41. Stress and immunity in humans: a meta-analytic review.

Herbert TB, Cohen S
Brain, Behavior and Immunity Center, University of Pittsburgh School of
Medicine, Pennsylvania.
Psychosom Med 1993 Jul-Aug;55(4):364-79

This article presents a meta-analysis of the literature on stress and immunity in humans. The primary analyses include all relevant studies irrespective of the measure or manipulation of stress. The results of these analyses show substantial evidence for a relation between stress and decreases in functional immune measures (proliferative response to mitogens and natural killer cell activity). Stress is also related to numbers and percent of circulating white blood cells, immunoglobulin levels, and antibody titers to herpesviruses. Subsequent analyses suggest that objective stressful events are related to larger immune changes than subjective self-reports of stress, that immune response varies with stressor duration, and that interpersonal events are related to different immune outcomes than nonsocial events. We discuss the way neuroendocrine mechanisms and health practices might explain immune alteration following stress, and outline issues that need to be investigated in this area.

42. Immunosenescence: potential causes and strategies for reversal.

Aspinall R, Andrew D
Department of Immunology, Imperial College of Medicine at Chelsea & Westminster
Hospital, London, UK.
Biochem Soc Trans 2000 Feb;28(2):250-4

Age-related deterioration in immune function has been recognized in many species. In humans the clinical manifestation of such immune dysfunction is age-related increases in the susceptibility to certain infections and in the incidence of some autoimmune disease and certain cancers. Laboratory investigations reveal age-related changes in the peripheral T cell pool, in the predominant phenotype, cytokine production profiles, signalling function and in replicative ability following stimulus with antigen, mitogens or anti-CD3 antibody. These changes in the properties of peripheral T cells are thought to be causally linked to an age-associated involution in the thymus. Our analysis reveals that thymic involution is due to a change in the thymic microenvironment linked to a reduction in the level of available interleukin 7. Treatment with interleukin 7 leads to a reversal of thymic atrophy with increased thymopoiesis. This provides the potential to reverse the immune dysfunction seen in the peripheral T cell pool by replacing old cells with new output generated in the thymus. Problems to overcome in order for such an experimental therapy to be successful require careful analysis in order to provide an optimal strategy to ensure that new T cell emigrants from the thymus have a broad range of specificities and are able to enter the peripheral T cell pool.

43. Chinese herbs: a clinical review of Astragalus, Ligusticum, and Schizandrae.

Sinclair S
Green Valley Health, 1305 Pennsylvania Ave, Hagerstown, MD 21742, USA.
Altern Med Rev 1998 Oct;3(5):338-44

Although Astragalus, Ligusticum and Schizandrae have a long history of medicinal use within the traditional Chinese system, only recently has the West begun to understand their pharmacological possibilities and clinical applications. Astragalus has demonstrated a wide range of immunopotentiating effects and has proven efficacious as an adjunct cancer therapy. Ligusticum, and its active components, have been investigated for enhancement of the immune system, treatment of ischemic disorders, and as an anti-inflammatory. Clinically, the hepato-protective and antioxidant actions of Schizandrae have proven beneficial in the treatment of chronic viral hepatitis.

44. Immunomodulating activity of Chinese medicinal herbs and Oldenlandia diffusa in particular.

Yoshida Y, Wang MQ, Liu JN, Shan BE, Yamashita U
Department of Immunology and Parasitology, Hiroshima University School of
Medicine, Japan.
Int J Immunopharmacol 1997 Jul;19(7):359-70

The effect of eight different Chinese medicinal herbs (CMHs) on lymphocytes was studied in vitro using murine spleen cells. Among the studied eight CMHs, Astragalus membranaceus and Oldenlandia diffusa markedly stimulated murine spleen cells to proliferate. The responder cells for CMHs were B cells, because the response was depleted by the treatment of spleen cells with anti-immunoglobulin (i.g.) antibody and complement and after purification by nylon wool column. This response was not due to contamination by lipopolysaccharide (LPS), because CMHs could stimulate C3H/HeJ spleen cells which are low responders to LPS. CMHs enhanced the production of Ig. CMHs also enhanced the induction of allo-antigen specific cytotoxic T lymphocytes. However, CMHs had no effect on natural killer cells. Furthermore, CMHs stimulated macrophages to produce interleukin-6 and tumor necrosis factor. The electroelution of the proteins from SDS-PAGE gel showed that the active components of Oldenlandia diffusa had an apparent molecular weight of 90-200 kD and were sensitive to pronase E and NaIO4 treatment, suggesting glycoproteins in nature. These results suggest that CMHs have immunomodulating activity in vitro and this activity could be used clinically for the modulation of immune responses.

