ greater reduction in NKCC following high stress that lasted rent stressors. In further analyses of these data, negative af­ longer than one week compared to less optimistic individuals fect predicted the probability of developing a cold across the (F. Cohen et al., 1999). Thus, optimism may have differential five different upper respiratory infection viruses independent effects on NKCC, depending on whether situational or dispo­ of negative life events (S. Cohen, Tyrrell, & Smith, 1993). sitional optimism is measured. Furthermore, the higher illness complaints in individuals high in state negative affect were associated with increased Daily Negative and Positive Mood severity of colds and influenza as seen in the amount of mucus produced (S. Cohen et al., 1995). However, negative The relationships between normal daily mood fluctuations affect was not related to the development of clinical colds and immune variables have been evaluated by tracking sub­ among already infected individuals but rather was associated jects' naturalistic mood changes and by inducing positive and with individuals' susceptibility to infection (S. Cohen et al., negative mood states in the laboratory. In the first case, nega­ 1993; Stone et al., 1992). tive mood over the course of two days was associated with In another study, baseline personality variables that are reduced NKCC, but there was evidence that positive mood thought to be characteristic of negative affect (high internal­ moderated this association (Valdimarsdottir & Bovbjerg, izing, neuroticism, and low self-esteem) predicted lower 1997). In the second case, studies of induced mood in the lab­ titers of rubella antibodies 10 weeks postvaccination in sub­ oratory have shown transient increases in NKCC (Futterman, jects who were seronegative prior to vaccination (Morag, Kemeny, Shapiro, & Fahey, 1994; Knapp et al., 1992), but Morag, Reichenberg, Lerer, & Yirmiya, 1999). This relation­ conflicting outcomes related to the lymphocyte proliferative ship was not found in subjects who were seropositive prior to response to PHA. Both positive and negative induced mood vaccination. conditions were associated with a decreased response to PHA Dispositional positive affect and the expectation of posi­ (Knapp et al., 1992), whereas positive induced mood was as­ tive outcomes, termed optimism, have been less well studied sociated with an increased response to PHA and negative in­ in relation to immune variables. Davidson and colleagues duced mood was associated with a decreased response to (Davidson, Coe, Dolski, & Donzella, 1999) demonstrated PHA (Futterman et al., 1994). The differences in immune positive relationships between NKCC and greater positive outcomes in these two laboratory-induced mood studies may dispositional mood, defined by relative left-sided anterior be, in part, due to different levels of arousal and physical brain activation. Greater relative left-sided activation was activity during the mood induction procedure and the use of 80 Psychoneuroimmunology

trained actors in one study (Futterman et aI., 1994). Never­ healthy controls (Herbert & Cohen, 1993). A classic study by theless, the different NKCC responses to mood in the Schleifer, Keller, Bond, Cohen, and Stein (1989) most clearly naturalistic and laboratory studies parallel the different showed the interactions of age, depression, and immune NKCC responses to stress in the acute and laboratory studies function; older depressed individuals had the lowest lympho­ described earlier. cyte proliferation to mitogen compared to controls. Mild to moderate levels of clinical depression in nonhos­ pitalized individuals were associated with reduced lympho­ Bereavement cyte proliferation and decreased NKCC (Miller, Cohen, & Early studies of bereavement and immune function showed Herbert, 1999). Nonclinical depressed mood also has been reduced lymphocyte proliferation to the mitogens Con A and reliably associated with decreased NKCC and decreased PHA relative to controls in bereaved spouses two months lymphocyte proliferative response to PHA, although the ef­ after the death of their spouse (Bartrop, Luckhurst, Lazarus, fect sizes of these relationships are smaller than for clinically Kiloh, & Penny, 1977). In a within-subjects design, lympho­ depressed mood (Herbert & Cohen, 1993). The time course cyte proliferation to Con A, PHA, and pokeweed mitogen of immunological correlates in depression is not known, but (PWM) was decreased for two months, relative to the prebe­ individuals that recovered from depression no longer showed reavement response (Schleifer, Keller, Camerino, Thorton, & decreased NKCC (Irwin, Lacher, & Caldwell, 1992). Stein, 1983). The severity of depressive symptoms in One potential pathway for the association of depression women experiencing bereavement or anticipating bereave­ and immune function includes alterations in health behav­ ment due to their husbands' diagnosis of metastatic lung can­ iors, such as sleep, exercise, smoking, diet, and alcohol and cer was negatively related to NKCC (Irwin, Daniels, Smith, drug use (Kiecolt-Glaser & Glaser, 1988). Patients with de­ Bloom, & Weiner, 1987). Conflicting immunological conse­ pression or alcoholism showed reduced NKCC relative to quences of bereavement in HIV seropositive gay males have controls, and dually diagnosed patients showed even greater been reported (Kemeny et al., 1995; Kessler et aI., 1991) but NKCC reductions (Irwin, Caldwell, et