دانلود مقاله ISI انگلیسی شماره 7076
عنوان فارسی مقاله

افزایش در شاخص بازسازی سیستم ایمنی بدن کاهش می یابد در خروجی کورتیزول ادرار 24 ساعته و خلق و خوی افسرده در طول 10 هفته مداخله مدیریت استرس در مردان آلوده به HIV علامتدار predated

کد مقاله سال انتشار مقاله انگلیسی ترجمه فارسی تعداد کلمات
7076 2005 11 صفحه PDF سفارش دهید محاسبه نشده
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عنوان انگلیسی
Increases in a marker of immune system reconstitution are predated by decreases in 24-h urinary cortisol output and depressed mood during a 10-week stress management intervention in symptomatic HIV-infected men
منبع

Publisher : Elsevier - Science Direct (الزویر - ساینس دایرکت)

Journal : Journal of Psychosomatic Research, Volume 58, Issue 1, January 2005, Pages 3–13

کلمات کلیدی
مدیریت استرس - ایمنی - کورتیزول - افسردگی
پیش نمایش مقاله
پیش نمایش مقاله افزایش در شاخص بازسازی سیستم ایمنی بدن کاهش می یابد در خروجی کورتیزول ادرار 24 ساعته و خلق و خوی افسرده در طول 10 هفته مداخله مدیریت استرس در مردان آلوده به HIV علامتدار predated

چکیده انگلیسی

Stress management interventions reduce distress symptoms and hypothalamic–pituitary–adrenal (HPA) axis hormones such as cortisol, which has been related to a down-regulation of immune system components relevant to the human immunodeficiency virus (HIV) infection. We previously showed that HIV+ men assigned to a 10-week cognitive behavioral stress management (CBSM) intervention showed more CD4+CD45RA+CD29+ lymphocytes, an indicator of immune system reconstitution, at a 6- to 12-month follow-up compared with controls. Here, we tested whether reductions in urinary cortisol output and depressed mood during the 10-week CBSM intervention period mediated its effects on this immune system reconstitution marker at follow-up.