45. The prostaglandin analogs, misoprostol and SC-46275, potently inhibit cytokine release from activated human monocytes.

Widomski D, Fretland DJ, Gasiecki AF, Collins PW
Searle Research and Development Skokie, Illinois 60077, USA.
Immunopharmacol Immunotoxicol 1997 May;19(2):165-74

Inflammatory mediator release is one of the body's responses to tissue injury and inflammation. These mediators, such as interleukin-1 beta (I1-1 beta), tumor necrosis factor (TNF-alpha), and products of arachidonic acid metabolism, are themselves proinflammatory. Purified human monocytes stimulated in vitro with E. coli-derived lipopolysaccharide (LPS) will release these key cytokines along with various other eicosanoid mediators. Monocytes incubated with LPS and the prostaglandin E-1 analog, misoprostol, released significantly lower levels of cytokines compared to monocytes incubated with LPS alone. Eicosanoid release was also affected by misoprostol. SC-46275, a more potent mucosal protective PGE1 analog, also altered the release of cytokines and eicosanoids from human monocytes. However SC-46275 inhibited I1-1 beta release with an IC50 value of 9 microM compared to 75 microM for misoprostol. SC-46275 and misoprostol both inhibited TNF-alpha release. These data suggest there is a potential immunomodulatory role for prostaglandin analogs in the therapeutic treatment of inflammatory diseases such as ulcerative colitis, Crohn's disease, and autoimmune inflammatory diseases of the central nervous system.

46. Research on coenzyme Q10 in clinical medicine and in immunomodulation.

Folkers K, Wolaniuk A
Drugs Exp Clin Res 1985;11(8):539-45

Coenzyme Q10 (CoQ10) is a redox component in the respiratory chain. CoQ10 is necessary for human life to exist; and a deficiency can be contributory to ill health and disease. A deficiency of CoQ10 in myocardial disease has been found and controlled therapeutic trials have established CoQ10 as a major advance in the therapy of resistant myocardial failure. The cardiotoxicity of adriamycin, used in treatment modalities of cancer, is significantly reduced by CoQ10, apparently because the side-effects of adriamycin include inhibition of mitochondrial CoQ10 enzymes. Models of the immune system including phagocytic rate, circulating antibody level, neoplasia, viral and parasitic infections were used to demonstrate that CoQ10 is an immunomodulating agent. It was concluded that CoQ10, at the mitochondrial level, is essential for the optimal function of the immune system.

47. Anti-Ro in Sjogren's syndrome and systemic lupus erythematosus.

Harley JB, Scofield RH, Reichlin M
University of Oklahoma Health Sciences Center, Oklahoma City.
Rheum Dis Clin North Am 1992 May;18(2):337-58

Anti-Ro autoantibodies are frequently found in the sera of patients with Sjogren's syndrome, systemic lupus erythematosus, and subacute cutaneous lupus erythematosus as well as in the sera of mothers of infants with the neonatal lupus syndrome. Close associations have been found between anti-Ro and a number of clinical manifestations, particularly including hematologic cytopenias, heart block, and photosensitive skin rashes. Serologic and genetic associations have been found between anti-Ro and anti-La, rheumatoid factor, hypergammaglobulinemia, the histocompatibility alleles DQ1 and DQ2, and alleles of the T-cell receptor beta chain gene. The origin of anti-Ro and other autoantigens is thought to relate to the etiology of Sjogren's syndrome and systemic lupus erythematosus and remains the most fundamental unanswered question preventing a comprehensive understanding of these diseases.

48. Antinuclear antibodies in Sjogren's syndrome.

Chan EK, Andrade LE
W. M. Keck Autoimmune Disease Center, Department of Molecular and Experimental
Medicine, Scripps Research Institute, La Jolla, California.
Rheum Dis Clin North Am 1992 Aug;18(3):551-70

The definition and characterization of the reactivity of ANA in patients with SS are greatly improved with the current advances in cellular and molecular biology. Based on the characteristic autoantibody profiles in different systemic rheumatic diseases and the nature of the defined autoantigens, it has been proposed that the polyclonal autoimmune response is induced and maintained through an antigen-driven mechanism. The autoantigens are presented in the cell as components of large particles or structures composed of protein-protein or RNA-protein complexes; however, the role of these autoantibodies in the etiology and immunopathogenesis of SS remains to be determined.