al., 1990). Physical may be, in part, due to individuals' different coping strategies activity mediated the association between mild to moderate in response to bereavement (Bower, Kemeny, Taylor, & depression and reduced proliferation to Con A and PHA in Fahey, 1998). ambulatory female outpatients (Miller, Cohen, et al., 1999). Studies of the immunological impact of bereavement have Depressed men who smoked light to moderate amounts had generally included small sample sizes and short follow-up the lowest NKCC, whereas nonsmoking depressed subjects, periods. The mechanisms underlying the association between control smokers, and control nonsmokers did not differ from bereavement and immune changes and the time line of such one another (Jung & Irwin, 1999). Other potential pathways changes have not been identified, but changes in mood, include SNS and endocrine dysregulation. Although such health behaviors, and neuroendocrine function have been physiological dysregulation has been shown in depression proposed. (Chrousos, Torpy, & Gold, 1998; Gold, Goodwin, & Chrousos, 1988), these pathways have not been consistently Depression linked to alterations in immune function in depressed indi­ viduals (Miller, Cohen, et aI., 1999; Schleifer, Keller, Clinical depression has been associated with reduced NKCC Bartlett, Eckholdt, & Delaney, 1996; Schleifer et aI., 1989). (Irwin, Patterson, & Smith, 1990; Irwin, Smith, & Gillin, 1987), decreased lymphocyte proliferation to mitogens Anxiety (Schleifer et aI., 1984), poorer specific proliferative response (memory) to varicella-zoster virus (Irwin et aI., 1998), and Higher levels of anxious mood have been related to a poorer decreased delayed-type hypersensitivity (Hickie, Hickie, immune response to a hepatitis B vaccination series (Glaser, Lloyd, Silove, & Wakefield, 1993). Nonmeta-analytic review Kiecolt-Glaser, Bonneau, Malarkey, & Hughes, 1992), lower studies have drawn different conclusions about the existence proliferative responses to Con A and lower plasma levels of of an association between depression and immune function lL-l f3 (Zorrilla, Redei, & DeRubeis, 1994), decreased NKCC (Stein, Miller, & Trestman, 1991; Weisse, 1992); however, a (Locke et aI., 1984), and higher antibody titers to latent EBV meta-analytic review concluded that clinically depressed in­ (Esterling, Antoni, Kumar, & Schneiderman, 1993). Anxiety dividuals, especially older and hospitalized individuals, have related to the anticipation of HIV serostatus notification has lower lymphocyte proliferative responses to PHA, Con A, been associated with higher plasma cortisol levels, which and PWM and have lower NKCC compared to nondepressed, were associated with lower lymphocyte proliferation to PHA Individual Psychological Differences 81

(Antoni et aI., 1990) and decreased NKCC in the postacute PHA and Con A in individuals who report high stress levels, notification period in gay males (Ironson et al., 1990). High but not in those who report low stress levels (Stowell, levels of trait worry, a central feature of generalized anxiety Kiecolt-G1aser, & Glaser, 2001). disorder (GAD), interfered with the increase in NK cells in Reactivation oflatent EBV in healthy college students was peripheral blood seen in individuals with a normal level of associated with a repressive personality style and a tendency traitworry during exposure to an acute stressor (Segerstrom, to not disclose emotion on a laboratory task (Esterling, Glover, Craske, & Fahey, 1999), and was associated with Antoni, Kumar, & Schneiderman, 1990) and to higher levels 25% fewer NK cells throughout a four-month follow-up of defensiveness (Esterling et al., 1993). Repressive person­ period following the natural disaster of an earthquake ality or coping style were not related to immune measures (Segerstrom et al., 1998b). following an earthquake, but an appropriate psychological re­ The association between clinical diagnoses of anxiety action to the realistic degree of life stress caused by the earth­ disorders and immune function is a recent focus of investi­ quake was described as least disruptive to immune measures gation. Significant associations have not been found with (Solomon et al., 1997). In partners of bone marrow transplant obsessive-compulsive disorder (Maes, Meltzer, & Bosmans, patients, escape-avoidance coping was the strongest and 1994), and discrepant outcomes have been reported with most consistent variable associated with changes indica­ panic disorder (Andreoli et al., 1992; Brambilla et al., 1992; tive of poorer immune function, especially during the Rapaport, 1998; Weizman, Laor, Wiener, Wolmer, & Bessler, anticipatory period prior to the initiation of the transplant 1999). More consistent immune relationships have been (Futterman, Weilisch, Zighelboim, Luna-Raines, & Weiner, reported for GAD and posttraumatic stress disorder (PTSD). 1996). Greater denial in gay men awaiting notification Patients with GAD showed changes in monocyte function of HIV seronegative status was associated with less impair­ andstructure, reduced NKCC, reduced lymphocyte prolifera­ ment in PHA response at baseline, perhaps through a reduc­ tion to PHA, and a poorer response to two DTH tests com­ tion in intrusive thoughts related to notification (Antoni et al., pared to controls (Castilla-Cortazar, Castilla, & Gurpegui, 1990). 