مقدمه انگلیسی

The human immunodeficiency virus (HIV) infection is a chronic disease involving a progressive loss of the cellular immune system repertoire [1]. Research has illuminated specific components of the immune system that seem most susceptible to HIV, the pattern of cellular declines, and even provided evidence that these specific components of the immune system may be reconstituted at different rates with successful antiretroviral therapy. We know that while T-helper-inducer (CD3+CD4+) cells show reliable declines with the progression of HIV infection, there appears to be a preferential decline in the naive CD4 T-cell subset (CD4+CD45RA+) over the memory subset (CD4+CD29+; [2] and [3]). This preferential decline in naive CD4+ T-cells appears to be responsible for the disruptions in the cellular immune repertoire for novel antigens, this underlying the increased susceptibility to opportunistic infections and neoplasias [2] and [4]. It is also becoming clear that the sharp rise in CD4+ T-cell counts shortly following the advent of antiretroviral therapy is due primarily to the redistribution of memory CD4+ T-cells, with increases in naive CD4+ T-cells being unlikely for at least several months [5] and [6]. Some have proposed that only these delayed increases in naive CD4+ T-cells occurring after such therapy constitute true “immune reconstitution” [7]. Moreover, incomplete or substantially delayed reconstitution of the T-cell repertoire may actually increase susceptibility to certain neoplasms, such as squamous cell skin cancers, testicular cancer, myeloma, and Hodgkin's disease, among HIV-infected persons receiving antiretroviral therapy [8] and [9]. As naive CD4+ T-cells emerge from the thymus, they express high molecular weight forms of a tyrosine phosphatase identified by CD45RA monoclonal antibodies [10]. Increases in CD4+CD45RA+ cells following antiretroviral therapy may represent cells newly generated by the thymus (i.e., renewed thymopoiesis) or a simple expansion of naive T-cells from the periphery [11] and [12]. One strategy for delineating those naive CD4+ T-cells that are newly differentiated from the thymus is to enumerate “transitional” naive CD4 T-cells—those that are actively converting from a CD45RA+CD29—or “virgin” condition to a CD45RA–CD29+ memory phenotype in response to in vivo stimuli [13]. Because this progression is believed to be unidirectional, increases in transitional naive CD4 T-cells (CD45RA+CD29+) are likely to have come from newly created naive cells rather than from a peripheral expansion of naive phenotype cells that had not been depleted before antiretroviral therapy. No work to date has identified external factors that may contribute to the rate of reconstitution of these naive CD4 T-cells in HIV-infected persons. Given their well-known effects on the cellular immune repertoire, it is plausible that adrenal hormones such as corticosteroids may retard the ability of the immune system to reconstitute naive CD4 T-cells over time in HIV-infected persons. The present study will focus on this question. Recent work suggests that HIV-infected persons show abnormalities in the hypothalamic–pituitary–adrenal (HPA) axis, which may increase with the progression of disease and which favor a shift from Th1- to Th2-like cytokine production [14], [15] and [16]. It is well known that cortisol directly impairs or modifies several components of cellular immunity, including T-lymphocytes [17], macrophages [18], and natural killer (NK) cells [19]. After corticosteroids bind to intracytoplasmic receptors on these cells, the complex travels to the nucleus and binds to DNA sequences that control glucocorticoid-regulated transcription genes for functions such as cytokine synthesis and apoptosis [20] and [21]. Among HIV-infected persons, elevations in peripheral cortisol levels are associated with lower T-helper-inducer cell counts [16]. Cortisol also appears to promote decreases in the production of Th1-like cytokines, such as interleukin-2 (IL-2), while promoting production of Th2-like cytokines, such as IL-4 and IL-10 [21]. Cortisol can induce programmed cell death in mature lymphocytes as well [14] and [22]. However, nothing is known about cortisol's effects on naive CD4 T-cell reconstitution over time. HIV-infected persons may experience abnormal HPA axis functioning, in part, due to the chronic stressors that they must deal with, their increased prevalence of depressed mood, and multiple bereavements and other personal losses [23], [24] and [25]. These stressful experiences and mood disturbances may contribute to the elevated urinary output of cortisol [26], [27] and [28]. An accumulating stress burden due to the lack of mastery over daily stressors, with associated HPA hormone elevations [29], may alter homeostatic mechanisms within the HPA axis that have important implications for HIV+ persons [14]. Such physiologic changes may mediate the documented immunologic deficits associated with some of these psychosocial phenomena in healthy and HIV-infected persons [30] and [31]. Stress management techniques teach people more efficient methods for coping with stressors, reduce depressed mood, and may also normalize cortisol output that may occur during stressful periods [32], [33], [34] and [35]. Improvements in depressed mood [36], [37], [38] and [39] have been demonstrated in HIV-infected persons with a number of time-limited group-based interventions. Decreases in depressed mood during such interventions have been shown to predict slower rates of T-helper-inducer cell (CD3+CD4+) declines and clinical disease progression over a 2-year period [40]. Little is known about the possible neuroendocrine changes occurring with these intervention-associated improvements in depressed mood that might influence the reconstitution of naive CD4+ T-cells. Previously, we monitored levels of transitional naive T-cells (CD4+CD45RA+CD29+) following cognitive behavioral stress management (CBSM) intervention in HIV-infected gay men dealing with the stress of symptomatic disease and found that men assigned to CBSM showed greater numbers of transitional naive T-cells compared with controls at 12-month follow-up [41]. The present study sought to examine possible mechanisms to explain these effects. To test a psychoneuroimmunological (PNI) model underlying this research, we related reductions in 24-h urinary-free cortisol output and depressed mood during the 10-week intervention to the magnitude of immune reconstitution over this 6- to 12-month follow-up period among participants in the initial study who were willing to be contacted and returned to our facility. We hypothesized that the intervention's effects on immune system reconstitution over the follow-up period would be explained by decreased depressed mood and cortisol output during the intervention period. To investigate alternative mechanisms, we also examined the contribution of changes in mood, medication regimen, and health behaviors over the follow-up period.

