A Randomized Controlled Trial of the Effects of Mindfulness-Based Stress Reduction (MBSR[BC]) on Levels of Inflammatory Biomarkers Among Recovering Breast Cancer Survivors.

PURPOSE: The purpose of this substudy of a large randomized controlled trial was to evaluate the efficacy of the Mindfulness-Based Stress Reduction (Breast Cancer) (MBSR[BC]) program compared to usual care (UC) in normalizing blood levels of pro-inflammatory cytokines among breast cancer survivors (BCS). METHOD: A total of 322 BCS were randomized to either a 6-week MBSR(BC) program or a UC. At baseline and 6 and 12 weeks, 10 ml of venous blood and demographic and clinical data were collected and/or updated. Plasma cytokines (interleukin [IL]-1ß, IL-6, IL-10, tumor necrosis factor [TNF] α, transforming growth factor [TGF] ß1, soluble tumor necrosis factor receptor [sTNFR] 1) were assayed. Linear mixed models were used to assess cytokine levels across three time points (baseline and 6 and 12 weeks) by group (MBSR[BC] vs. UC). RESULTS: Of the six measured cytokines, three were nondetectable at rates greater than 50% (IL-10, IL-1ß, TGF-ß1) and, because of overall low prevalence, were not analyzed further. For the remaining cytokines (TNFα, IL-6, sTNFR1), results showed that TNFα and IL-6 increased during the follow-up period (between 6 and 12 weeks) rather than during the MBSR(BC) training period (between baseline and 6 weeks), while sTNFR1 levels did not change significantly across the 12-week period. CONCLUSIONS: Study results suggest that MBSR(BC) affects cytokine levels in BCS, mainly with increases in TNFα and IL-6. The data further suggest that B-cell modulation may be a part of immune recovery during breast cancer management and that increases in TNFα and IL-6 may be markers for MBSR(BC)-related recovery.

Δ(9)-Tetrahydrocannabinol treatment during human monocyte differentiation reduces macrophage susceptibility to HIV-1 infection.

The major psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), also acts to suppress inflammatory responses. Receptors for THC, CB1, CB2, and GPR55, are differentially expressed on multiple cell types including monocytes and macrophages, which are important modulators of inflammation in vivo and target cells for HIV-1 infection. Use of recreational and medicinal marijuana is increasing, but the consequences of marijuana exposure on HIV-1 infection are unclear. Ex vivo studies were designed to investigate effects on HIV-1 infection in macrophages exposed to THC during or following differentiation. THC treatment of primary human monocytes during differentiation reduced HIV-1 infection of subsequent macrophages by replication competent or single cycle CCR5 using viruses. In contrast, treatment of macrophages with THC immediately prior to or continuously following HIV-1 exposure failed to alter infection. Specific receptor agonists indicated that the THC effect during monocyte differentiation was mediated primarily through CB2. THC reduced the number of p24 positive cells with little to no effect on virus production per infected cell, while quantitation of intracellular viral gag pinpointed the THC effect to an early event in the viral life cycle. Cells treated during differentiation with THC displayed reduced expression of CD14, CD16, and CD163 and donor dependent increases in mRNA expression of selected viral restriction factors, suggesting a fundamental alteration in phenotype. Ultimately, the mechanism of THC suppression of HIV-1 infection was traced to a reduction in cell surface HIV receptor (CD4, CCR5 and CXCR4) expression that diminished entry efficiency.

Baseline immune biomarkers as predictors of MBSR(BC) treatment success in off-treatment breast cancer patients.

Researchers focused on patient-centered medicine are increasingly trying to identify baseline factors that predict treatment success. Because the quantity and function of lymphocyte subsets change during stress, we hypothesized that these subsets would serve as stress markers and therefore predict which breast cancer patients would benefit most from mindfulness-based stress reduction (MBSR)-facilitated stress relief. The purpose of this study was to assess whether baseline biomarker levels predicted symptom improvement following an MBSR intervention for breast cancer survivors (MBSR[BC]). This randomized controlled trial involved 41 patients assigned to either an MBSR(BC) intervention group or a no-treatment control group. Biomarkers were assessed at baseline, and symptom change was assessed 6 weeks later. Biomarkers included common lymphocyte subsets in the peripheral blood as well as the ability of T cells to become activated and secrete cytokines in response to stimulation with mitogens. Spearman correlations were used to identify univariate relationships between baseline biomarkers and 6-week improvement of symptoms. Next, backward elimination regression models were used to identify the strongest predictors from the univariate analyses. Multiple baseline biomarkers were significantly positively related to 6-week symptom improvement. The regression models identified B-lymphocytes and interferon-γ as the strongest predictors of gastrointestinal improvement (p < .01), +CD4+CD8 as the strongest predictor of cognitive/psychological (CP) improvement (p = .02), and lymphocytes and interleukin (IL)-4 as the strongest predictors of fatigue improvement (p < .01). These results provide preliminary evidence of the potential to use baseline biomarkers as predictors to identify the patients likely to benefit from this intervention.