1998), reduced IL-2 production (Koh & Lee, 1998), and lower expression of IL-2 receptors on stimulated T cells com­ Disease Progression pared to controls (La Via et aI., 1996). Chronic PTSD has been associated with elevated lymphocyte, total T cell, and Evidence of greater risk of physical morbidity and mortal­ CD4+T cell counts in Vietnam combat veterans (Boscarino & ity in individuals with depression (Herrmann et al., 1998; Chang, 1999) and a higher index of lymphocyte activation in Penninx et al., 1999) suggests an important association patients with a history of childhood sexual abuse (Wilson, van between psychosocial factors and disease onset and progres­ derKolk,Burbridge, Fisler, & Kradin, 1999). sion. The association of psychosocial factors and cancer re­ The outcomes of the studies that have evaluated the asso­ mains controversial due to conflicting study outcomes. Some ciation of clinical anxiety disorders and immune function prospective studies have found greater cancer-related mortal­ should be considered preliminary. The sample sizes are small ity in depressed individuals (Persky, Kempthorne-Rawson, & andthere is wide variability in the methodology and rigor of Shekelle, 1987; Shekelle et al., 1981), while other studies thestudies. It is not yet known what aspects of clinical anxi­ have not found this relationship (Kaplan & Reynolds, 1988; etydisorders, such as classes of symptoms, severity and time Zonderman, Costa, & McCrae, 1989). The most promising course of symptoms, arousal, or hypervigilance, are most psychological factors related to tumor progression include a important for immunity. The consequences of comorbid dis­ low level of social support, hopelessness, and repression of orders, especially depression, and mixed groups of anxiety negative emotions (see for review Garssen & Goodkin, 1999; disorder patients require further evaluation. Kiecolt-Glaser & Glaser, 1999). Significant psychosocial associations have been found in the progression of HIY. Depression has been associated with Coping an increased rate of CD4+ T-cell decline in HIV-seropositive Individual differences in appraisal and response to stress­ men, but the relationship appears to depend on the pres­ ful situations have been evaluated through assessment of ence of higher levels of CD4+ cells in the early stage of coping strategies. The positive or negative association disease (Burack et al., 1993; Lyketsos et al., 1993). More rapid ofcoping strategies with immune function appears to depend, disease progression has been associated with greater conceal­ tosomeextent, on stress levels, with active coping being sig­ ment of homosexual identity (Cole, Kemeny, Taylor, Visscher, nificantly related to more vigorous proliferative responses to & Fahey, 1996), high realistic acceptance and negative 82 Psychoneuroimmunology expectations about future health (Reed, Kemeny, Taylor, provided by social relationships protects against susceptibility Wang, & Visscher, 1994), attribution of negative events to the to disease by promoting immune competence. At the same self (Segerstrom, Taylor, Kemeny, Reed, & Visscher, 1996), a time, negative qualities of social relationships may act as passive coping style (Goodkin, Fuchs, Feaster, Leeka, & stressors, resulting in compromised immune function. Rishel, 1992), and denial of diagnosis in seropositive gay men (Ironson et aI., 1994). Alternatively, more deliberate cognitive processing about the death of a close friend or partner was as­ Social Relationships sociated with greater likelihood of finding positive meaning in Cross-Sectional Studies the loss, and greater positive meaning was associated with a less rapid decline in levels of CD4+ cells over three years and In the first published cross-sectional study of social support lower rates of AIDS-related mortality nine years later in HIV­ and immune function, a greater number of frank and confiding seropositive men (Bower et al., 1998). relationships was associated with higher total lymphocyte From the studies reviewed, it appears that the immunolog­ counts and a greater blastogenic response to PHA in women, ical effects of stressors are influenced by affective, cognitive, with smaller effects found for men (Thomas, Goodwin, & behavioral, and psychosocial individual differences in ap­ Goodwin, 1985). Subsequent studies examined these relation­ praisal and response to stressors. Through better understand­ ships in the context of stressful life events. In the context of job ing and assessment of the role of individual differences in strain, greater social support was associated with lower levels physiological responses, we may more accurately predict im­ of serum IgG, but only for persons under high job strain mune changes in the context of stress. The physiological (Theorell, Orth-Gomer, & Eneroth, 1990). As previously dis­ mechanisms that underlie the psychosocial and immune cussed, in a series of studies of spousal caregivers for AD pa­ function associations are not yet fully known, but the HPA, tients, lower levels of helpful emotional and tangible support SAM, SNS, and opioid systems are likely involved (Rabin, in caregivers were associated with an inhibition ofNK cell re­ 1999). sponses (Esterling, Kiecolt-Glaser, et aI., 1994; Esterling et al., 1996). Similarly, in spouses of cancer patients, lymphocyte proliferation to PHA and NK cell activity were positively as­ SOCIAL RELATIONSHIPS AND sociated with perceived provision of various types of social PSYCHONEUROIMMUNOLOGY support (Baron, Cutrona, Hicklin, Russell, & Lubaroff, 1990).