49. The regulation of prostaglandin biosynthesis by the manipulation of essential fatty acid metabolism.

Horrobin DF
Rev Pure Appl Pharmacol Sci 1983 Oct-Dec;4(4):339-83

Two of the most widely used groups of drugs in medical practice are the non-steroidal anti-inflammatory agents and the steroids. Both act by modulating the conversion of essential fatty acids to prostaglandins, leukotrienes and related substances. The actions of these drugs are therefore likely to be modified by variations in the levels of substrates, notably arachidonic acid and dihomogammalinolenic acid, available for metabolism by lipoxygenase and cyclo-oxygenase enzymes. Yet most doctors who use the drugs and many scientists who carry out research on them seem unaware of the factors which determine the concentrations of the substrate essential fatty acids. This paper reviews in detail the metabolism of essential fatty acids and the interactions between nutrient intake and subsequent metabolism which determine the concentrations of the individual fatty acids. It is concluded that the efficacy of drug therapy as far as the steroids and the non-steroidal anti-inflammatory drugs are concerned could be substantially enhanced by greater knowledge of the factors which determine the availability of substrates to the key enzymes.

50. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group.

Sall K, Stevenson OD, Mundorf TK, Reis BL
Sall Eye Surgery Center, Bellflower, California, USA.
Ophthalmology 2000 Apr;107(4):631-9
Published erratum appears in Ophthalmology 2000 Jul;107(7):1220

OBJECTIVE: To compare the efficacy and safety of cyclosporin A ([CsA] 0.05% and
0.1% ophthalmic emulsions) to vehicle in patients with moderate to severe dry
eye disease. DESIGN: Multicenter, randomized, double-masked, parallel-group,
6-month, vehicle-controlled. PARTICIPANTS: A total of 877 patients with defined
moderate to severe dry eye disease (292 to 293 in each treatment group).
METHODS: Two identical clinical trials; patients were treated twice daily with
either CsA, 0.05% or 0.1%, or vehicle. The results of these two trials were
combined for analysis. MAIN OUTCOME MEASURES: Efficacy: corneal and
interpalpebral dye staining, Schirmer tear test (with and without anesthesia),
tear break-up time, Ocular Surface Disease Index (OSDI), facial expression,
patient subjective rating scale, symptoms of dry eye, investigator's evaluation
of global response to treatment, treatment success, and daily use of artificial
tears. Safety: occurrence of adverse events, best-corrected visual acuity,
intraocular pressure, biomicroscopy, and blood trough CsA concentrations.

RESULTS: Treatment with CsA, 0.05% or 0.1%, gave significantly (P < or = 0.05)
greater improvements than vehicle in two objective signs of dry eye disease
(corneal staining and categorized Schirmer values). CsA 0.05% treatment also
gave significantly greater improvements (P < 0.05) in three subjective measures
of dry eye disease (blurred vision, need for concomitant artificial tears, and
the physician's evaluation of global response to treatment). There was no
dose-response effect. Both CsA treatments exhibited an excellent safety profile,
and there were no significant topical or systemic adverse safety findings.
CONCLUSIONS: The novel ophthalmic formulations CsA 0.05% and 0.1% were safe and effective in the treatment of moderate to severe dry eye disease yielding
improvements in both objective and subjective measures. Topical CsA represents a
new pharmacologically based treatment for dry eye disease that may provide
significant patient benefits.

51. Autonomic cardiovascular neuropathy in Sjogren's syndrome. A controlled study.

Andonopoulos AP, Christodoulou J, Ballas C, Bounas A, Alexopoulos D
Department of Medicine, Patras University School of Medicine, Greece.
J Rheumatol 1998 Dec;25(12):2385-8