Lymphocyte recovery after breast cancer treatment and mindfulness-based stress reduction (MBSR) therapy.

OBJECTIVES: This randomized controlled trial was conducted to examine immune recovery following breast cancer (BC) therapy and evaluate the effect of mindfulness-based stress reduction therapy (MBSR) on immune recovery with emphasis on lymphocyte subsets, T cell activation, and production of T-helper 1 (Th1; interferon [IFN]-γ) and T-helper 2 (Th2; interleukin-4 [IL-4]) cytokines. METHOD: Participants who completed the study consisted of 82 patients diagnosed with Stage 0-III BC, who received lumpectomy and adjuvant radiation ± chemotherapy. Patients were randomized into an MBSR(BC) intervention program or a control (usual care) group. Immune cell measures were assessed at baseline and within 2 weeks after the 6-week intervention. The numbers and percentages of lymphocyte subsets, activated T cells, and Th1 and Th2 cells in peripheral blood samples were determined by immunostaining and flow cytometry. RESULTS: Immune subset recovery after cancer treatment showed positive associations with time since treatment completion. The B and natural killer (NK) cells were more susceptible than T cells in being suppressed by cancer treatment. Women who received MBSR(BC) had T cells more readily activated by the mitogen phytohemagglutinin (PHA) and an increase in the Th1/Th2 ratio. Activation was also higher for the MBSR(BC) group if <12 weeks from the end of treatment and women in MBSR(BC) <12 weeks had higher T cell count for CD4(+). CONCLUSION: MBSR(BC) promotes a more rapid recovery of functional T cells capable of being activated by a mitogen with the Th1 phenotype, whereas substantial recovery of B and NK cells after completion of cancer treatment appears to occur independent of stress-reducing interventions.

Randomized controlled trial of mindfulness-based stress reduction (MBSR) for survivors of breast cancer.

OBJECTIVES: Considerable morbidity persists among survivors of breast cancer (BC) including high levels of psychological stress, anxiety, depression, fear of recurrence, and physical symptoms including pain, fatigue, and sleep disturbances, and impaired quality of life. Effective interventions are needed during this difficult transitional period. METHODS: We conducted a randomized controlled trial of 84 female BC survivors (Stages 0-III) recruited from the H. Lee Moffitt Cancer and Research Institute. All subjects were within 18 months of treatment completion with surgery and adjuvant radiation and/or chemotherapy. Subjects were randomly assigned to a 6-week Mindfulness-Based Stress Reduction (MBSR) program designed to self-regulate arousal to stressful circumstances or symptoms (n=41) or to usual care (n=43). Outcome measures compared at 6 weeks by random assignment included validated measures of psychological status (depression, anxiety, perceived stress, fear of recurrence, optimism, social support) and psychological and physical subscales of quality of life (SF-36). RESULTS: Compared with usual care, subjects assigned to MBSR(BC) had significantly lower (two-sided p<0.05) adjusted mean levels of depression (6.3 vs 9.6), anxiety (28.3 vs 33.0), and fear of recurrence (9.3 vs 11.6) at 6 weeks, along with higher energy (53.5 vs 49.2), physical functioning (50.1 vs 47.0), and physical role functioning (49.1 vs 42.8). In stratified analyses, subjects more compliant with MBSR tended to experience greater improvements in measures of energy and physical functioning. CONCLUSIONS: Among BC survivors within 18 months of treatment completion, a 6-week MBSR(BC) program resulted in significant improvements in psychological status and quality of life compared with usual care.

Therapeutic potential of cannabinoid-based drugs.

Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer's disease, atherosclerosis, and osteoporosis.

Cannabinoid treatment suppresses the T-helper cell-polarizing function of mouse dendritic cells stimulated with Legionella pneumophila infection.