Psychoneuroimmunology research focusing on social rela­ Prospective Studies tionships originated from a larger literature on the relation­ ships between social support and health. Cassel (1976) and Prospective studies of social support and immune function Cobb (1976) provided important theoretical and empirical have focused on samples undergoing both chronic and acute integration of social support and health research, concluding life events. Caregivers of AD patients reported less social that social support was positively associated with health out­ support than controls, and caregivers with low social support comes. Following the publication of these reviews, research showed a greater negative change in immune function from on social support and health experienced "geometric growth" intake to follow-up (Kiecolt-Glaser et aI., 1991). In patients (House, Landis, & Umberson, 1988). In particular, epidemi­ undergoing an acute stress, hernia surgery, perceived social ological studies showed that lower social integration (lower support was positively correlated with lymphocyte prolifera­ number of social relationships and activities) was consis­ tion to mitogens both pre- and post-operation (Linn, Linn, & tently associated with higher risk of mortality, independent of Klimas, 1988). Finally, in a sample of both healthy and asth­ age, physical health, and a number of other health behavior matic adolescents, social support was positively associated risk factors (Berkman & Syme, 1979; House, Robbins, & with CD4+/CD8+ ratios and neutrophil superoxide produc­ Metzner, 1982; Schoenbach, Kaplan, Fredman, & Kleinbaum, tion at higher levels of perceived stress (Kang, Coe, 1986). In their seminal review ofthis work, House et aI. (1988) Karszewski, & McCarthy, 1998). concluded that "social relationships, or the relative lack thereof, constitute a major risk factor for health-rivaling the Clinical Disease Studies effects of well-established health risk factors such as cigarette smoking, blood pressure, blood lipids, obesity, and physical Studies of clinical disease and social support are important activity" (p. 541). The underlying theme of psychoneuroim­ in psychoneuroimmunology research because they are di­ munology and social support research is that positive support rectly relevant to clinical health outcomes. This research is r ! Social Relationships and Psychoneuroimmunology 83

especially informative to current approaches to clinical treat­ relationships can be associated with both disease susceptibil­ mentof infectious disease and cancer, by suggesting that psy­ ity (common cold, hepatitis B studies) and progression chosocial interventions can promote lower susceptibility and (breast cancer, HIV/AIDS). Moreover, this effect is impres­ increased resistance (Andersen, Kiecolt-Glaser, & Glaser, sive given the diverse conceptualizations and assessments of 1994; Glaser, Rabin, Chesney, Cohen, & Natelson, 1999). both social support and immune function. One of the first studies used an academic examination para­ digmto investigate acute stress, social support, and immune Close Personal Relationships response to hepatitis B vaccination (Glaser, Kiecolt-Glaser, Bonneau, Malarkey, & Hughes, 1992). Although no differ­ While the previously reviewed studies explored the support ences in seroconversion rates were found when comparing relationships provided by one's social network (friends, fam­ subjects on social support, social support was positively ily, coworkers, etc.), certain social relationships have greater associated with the immune response to the vaccine as mea­ psychological and physiological importance than others. suredby total antibody titers and T cell responses to the vac­ Close personal relationships provide a unique source of cine antigen. Similarly, subjects with low social integration social support, often encompassing all of the four general (lessdiverse social roles) were three times more likely to de­ components of social support (e.g., emotional support, in­ velop clinical symptoms of cold when infected with a cold strumental support, informational support, and appraisal virus compared to subjects with high social integration support). Arguably, the most important close personal rela­ (Cohen,Doyle, Skoner, Rabin, & Gwaltney, 1997). tionship is the marital relationship. Married persons have A large number of studies on social support have involved lower rates of morbidity and mortality compared to nonmar­ Hl'V-positive individuals who had not yet progressed to AIDS ried persons across a variety of conditions, including (asymptomatic). Given the positive benefits of social support cancer, myocardial infarction, and surgery (Chandra, Szklo, on immune function, perhaps HIV-positive individuals with Goldberg, & Tonascia, 1983; Goodwin, Hunt, Key, & Samet, high social support would show a slower decline in immune 1987; Gordon & Rosenthal, 1995; House et al., 1988). competence associated with progression to AIDS. Although Although healthy marital relationships afford health bene­ initial studies indicated negative findings (Goodkin, Blaney, fits, disruptions in the marital relationship are associated with et al., 1992; Perry, Fishman, Jacobsberg, & Frances, 1992), health risks. Separated or divorced adults have higher rates of later studies found increased social participation and de­ acute illness and physician visits compared to married per­ creased lonelir-ess to be associated with higher CD4+ counts sons and higher rates of mortality from infectious diseases, (Persson, Gullberg, Hanson, Moestrup, & Ostergren, 1994; including pneumonia (Somers, 1979; Verbrugge, 1979, Straits-Troester et al., 1994). Moreover, low perceived emo­ 1982). As such, PNI studies in this domain have focused on tional support was associated with a more rapid decline in disruptive aspects of the marital relationship and their conse­ CD4+ cells (Theorell et al., 1995). quences for immune competence.