OBJECTIVE: To test patients with primary Sjogren's syndrome (SS) for evidence of autonomic neuropathy. METHODS: Thirty-two patients with primary SS and 22 age and sex matched healthy individuals were asked specific questions about symptoms suggestive of autonomic neuropathy, and were subjected to a battery of 5 cardiovascular tests: response of blood pressure to sustained hand grip, Valsalva maneuver, heart rate response to deep breathing, and heart rate and blood pressure response to standing up. The chi-squared test with Yates' correction and 95% confidence intervals were used for statistical analysis of the results. RESULTS: Sixteen patients (50%) had symptoms of autonomic neuropathy when specifically asked versus none of the controls (p < 0.0005). The frequency of abnormal responses to the tests was 68.8% in patients and 12.7% in controls (p < 0.0001). Severe autonomic cardiovascular neuropathy was found in 87.5% of the patients but in none of the healthy individuals (p < 0.0001). CONCLUSION: Our results suggest that autonomic neuropathy is a feature of a significant portion of the SS population, and such patients should have appropriate evaluation. Similarly, patients with unexplained autonomic neuropathy should be investigated for evidence of SS.

52. Sjogren's syndrome: Treatment with Cyclosporin.

Klin Monatsbl Augenheilkd (Germany, West) 1987;190(4):290-2.

53. Thymosin administration in autoimmune disorders.

Lavastida MT, Goldstein AL, Daniels JC
Thymus 1981 Feb;2(4-5):287-95

Five patients with autoimmune disorders were given thymosin, fraction 5, parenterally for periods ranging from 2 to 35 mth. Four patients had systemic lupus erythematosus and the 5th had rheumatoid arthritis and Sjogren's syndrome. Treatment with thymosin was based on the hypothesis of a T-suppressor defect in these autoimmune disorders. Circulating T lymphocytes increased and remained above pretreatment levels in all patients. Assays for cytotoxicity, using mouse thymocytes and patients' sera, were positive initially and declined during the course of the treatment. In all patients, serum cytotoxicity levels were reduced to zero. There has been clinical improvement in 3 patients, and in 1, the disease has become stable. The evaluation of the 5th patient has been inconclusive. No ill effects related to the administration of thymosin were observed.

54. Immune complex glomerulonephritis in sicca syndrome.

Moutsopoulos HM, Balow JE, Lawley TJ, Stahl NI, Antonovych TT, Chused TM
Am J Med 1978 Jun;64(6):955-60

In three patients with the sicca syndrome (Sjogren's syndrome), who were followed for one to seven years, glomerulonephritis developed. None of these patients fulfilled the diagnostic criteria for systemic lupus erythematosus. All of these patients had circulating immune complexes as detected by the Clq binding assay. Glomerular histology by light and electron microscopy revealed changes compatible with membranoproliferative glomerulonephritis in two of the patients and membranous glomerulonephritis in the third. All patients showed rapid improvement in renal function following moderate doses of corticosteroids. In addition, the treatment decreased the level of circulating immune complexes in two patients who were followed for a sufficient period of time.

55. Sjogren's syndrome with immune-complex tubulointerstitial renal disease.

Winer RL, Cohen AH, Sawhney AS, Gorman JT
Clin Immunol Immunopathol 1977 Nov;8(3):494-503

56. Modification of a transplantable colon tumor and immune responses in mice fed different sources of protein, fat and carbohydrate.

Nutter RL, Gridley DS, Kettering JD, Andres ML, Aprecio RM, Slater JM
Cancer Lett 1983 Feb;18(1):49-62

The effects of different sources of dietary protein, fat and carbohydrate on tumor development and on tests relating to cell-mediated immunity were investigated in male BALB/c mice after subcutaneous injection of 8 X 10(4) 1,2-dimethylhydrazine (DMH)-induced colon tumor (no. 51) cells. Results indicated that mice fed the milk protein source (especially at the low protein level) had smaller tumors, a higher spleen cell proliferative response to stimulation by phytohemagglutinin (PHA), and greater cytotoxic T-cell activity against the tumor cells than those fed the comparable diets containing protein from the other sources. Peripheral blood lymphocytes only from the milk-fed mice, regardless of tumor presence, exhibited a relatively low response to PHA stimulation, thereby suggesting a dietary effect on the migration pattern of PHA-responsive lymphocytes. The level of protein significantly affected both T-cell and natural killer cell cytotoxicity. The tumor-bearing mice fed the diet containing sucrose (table sugar) had a significantly lower spleen cell response to PHA stimulation than those fed the comparable diet containing dextrin. The level or source of fat did not significantly affect any of the parameters tested in this system.

