Hypnosis, defferential expression of cytokines by T-cell subsets, and the hypothalamo-pituitary-adrenal axis

Wood, Gary J

This investigation tested the hypothesis that hypnosis can differentially modulate T-cell subsets, and that this effect is mediated by changes in hypothalamo-pituitary-adrenal (HPA) mediators. Seven healthy, highly hypnotizable volunteers participated in three one-day sessions, a baseline and two intervention sessions. Hypnosis intervention entailed a standardized induction, suggestions for ego strengthening and optimally balanced functioning of the immune and neuroendocrine systems, and post-hypnotic suggestions for stress management and continued optimal balance of bodily systems. Blood samples were drawn at five time points between 8:00 a.m. and 3:00 p.m. and were analyzed for T-cell activation and intracellular cytokine expression (Interferon (IFN)-gamma, Interleukin-2, Interleukin-4,) and HPA axis mediators (ACTH, cortisol, and beta-endorphin). Following hypnosis intervention, statistically significant immunological effects were noted. Specifically, the proportion of T-cells expressing IFN-gamma (p=.0001) and IL-2 (p = .013) were lower after hypnosis. T-cell activation response to polyclonal stimulation was positively correlated with ACTH (p = .01) and [3-endorphin (p = .001) while IFN-gamma expression was correlated with levels of cortisol (p

Keywords: Cytokines, T-cell, hypnosis, hypothalamo--pituitary--adrenal axis, immunity, neuro-endocrine, psychoneuroimmunology

Introduction

T-lymphocytes are a central component of the adaptive immune response, since these cells have a myriad of functions, including antigen recognition, regulation of antibody and cell-mediated immunity, as well as effector functions, e.g. killing of virally-infected or neoplastic target cells. These functions are essential for maintenance of immunological homeostasis. Moreover, T-cells have been implicated in the pathogenesis of a variety of autoimmune and infectious diseases including rheumatoid arthritis, diabetes mellitus, AIDS, tuberculosis, and periodontitis. Consequently, the ability to modulate the T-cell response will be of interest in the maintenance of health as well as the treatment of disease states.

The ACTH levels in weeks 2 and 3 were lower than baseline not only at 8:00 a.m. but also at 11:00 a.m. and 3:00 p.m. These changes suggest that hypnosis may attenuate ACTH release, most likely mediated via a decrease in corticotropin releasing hormone (CRH) secretion. Since ACTH is under CRH control, which is under tonic inhibition from hippocampal areas, a lower ACTH in the morning during the second and third weeks of the study may suggest either attenuation of the diurnal variations due to an anticipated state of relaxation, or a secondary response to a decreased level of anxiety on weeks 2 and 3 compared with the initial visit. These changes were not significant due to the small number of subjects in the study. We did not, however, observe similar changes in the cortisol levels, probably since ACTH response to hypnotic intervention is more sensitive than the changes in cortisol level. Moreover, the cortisol tested in this study was total serum cortisol, which includes both free, as well as bound cortisol. Inasmuch as more than 90% of circulating cortisol is bound to cortisol-binding globulin (CBG) or albumin, and the free or unbound cortisol is the physiologically active form, it will be important for future studies to test free cortisol. This unbound cortisol is more likely to be available for biologic interaction with T-cells. These findings warrant further investigation using a larger number of subjects and measurements of ACTH and cortisol (total and free), as well as CRH levels.

The exploratory correlational analysis indicated that cortisol and IFN-gamma appear to be positively associated. However, the causality of this association cannot be ascertained from the current evidence. There are several possibilities as to the nature of the causal association, if any, between cortisol and IFN-gamma. Although it is possible that cortisol may have a positive effect on IFN-gamma expression, previous studies predominantly report an inhibitory effect of cortisol on T-cells (Kronfol, Nair, Zhang, Hill, & Brown, 1997; Nair & Schwartz, 1984). Hence, it is possible that the positive association between cortisol and IFN-gamma is the result of an indirect effect of cortisol on other mediators. The hypothesis that we are currently pursuing is that cortisol has a negative effect on the Th2 subset of T-cells. In that regard, our data indicate a trend toward a negative correlation between cortisol and IL-4 (r = -.23, p = .07). Thus, we have hypothesized that cortisol has an inhibitory effect on Th2 cells that express IL-4. Normally, IL-4 produced by the Th2 subset of T-cells has an inhibitory effect on IFN-gamma production by Thl Tcells. Thus, it is possible that the removal of the inhibitory feedback of IL-4 leads to a rise in IFN-gamma production, or vice versa.