Social Support-Immune Pathways Marital Disruption

Considerable evidence suggests that social support con­ Initial studies of marital relationships and immune function tributes positively to immune function. The pathways focused on the immune consequences of separation and/or through which social relationships can influence immune divorce (Kiecolt-Glaser, Fisher, et al., 1987; Kiecolt-Glaser competence appear to be through primarily stress-buffering et al., 1988). In these studies, married adults were compared effects (Esterling, Kiecolt-Glaser, et al., 1994; Esterling to separated and/or divorced adults on enumerative and func­ et al., 1996; Goodkin, Blaney, et al., 1992; Kang et al., 1998; tional measures of immune function. Separated/divorced Kiecolt-Glaser et aI., 1991; Theorell et al., 1990), although males and females showed higher IgG antibody titers to ample evidence suggests that immunological regulation is latent EBV, indicative of poorer immune competence in promoted by the mere presence of supportive others controlling the latent virus. Separated/divorced males also (S. Cohen et al., 1997; Levy et al., 1990; Linn et al., 1988; showed higher antibody titers to latent HSV, and separated/ Persson et al., 1994; Theorell et al., 1995; Thomas et al., divorced females showed poorer blastogenic response to 1985). The magnitude of these effects appears to be small PHA compared to married counterparts. Poorer psychologi­ (r = .21), as shown in a meta-analysis of the literature up to cal adjustment to separation, particularly stronger feelings of 1995(Uchino, Cacioppo, & Kiecolt-Glaser, 1996). However, attachment and shorter separation periods, were associated these effects may have clinical relevance because social with increased distress, lower helper to suppressor T-cell 84 Psychoneuroimmunology

ratios, and poorer blastogenic responses to mitogen. Subjec­ Other studies of marital interaction also show that behav­ tive ratings of low marital quality, as measured by the Dyadic ior during conflict is associated with immune modulation. A Adjustment Scale (Spanier, 1976), were associated with decrease in the blastogenic response to PHA was found in fe­ higher antibody titers to latent EBV for males and females. males, but not in males, in response to marital conflict, and These findings suggest separation and divorce result in dys­ this negative change was associated with increased hostility regulation of cell-mediated immunity, particularly for per­ (Mayne, O'Leary, McCrady, Contrada, & Labouvie, 1997). sons who have difficulty adapting. Consistent with immunological changes during acute labora­ tory stress, marital conflict was associated with increased NK Marital Interaction cell cytotoxicity, specific to male subjects high in hostility (Miller, Dopp, Myers, Felten, & Fahey, 1999). This is likely Further studies of marital disruption focused on how behav­ due to altered trafficking of specific NK cell subtypes into iors exhibited during a couple's interaction were related to peripheral blood (Dopp, Miller, Myers, & Fahey, 2000). immune function. In the first study, we assessed autonomic, In the context of the marital relationship, negative behav­ endocrine, and immune function over a 24-hour period in 90 iors during an interaction are also reliably associated with newlywed couples who met stringent mental and physical endocrine changes. Newlywed couples exhibiting higher criteria (Kiecolt-Glaser et al., 1993). Couples engaged in a levels of hostile and negative behavior during conflict 30-minute conflict resolution task in which they discussed showed elevated levels of epinephrine, norepinephrine, current marital problems. Individuals who exhibited more ACTH, and growth hormone, and lower levels of prolactin hostile or negative behaviors during conflict showed greater (Malarkey, Kiecolt-Glaser, Pearl, & Glaser, 1994). More­ decrements in functional immune measures, including de­ over, the association between high negative behavior and en­ creased NK cell lysis, blastogenic response to PHA and docrine changes were stronger and more consistent for Con A, and proliferative response to a monoclonal antibody women compared to men. Higher probabilities of a hus­ against the T cell receptor. Notably, these declines in immune band's withdrawal in response to their wife's negative function were more likely to occur in women than men. In behavior were associated with higher norepinephrine and addition, similar to the previous findings, individuals who ex­ cortisol in wives. Behavior during marital conflict accounted hibited more negative or hostile behaviors during conflict had for a significant proportion of variance in various endocrine higher antibody titers to latent EBY. Thus, not only were measures, accounting for 24% to 37% of the variance over a negative behaviors during conflict a significant predictor 24-hour period (Kiecolt-Glaser, Newton, et al., 1996). Simi­ of declines in marital satisfaction (Markman, 1991), but lar effects were found in older couples, with negative behav­ these same behaviors significantly predicted declines in im­ iors accounting for 16% to 21% of the variance in changes in mune function during a 24-hour period and in immune com­ cortisol, ACTH, and epinephrine (Kiecolt-Glaser et al., petence in controlling latent herpes viruses. 