57. Impaired function of immune reactivity to Listeria monocytogenes in diet-fed mice.

Kos WL, Kos KA, Kaplan AM
Infect Immun 1984 Mar;43(3):1094-6

Mice fed a diet high in cholesterol, lard, and sucrose were shown to exhibit an impairment of specific immunity to Listeria monocytogenes. Whereas titers of L. monocytogenes in livers of normal mice decreased rapidly after 6 days of infection, L. monocytogenes persisted in livers of diet-fed mice. Adoptive transfer experiments indicated that L. monocytogenes-immune spleen cells are generated in diet-fed mice. However, the function of immune spleen cells from donors of either nutritional status was impaired in diet-fed recipients. The results indicate that the site(s) of impairment of specific immunity to L. monocytogenes in diet-fed mice occurs at a stage beyond the generation of immune T-cells.

58. Influence of oral zinc supplementation on the lymphocyte response to mitogens of normal subjects.

Duchateau J, Delespesse G, Vereecke P
Am J Clin Nutr 1981 Jan;34(1):88-93

Oral zinc sulfate was given for 1 month to 83 normal subjects distributed in four groups according to age (20 to 40; 40 to 60), sex, and oral contraception. Their in vitro lymphocyte response to phytohemagglutinin and Concanavalin A, and their serum zinc and copper levels were measured before and after treatment. They were compared in 20 untreated subjects. Zinc treatment significantly increased the lymphocyte response to phytohemagglutinin and Concanavalin A. In the group of women aged 40 to 60, this resulted in a normalisation of the response to Concanavalin A. The response to zinc was related to the starting value of lymphocyte stimulation obtained by phytohemagglutinin, i.e., in low responders this was enhanced whereas in high responders it tended to be reduced. Treatment increased serum zinc and had no effect on serum copper. There was no correlation between serum zinc or copper and the lymphocyte response. The beneficial effect of zinc supplementation on the lymphocyte response does not result from a correction of latent zinc deficiency.

59. Beneficial effects of oral zinc supplementation on the immune response of old people.

Duchateau J, Delepesse G, Vrijens R, Collet H
Am J Med 1981 May;70(5):1001-4

Zinc is known to have beneficial effects on the immune response. In an attempt to modify age-associated immune dysfunction, supplemental zinc was administered to 15 subjects over 70 years of age (220 mg zinc sulfate twice daily for a month). As compared to 15 controls, matched for age and sex, there was a significant improvement in the following immune parameters in the treated group: (1) number of circulating T lymphocytes; (2) delayed cutaneous hypersensitivity reactions to purified protein derivative, Candidin and streptokinase-streptodornase; (3) immunoglobulin G (IgG) antibody response to tetanus vaccine. Zinc treatment had no influence on the number of total circulating leukocytes or lymphocytes, or on the in vitro lymphocyte response to three mitogens: phytohemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM). The data suggest that the addition of zinc to the diet of old persons could be an effective and simple way to improve their immune function.

60. Interrelationships between zinc and immune function.

Fraker PJ, Gershwin ME, Good RA, Prasad A
Fed Proc 1986 Apr;45(5):1474-9

Zinc deficiency is a common nutritional problem observed both in human and in animal populations that has profound effects on host defense mechanisms. Using the young adult mouse as a model, it has been demonstrated that a moderate period of suboptimal zinc causes thymic atrophy, lymphopenia, and alterations in the proportions of the various subsets of lymphocytes and mononuclear phagocytes. As a result, antibody-mediated responses to both T cell-dependent and T cell independent antigens are significantly reduced. Cytolytic T cell responses, natural killer (NK) cell activity, and delayed-type hypersensitivity (DTH) reactions are also depressed. Suboptimal zinc during in utero development of mice causes persistent states of immunodeficiency in the offspring that can even be transferred to subsequent generations. In regard to human immunological consequences of zinc deficiency, patients with the genetic disorder of zinc absorption, acrodermatitis enteropathica, also exhibit atrophic thymuses, lymphopenia, anergic DTH responses, and reduced NK cell activity. Patients suffering from sickle cell anemia or uremia with associated deficiencies in zinc exhibit similar immune deficiencies. An additional outcome of these studies has been shown to be an essential cofactor for thymulin, one of the thymic hormones. Furthermore, addition of zinc salts to culture can polyclonally activate lymphocytes as well as augment responses to mitogens in adjuvant-like manner.

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