نتیجه گیری انگلیسی

This study examined the possible mechanisms underlying the effects of a 10-week stress management intervention on a subpopulation of helper T-lymphocytes measured up to 1 year later in men dealing with symptomatic HIV infection. We focused specifically on changes in depressed mood and cortisol previously documented for this intervention. Because increased activation of the HPA axis during stressful experiences has a down-regulatory effect on cellular immune responses to viral infections [22], HIV-infected persons may be at heightened risk for significant pathophysiologic consequences from chronic stress and depressed mood [58], [59] and [60]. Because people's appraisals of personal control over stressors may determine their neuroendocrine responses (e.g., cortisol output) and associated mood state (depressed affect; [22]), stress reduction strategies such as CBSM might influence immune status in HIV-infected persons by modulating mood and neuroendocrine responses through its focus on modifying stressor appraisals. This form of stress reduction modifies stress responses by using tension-reduction skills (relaxation, guided imagery, autogenics, and meditation) and cognitive–behavioral techniques that alter maladaptive cognitive appraisals of stressful events and teach behavioral and interpersonal coping skills for managing stressors [51]. We previously documented that HIV+ men assigned to CBSM show decreases in cortisol output that accompany reductions in depressed mood over a 10-week period [35]. We further showed that men assigned to this intervention showed greater numbers of transitional naive T-cells, an indicator of immune reconstitution, up to 1 year after the completion of CBSM [41]. Here, we examined whether reductions in depressed mood and 24-h cortisol output during CBSM intervention predicted signs of immune system reconstitution over a 6- to 12-month posttreatment period in these men. This study showed that greater reductions in cortisol and depressed mood during CBSM appeared to mediate, in part, the effects of this intervention on transitional naive T-cells over this follow-up period. Importantly, these groups did not differ in HIV viral load either before or after the intervention, suggesting that changes in immune system reconstitution over the subsequent year began from an even playing field of viral burden. In addition, we found no evidence that further changes in mood, medication status, or heath behaviors after the intervention were associated with these immune changes, thus increasing our confidence that it was the mood and endocrine changes during CBSM training that were the unique predictors of longer term immune effects observed at follow-up. Although mood changes following the 10-week intervention period were not predictive of immune changes over follow-up, we cannot rule out that longer term immune effects were associated with further changes in cortisol over the follow-up period because urine data were not collected beyond the initial 10-week period. While changes in medication classification did not account for the effects of CBSM on immune status during the study, we are not able to examine medication adherence as a potential mediator of longer term immune effects associated with CBSM. How might cortisol reductions during CBSM have contributed to immune system reconstitution at follow-up? HPA activation may compound the immunosuppressive effects of HIV infection, including declines in cell-mediated immunity, a shift toward a predominance of Th2-like cytokines, and increases in programmed cell death among mature T-lymphocytes [21]. In addition, the ability of HIV to infect lymphocytes appears to be facilitated by corticosteroids in vitro [61]. Recent work suggests that greater cummulative stress and higher serum cortisol levels predict faster progression to AIDS over a 7.5-year period in HIV-infected gay men, even after controlling for initial HIV viral load levels [62]. The present findings suggest that reductions in HPA activity and depressed mood during a stress-reduction intervention may predate the ability of the immune system to reconstitute over time. Such immune system changes may facilitate a normalization of cell-mediated immune responses to novel antigens and could provide greater protection against opportunistic infections. It is important to note, however, that since we know very little about the effects of this intervention on HIV disease progression, it is premature to conclude that CBSM offers clinical health benefits for HIV-infected persons. It is worth noting, however, that prior work has related greater adherence to the use of stress management techniques with less progression to AIDS over a 2-year period among HIV+ men undergoing a similar CBSM intervention [40]. One should exercise caution in interpreting the precise meaning of these findings. In a study we published from this same set of data, we were only able to obtain 6- to 12-month follow-up immunologic data on just over half of the men who had initially provided pre- to postintervention mood and cortisol data [41]. While we detected no systematic differences between those who did and did not provide follow-up immune data, there still exists the possibility of a systematic bias. This brings into question the reliability and external validity of the findings. Although the primary outcomes—transitional naive T-cells, cortisol, and depressed mood—were evaluated with a finite and reasonable number of statistical tests, we acknowledge that additional tests to explore alternative mechanisms were large, given the present sample size. The combination of a large number of statistical comparisons in a small sample may have resulted in our identifying spurious effects of the intervention and/or failing to detect important effects, which were, in fact, present in control variables. Thus, future work will need to replicate these effects in a larger sample before a great deal of confidence can be placed in the current findings. Beyond the putative confounding variables that we did examine, it should be noted that the endocrine and immune changes we observed over time may also have been due to changes in the direct effects of HIV on the adrenals, antiviral medications, HIV-associated infections, nutritional deficiencies, and altered glucose metabolism [49]. However, these men were all of the same stage of disease (pre-AIDS symptomatic), had not undergone any medication changes in the past month, had no hospitalizations or acute infectious outbreaks in the past month, and were free of any metabolic disorders (e.g., diabetes mellitus). Finally, men randomized to CBSM or control conditions did not differ on antiretroviral medication type, time since diagnosis or T-helper-inducer cell counts, or transitional naive T-cells at study entry. Thus, these men began the study with similar medical, sociodemographic, and behavioral characteristics. Although some men did change their antiretroviral medication regimen over the follow-up period, there were no significant differences in “medication switching” between groups. Thus, it is unlikely that changes in medications after the CBSM intervention were responsible for the greater numbers of CD4+CD45+CD29+ cells among CBSM participants at follow-up. As previously noted, it was unlikely that any changes in mood, depressive symptoms, or health behaviors after the CBSM intervention had concluded were responsible for the effects of CBSM on immune status at follow-up. In fact, direct tests of the relative contribution of mood changes during and after CBSM training revealed that it was only the former that made a unique contribution in predicting changes in immune status over the follow-up period. Such delayed immunologic effects are not totally uncommon in the PNI-intervention literature. Fawzy et al. [63] showed that the effects of group-based stress management intervention on NK cell function lagged the mood effects of this intervention by 6 months among patients being treated for malignant melanoma.

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