1997). These endocrine changes may mediate the immune Older couples display less negative behavior and more af­ function changes observed during conflict. fectionate behavior than younger couples during conflict Overall, these findings suggest that marital disruption can (Carstensen, Levenson, & Gottman, 1995), and therefore influence health outcomes through immunological pathways. may display a different pattern of immune changes. To ex­ In particular, high levels of hostile and negative behavior dur­ plore this possibility, older couples (mean age = 67) who had ing marital conflict may be particularly harmful. Moreover, been married an average of 42 years, were studied using the the endocrine and immunological changes in response to same paradigm as our newlywed study (Kiecolt-Glaser et al., negative behavior are more readily observed in women com­ 1997). Subjects who showed poorer responses on functional pared to men. This suggests that the negative physiological immune measures, including blastogenic responses to PHA impacts of marital discord are greater for women compared and Con A, and antibody titers to latent EBV, engaged in to men, though the gender discrepancy in health outcomes is more negative behavior during conflict. Moreover, these sub­ less clear (Kiecolt-Glaser & Newton, 2001). jects characterized their typical marital disagreements as more negative than subjects with relatively better immune function. Overall, these results are particularly striking given PSYCHOLOGICAL INTERVENTIONS that these couples, both young and old, had happy marriages and were mentally and physically fit. Thus, it is likely that Evidence that psychosocial characteristics are associated these findings actually underestimate the physiological im­ with alterations in immune function suggests that psycholog­ pact of marital strife (Kiecolt-Glaser, 1999). ical interventions targeting psychosocial vulnerability factors Psychological Interventions 85 may have beneficial immune outcomes. In both healthy and at one-month follow-up. In a subsequent study, relaxation in­ ill (e.g., cancer, HIV) populations, psychological interven­ tervention with medical students prior to exams did not sig­ tions, such as classical conditioning, relaxation and hypnosis, nificantly alter stress-induced changes in immune function in emotional disclosure, and cognitive-behavioral strategies, the group as a whole. However, students who practiced relax­ havebeen used to improve mood, coping ability, and social ation more frequently had higher helper T-lymphocyte per­ support in attempts to modulate immune function. centages during examinations, after controlling for baseline levels (Kiecolt-Glaser et al., 1986). Varied methods of relaxation and guided imagery intervention have been associ­ ClassicalConditioning ated with increased lymphocyte proliferation to mitogens Classical conditioning studies in rodents have demonstrated (McGrady et aI., 1992), increased NKCC (Zachariae et a!., modulation of humoral, cell mediated, and nonspecific immu­ 1990), increased plasma IL-l (Keppel, Regan, Heffeneider, & nitywith potential biological significance related to the onset McCoy, 1993), and enhanced neutrophil phagocytic activity andcourse of autoimmune diseases, morbidity, and mortality (Peavey, Lawlis, & Goven, 1986). (seefor review, Ader & Cohen, 1993; Ader, Felten, & Cohen, Hypnosis studies using the "double arm" technique have 1991). Although there have been few human studies of classi­ evaluated whether individuals can intentionally modify their calconditioning, their findings are encouraging. In one study, immunological response, such as immediate and delayed hy­ tuberculin DTH responses were conditioned by administering persensitivity. In these studies, the same allergic substance is tuberculin once a month for six months. Tuberculin was injected into both arms of a subject and hypnotic suggestions drawn from a red vial and administered to one arm, while are made about inflammatory response changes (e.g., itching, saline was drawn from a green vial and administered to wheal, erythema) in one arm and no changes in the other arm. the other arm. On the double blind test trial, the contents of Differences in the responses of both arms have been found in thevials were switched. Saline did not produce a skin reaction several studies (Black, 1963; Black & Friedman, 1965; Black, onthe arm that had previously received tuberculin, but the re­ Humphrey, & Niven, 1963; Zachariae & Bjerring, 1990; actionto tuberculin was diminished on the arm that normally Zachariae, Bjerring, & Arendt-Nielsen, 1989), but not in oth­ received saline (Smith & McDaniels, 1983). ers (Beahrs, Harris, & Hilgard, 1970; Locke