The present study introduces a model for studying non-pharmacological modulation of the T cell response and the cellular and molecular mediators involved. This model is of possible interest not only for understanding the basic psychoneuroimmunological interactions involved, but also potential clinical applications of this form of immuno-modulation. Experiments are currently in progress to address some of the issues raised by the present study.

Acknowledgments

This research was supported in part by the NIH NCRR GCRC Grant MOI RR-43 and grant 1 R03 DE13271-O1A1 from the National Institute of Dental and Craniofacial Research.

References

Ader, R., Cohen, N., & Felten, D. (1995). Psychoneuroimmunology: Interactions between the nervous system and the immune system. Lancet, 345(8942), 99-103.

Altman, S.A., Randers, L., & Rao, G. (1993). Comparison of trypan blue dye exclusion and fluorometric assays for mammalian cell viability determinations. Biotechnology Progress 19, (Nov-Dec 9:6) 671-4.

Bongartz, W., Lyncker, I., & Kossman, K. (1987). The influence of hypnosis on white blood cell count and urinary levels of catecholamines and vanillyl mandelic acid. Hypnos, XIV(2), 52-61.

Boyum, A. (1968). Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scandinavian Journal of Clinical and Laboratory Investigation, Supplement, 97, 77-89.

Domangue, B. B., Margolis, C. G., Lieberman, D., & Kaji, H. (1985). Biochemical correlates of hypnoanalgesia in arthritic pain patients. Journal of Clinical Psychiatry, 46(6), 235-8.

Finkelstein, S. (1990). The private refuge. In D. C. Hammond (Ed.), Handbook of hypnotic suggestions and metaphors (pp. 158). New York: W. W. Norton and Co.

Gruber, B. L., Hall, N. R., Hersh, S. P., & Dubois, P. (1988). Immune system and psychological changes in metastatic cancer patients using relaxation and guided

imagery: A pilot study. Scandinavian Journal of Behaviour Therapy, 17(1), 25-46.

Gruber, B. L., Hersh, S. P., Hall, N. R., Waletzky, L. R., Kunz, J. F., Carpenter, J. K., Kverno, K. S., & Weiss, S. M. (1993). Immunological responses of breast cancer patients to behavioral interventions. Biofeedback and Self Regulation, 18(1), 1-22.

Hall, H. R. (1982-83). Hypnosis and the immune system: A review with implications for cancer and the psychology of healing. American Journal of Clinical Hypnosis, 25(2-3), 92-103.

Hall, H. R., Mumma, G. H., Longo, S., & Dixon, R. (1992). Voluntary immunomodulation: a preliminary study. International Journal of Neuroscience, 63(3-4), 275-85. Hartland, J. (1971). Further observations on the use of "ego-strengthening" techniques. American Journal of Clinical Hypnosis, 14(1), 1-8.

Keown, P. A. (1998). New immunosuppressive strategies. Current Opinion in Nephrology & Hypertension, 7(6), 659-63.

Kronfol, Z., Nair, M., Zhang, Q., Hill, E. E., & Brown, M. B. (1997). Circadian immune measures in healthy volunteers: relationship to hypothalamic-pituitary-adrenal axis hormones and sympathetic neurotransmitters. Psychosomatic Medicine, 59(1), 42-50.

Levitsky, H. I. (2000). Augmentation of host immune responses to cancer: Overcoming the barrier of tumor antigen-specific T-cell tolerance. Cancer Journal from Scientific American, 6 Suppl 3, S281-90.

Maino, V. C., Suni, M. A., & Ruitenberg, J. J. (1995). Rapid flow cytometric method for measuring lymphocyte subset activation. Cytometry, 20(2), 127-33.