Marijuana cannabinoids, such as delta-9-tetrahydrocannabinoid (THC), suppress type 1 T-helper 1 (Th1) immunity in a variety of models, including infection with the intracellular pathogen Legionella pneumophila (Lp). To examine the cellular mechanism of this effect, bone marrow-derived dendritic cells (DCs) were purified from BALB/c mice and studied following infection and drug treatment. DCs infected in vitro with Lp were able to protect mice when injected prior to a lethal Lp infection; however, the immunization potential of the Lp-loaded cells along with Th1 cytokine production was attenuated by THC treatment at the time of in vitro infection. In addition, THC-treated and Lp-loaded DCs were poorly stimulated in culture-primed splenic CD4(+) T cells to produce interferon-gamma; however, this stimulating deficiency was reversed by adding recombinant interleukin (IL)-12p40 protein to the cultures. Moreover, THC treatment inhibited the expression of DC maturation markers, such as major histocompatibility complex class II and costimulatory molecules CD86 and CD40 as determined by flow cytometry and suppressed the Notch ligand, Del-ta4, as determined by reverse transcription-polymerase chain reaction. However, THC treatment did not affect other DC functions, such as intracellular killing of Lp, determined by colony-forming unit counts of bacteria, and Lp-induced apoptosis, determined by annexin V staining. In conclusion, the data suggest that THC inhibits Th1 activation by targeting essential DC functions, such as IL-12p40 secretion, maturation, and expression of costimulatory and polarizing molecules.

Cannabinoid-based drugs as anti-inflammatory therapeutics.

In the nineteenth century, marijuana was prescribed by physicians for maladies ranging from eating disorders to rabies. However, as newer, more effective drugs were discovered and as the potential for abuse of marijuana was recognized, its use as a therapeutic became restricted, and only recently has its therapeutic potential been re-evaluated. Recent studies in animal models and in humans have produced promising results for the treatment of various disorders - such as obesity, cancer, and spasticity and tremor due to neuropathology - with drugs based on marijuana-derived cannabinoids. Moreover, as I discuss here, a wealth of information also indicates that these drugs have immunosuppressive and anti-inflammatory properties; therefore, on the basis of this mode of action, the therapeutic usefulness of these drugs in chronic inflammatory diseases is now being reassessed.

Epigallocatechin gallate, a potential immunomodulatory agent of tea components, diminishes cigarette smoke condensate-induced suppression of anti-Legionella pneumophila activity and cytokine responses of alveolar macrophages.

Even though cigarette smoking has been shown to suppress immune responses in the lungs, little is known about the effect of cigarette smoke components on respiratory infections. In the present study, the effects of cigarette smoke condensate (CSC) on bacterial replication in alveolar macrophages and the immune responses of macrophages to infection were examined. Furthermore, a possible immunotherapeutic effect of epigallocatechin gallate (EGCg), a major form of tea catechins, on the CSC-induced suppression of antimicrobial activity and immune responses of alveolar macrophages was also determined. The treatment of murine alveolar macrophage cell line (MH-S) cells with CSC significantly enhanced the replication of Legionella pneumophila in macrophages and selectively down-regulated the production of interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) induced by bacterial infection. The treatment of macrophages with EGCg not only overcame the CSC-induced suppression of antimicrobial activity but also strengthened the resistance of macrophages to infection. EGCg also markedly up-regulated the CSC-suppressed IL-6 and TNF-alpha production by macrophages in response to infection. The results of exogenous TNF-alpha treatment and neutralization treatment with anti-TNF-alpha and anti-gamma-interferon (IFN-gamma) antibodies and the determination of IFN-gamma mRNA levels indicate that CSC-suppressed macrophages can be activated by EGCg to inhibit L. pneumophila growth by up-regulation of TNF-alpha and IFN-gamma production. Thus, this study revealed that CSC selectively alters the immune responses of macrophages to L. pneumophila infection and leads to an enhancement of bacterial replication in macrophages. In addition, the tea catechin EGCg can diminish such suppressive effects of CSC on alveolar macrophages.

In vitro therapeutic effect of epigallocatechin gallate on nicotine-induced impairment of resistance to Legionella pneumophila infection of established MH-S alveolar macrophages.

Epigallocatechin gallate (EGCg), a major form of tea catechins, has a variety of biological activities. Tobacco smoking, nicotine in particular, is one of the risk factors for respiratory infections. In the present study, a possible immunotherapeutic effect of EGCg on the nicotine-induced impairment of alveolar macrophages regarding antimicrobial activity, as well as immune function, was examined. The treatment of MH-S macrophages with nicotine significantly enhanced Legionella pneumophila replication in the cells and selectively down-regulated the production of interleukin (IL)-6, IL-12, and tumor necrosis factor (TNF)-alpha induced by infection but did not alter IL-10 production. The EGCg treatment of nicotine-suppressed macrophages reconstituted the resistance to the infection. Furthermore, EGCg diminished the nicotine-induced inhibition of cytokine production. Experiments with TNF-alpha treatment, neutralization of cytokines with antibodies, and analysis of interferon (IFN)-gamma messenger RNA showed that the mechanism of the EGCg-induced recovery of anti-L. pneumophila activity impaired by nicotine may be due to the recovery of TNF-alpha and IFN-gamma production by the macrophages.