et aI., 1987). In a second study, conditioning in a naturalistic setting was Whether the hypersensitivity changes found in some observed in women undergoing chemotherapy for ovarian studies are due to immune function changes or only skin sur­ cancer. Following repeated pairing of immunosuppressive face changes remains to be determined. However, high hyp­ chemotherapy with hospital stimuli, the hospital stimuli alone notizable individuals do produce greater immune changes produced a suppression of lymphocyte proliferation to PHA than low hypnotizable subjects (Gregerson, Roberts, & andConA (Bovbjerg et aI., 1990). In a case study of pediatric Amiri, 1996; Ruzyla-Smith, Barabasz, Barabasz, & Warner, lupus, neutral stimuli (a taste and a smell) were paired with a 1995; Zachariae, Jorgensen, Christensen, & Bjerring, 1997; toxic immunosuppressive medication (cyclophosphamide). Zachariae, Oster, & Bjerring, 1994). Following monthly conditioning trials, the patient showed clinicalimprovement and required only one-half the cumula­ Emotional Disclosure tive typical dose of medication (Olness & Ader, 1992). Additional studies have shown enhanced NKCC activity in Negative life events can have psychological impact for many responseto neutral stimuli after they were paired with injec­ years (Tait & Silver, 1989) and can result in persistent eleva­ tions of epinephrine (Buske-Kirschbaum, Kirschbaum, tion of stress hormones (Baum, Cohen, & Hall, 1993). There Stierle, Jabaij, & Hellhammer, 1994; Buske-Kirschbaum, is evidence that social constraints to emotional expression Kirschbaum,Stierle, Lehnert, & Hellhammer, 1992). and discussion of negative events are associated with nega­ tive emotional (Lepore & Helgeson, 1998) and physiological (Helgeson, 1991) outcomes, including increased intrusive Relaxation and Hypnosis thoughts, more avoidant coping, and greater depression and Arelaxation study with older adults in independent living fa­ anxiety. Emotional disclosure interventions, to the extent that cilitiesshowed significant increases in NKCC and better con­ they increase cognitive processing, alter appraisals, reduce trolof latent HSV following one month, three times weekly, intrusive thoughts, and reduce negative mental health conse­ of progressive muscle relaxation training with guided im­ quences of negative events, have been related to positive agery, compared to social contact and no intervention alterations in immune function. These immune changes (Kiecolt-Glaser et aI., 1985). These benefits were maintained are found typically weeks to months postintervention. For 86 Psychoneuroimmunology example, healthy college students who wrote about personal, women receiving chemotherapy for ovarian cancer. The in­ traumatic experiences showed increased lymphocyte prolif­ tervention included progressive muscle, release-only, and eration to PHA and fewer health center visits at the six­ cue-controlled relaxation techniques and was practiced daily week follow-up, and this effect was strongest for those who for more than four weeks. Training began the day before wrote about experiences they had not previously shared the start of the first course of chemotherapy. In this case, (Pennebaker, Kiecolt-Glaser, & Glaser, 1988). In another the relaxation intervention was not associated with reli­ study, medical students who wrote about a highly traumatic able changes in NKCC or lymphocyte proliferation to Con A personal event generated higher antibody titers to a hepatitis measured prior to subsequent courses of chemotherapy vaccination given on the last day of writing by four- and six­ (Lekander, Furst, Rotstein, Hursti, & Fredrikson, 1997). Dif­ month follow-up than did control subjects who wrote about ficulties in interpreting the outcomes of cancer-related inter­ trivial topics (Petrie, Booth, Pennebaker, Davison, & vention studies stem from such methodological differences Thomas, 1995). Four months following a written emotional as method of assignment of subjects to control and interven­ disclosure intervention, asthma patients experienced im­ tion conditions, control for type and stage of disease, variable proved lung function and rheumatoid arthritis patients had outcome measures, and different follow-up periods. clinically significant improvements in overall disease activ­ ity, compared to controls (Smyth, Stone, Hurewitz, & Kaell, HIV 1999). Finally, the extent to which individuals became emo­ tionally and cognitively involved in the disclosure process, Several intervention studies involving HIV seropositive and reorganized the meaning of the traumatic event, and reduced seronegative gay men have found some positive effects of inter­ avoidance of the topic was correlated with the degree of vention on immune function. In the first of these studies, exer­ change in antibody titers to latent EBV (Esterling, Antoni, cise interventions protected asymptomatic seropositive gay men Fletcher, Margulies, & Schneiderman, 1994; Lutgendorf, from depression, anxiety, and a decrease