Nair, M. P., & Schwartz, S. A. (1984). Immunomodulatory effects of corticosteroids on natural killer and antibody-dependent cellular cytotoxic activities of human lymphocytes. Journal of Immunology, 132(6), 2876-82.

Pert, C. B., Dreher, H. E., & Ruff, M. R. (1998). The psychosomatic network: foundations of mind-body medicine. Alternative Therapies in Health & Medicine, 4(4), 3041.

Petrovsky, N., & Harrison, L. (1997). Diurnal rhythmicity of human cytokine production: a dynamic disequilibrium in T helper cell type 1/T helper cell type 2 balance? Journal of Immunology, 158(11), 5163-8.

Rider, M. S., & Achterberg, J. (1989). Effect of music-assisted imagery on neutrophils and lymphocytes. Biofeedback and Self Regulation, 14(3), 247-57.

Ruzyla Smith, P., Barabasz, A., Barabasz, M., & Warner, D. (1995). Effects of hypnosis on the immune response: B-cells, T-cells, helper and suppressor cells. American Journal of Clinical Hypnosis, 38(2), 71-9.

Sachar, E., Fishman, J., & Mason, J. (1965). Influence of the hypnotic trance on plasma 17-hydroxycorticosteroid concentration. Psychosomatic Medicine, XXVII(4), 330-341.

Sachar, E. J., Cobb, J. C., & Shor, R. E. (1966). Plasma cortisol changes during hypnotic trance: Relation to depth of hypnosis. Archives of General Psychiatry, 14(5), 482-90.

Shor, R., & Orne, E. (1962). Harvard Group Scale of Hypnotic Susceptibility. Palo Alto, CA: Consulting Psychologists Press, Inc.

Simmons, C. P., Ghaem-Magami, M., Petrovska, L., Lopes, L., Chain, B. M., Williams, N. A., & Dougan, G. (2001). Immunomodulation using bacterial enterotoxins. Scandinavian Journal of Immunology, 53(3), 218-26.

Taylor, D. N. (1995). Effects of a behavioral stress-management program on anxiety, mood, self-esteem, and T-cell count in HIV positive men. Psychological Reports, 76(2), 451-7.

Teshima, H., Sogawa, H., Mizobe, K., Kuroki, N., & Nakagawa, T. (1991). Application of psychoimmunotherapy in patients with alopecia universalis. Psychotherapy & Psychosomatics, 56(4), 235-41.

Watschinger, B., Wenter, C., & Demetriou, D. (2000). New developments in clinical immunosuppression. Kidney & Blood Pressure Research, 23(3-5), 191-2. Zachariae, R., Bjerring, P., Zachariae, C., Arendt Nielsen, L., Nielsen, T., Eldrup, E.,

Larsen, C. S., & Gotliebsen, K. (1991). Monocyte chemotactic activity in sera after hypnotically induced emotional states. Scandinavian Journal of Immunology, 34(1), 71-9.

Zachariae, R., Hansen, J. B., Andersen, M., Jinquan, T., Petersen, K. S., Simonsen, C., Zachariae, C., & Thestrup Pedersen, K. (1994). Changes in cellular immune function after immune specific guided imagery and relaxation in high and low hypnotizable healthy subjects. Psychotherapy & Psychosomatics, 61(1-2), 74-92.

Zadeh, H. H., Tanavoli, S., Haines, D. D., & Kreutzer, D. L. (2000). Despite large-scale T cell activation, only a minor subset of T cells responding in vitro to Actinobacillus actinomycetemcomitans differentiate into effector T cells. Journal of Periodontal Research, 35(3), 127-36.

Gary J. Wood

Stefan Bughi

John Morrison

Sara Tanavoli

Sohrab Tanavoli

Homayoun H. Zadeh

University of Southern California

Request reprints from:

Gary J. Wood, Ph.D.

10801 National Blvd., Suite 240

Los Angeles CA, 90064

email: gwood@use.edu

Copyright American Society of Clinical Hypnosis Jan 2003
Provided by ProQuest Information and Learning Company. All rights Reserved