in NK cell numbers Antoni, Kumar, & Schneiderman, 1994). that was observed in seropositive control subjects following no­ tification of serostatus (LaPerriere et al., 1990). Similarly, a comprehensive 10-week cognitive-behavioral stress manage­ Cancer ment intervention, which included relaxation training, cognitive A classic, well-controlled study of the impact of a psycholog­ restructuring, assertiveness training, anger management, and ical intervention on immune function and progression of can­ social support, was associated with significant increases in cer involved Stage I and II malignant melanoma patients. A CD4+ and NK cell counts from 72 hours before to one week six-week structured group intervention included stress man­ after HIV-positive serostatus notification in healthy, asympto­ agement, relaxation, support, health education, and problem­ matic gay men (Antoni et al., 1991). Cognitive-behavioral and solving skills related to participants' illness (Fawzy et aI., exercise interventions were also associated with better cellular 1990). The patients who received the intervention had immunity to the latent herpesviruses, EBV, and human herpes reduced psychological distress, increased percentage of virus type-6 in asymptomatic seropositive gay men (Esterling NK cells, increased IFN-a augmented NKCC, and a small et aI., 1992), and HSV-2 in symptomatic gay men (Lutgendorf reduction in the percentage of helper T cells by six-month et al., 1997). Greater practice of relaxation (Antoni et al., 1991; follow-up. Decreased depression and anxiety symptoms and Lutgendorf et aI., 1997) and greater adherence to the interven­ increased assertiveness and defiance were related to in­ tion protocols (Ironson et al., 1994) were significant predictors creased NKCC. At the six-year follow-up, there was a trend of less distress and disease progression. In one other interven­ for fewer recurrences and significantly lower mortality in the tion study, progressive muscle relaxation and guided imagery intervention subjects, even after controlling for the size of the were both associated with decreased depression in HIV seropos­ initial malignant melanoma (Fawzy et aI., 1993). In a study of itive individuals, but only progressive muscle relaxation was breast cancer patients, a six-month intervention, including re­ associated with a significant increase in CD4+ cell counts com­ laxation, guided imagery, and biofeedback, was associated pared to controls (Eller, 1995). with greater NKCC, lymphocyte proliferative response to Psychosocial factors may play a role in HIV progres­ Con A, and mixed lymphocyte responsiveness in women post sion because there is great variability among individuals in radical mastectomy for stage I breast cancer (Gruber et al., the length of time to develop clinical symptoms and in 1993). the severity of illness at different stages of AIDS. However, Another relaxation intervention study was targeted at not all studies have shown significant relationships between altering conditioned anticipatory immune suppression in psychosocial measures and immune variables in HIV-l References 87

seropositive individuals (Perry et aI., 1992; Rabkin et al., immune function, health, and disease. Further understanding 1991) or between psychological intervention and immune of the bidirectional relationships between brain, behavior, changes (Coates, McKusick, Kuno, & Stites, 1989; Mulder and immunity will be attained with theoretical and method­ et aI., 1995). Such negative findings indicate the need for the­ ological refinements. In addition to these refinements, the oretically driven models of association between psychosocial next wave of PNI research will expand our knowledge of and immune or health outcomes, controls for health behav­ psychosocial factors and their role in the progression of im­ iors, inclusion of a broad range of immune measures, and munologically mediated conditions, including HIY/AIDS, control for stage of disease (Goodkin et al., 1994). rheumatoid arthritis, certain cancers, and surgical recovery. Psychological interventions that show evidence of immune From this knowledge, we can devise and implement effective function modulation likely have their effects through alter­ interventions to enhance quality of life and improve health. ations of appraisal, coping, or mood, which in turn affect Indeed, PNI embodies the biopsychosocial approach (Engel, health behaviors, endocrine activity, and immune function. 1977) that has come to define health psychology. The importance of intervention effects on negative emotions is demonstrated by studies showing covariation in immuno­ logical changes and reduced negative emotion (Antoni et al., REFERENCES 1991;Fawzy et al., 1990; Lutgendorfet al., 1997). The poten­ tial health outcomes of immunological changes that follow Ader, R., & Cohen, N. (1993). Psychoneuroimmunology: Condi­ psychological interventions remain to be determined. Further tioning and stress. 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