Carlo Bartoloni

Impairment of lymphocyte activities in depressed aged subjects

Lymphocyte activities were determined in a population of 26 institutionalized aged subjects, selected as healthy according to the SENIEUR protocol and previously reported to display immunological and endocrinological abnormalities correlated with depressive disorders. The lymphocyte mitotic response to PHA, which was reduced in aged as compared to adult subjects, was found to be significantly lower and negatively correlated with the depression score in the elderly subjects. In supernatants of PHA-stimulated lymphocyte culture from aged subjects, IL-2, IL-4 and gamma-IFN levels were very low and more severely affected in the depressed aged group. Each cytokine production was negatively correlated with age and depression score. NK activity was lower in the aged and it could be augmented by the addition of IL-2 or alpha-IFN, even though to a lesser extent than in the adult subjects. The nondepressed aged displayed higher levels of IL-2 inducible NK activity than the depressed aged subjects. IL-2 and alpha-IFN stimulated NK activities were negatively correlated with depression score. The present work indicates that the psychological status could affect lymphocyte reactivity in the aged. Given the relatively high frequency of affective disorders in these subjects, the psychological status should be considered in studies of immune senescence.

Neuropeptide Y plasma levels and immunological changes during academic Stress

Academic stress is a good model of psychological stress in humans for studying psychoneuroimmune correlations. We looked for correlations between psychological scores, immune tests and plasma levels of cortisol and neuropeptide Y (NPY). A group of medical students were evaluated at the beginning of the academic year (Baseline) and the day before an examination (Stress). They underwent evaluation by The Profile of Mood States (POMS), The Malaise Inventory, The Self Efficacy Scale and A Global Assessment of Recent Stress (GARS). The lymphocyte subsets, the lymphocyte proliferative response and the cytokine production were also evaluated. We detected modifications of some psychological test scores between the Baseline and Stress evaluation, a significant reduction of lymphocyte proliferation, IL-2 production and percentage of the lymphocyte CD19, and an increase in plasma cortisol levels during stress. The lymphocyte proliferation negatively correlated with the POMS score as well as the percentage of CD16+ cells with NPY plasma levels. NPY levels were not different from Baseline. The emotional and mood states seem to influence immunity.

Psychoneuroimmunology and Aging

Background: The senescence of the immune system is a complex phenomenon, characterized by impairment of several lymphocyte activities and generally considered a state of immune dysregulation. Aging is a condition associated with many social changes likely to induce psychological stress, which is often perceived as uncontrollable and can lead, in some cases, to clinically relevant depression. In the recent years a growing interest has been raised for the study of bidirectional interactions between the central nervous system and the immunological network (psychoneuroimmunology). Objective and Methods: We analyzed the possibility that chronic psychological distress and depression could worsen some immune functions in the aged. We postulate the neuroendocrine mechanisms of psychoimmune interaction, analyzing both the human and animal studies focused on aging. Results: The data from the literature reviewed suggest a significant impact of affective disorders on immune functions in the elderly subjects. This psychoimmune imbalance appears particularly important when the studies are carried out in otherwise healthy aged people. Conclusions: Here we reviewed the relationships between psychological stress and depression and immunological functions, with particular regard to those aspects pertinent to the aging process. The clinical relevance of these interactions remains to be elucidated, but the high frequency in the aged of autoimmune, infectious, and neoplastic diseases suggests to focus on the psychoneuroimmune interactions in the old age. We also propose some outlines for future studies concerning psychoneuroimmunology and aging.

The efficacy of chemotherapy with mebendazole in human cystic echinococcosis: long-term follow-up of 52 patients.

Sixty patients with Echinococcus granulosus infection of the liver, lungs, bone and/or soft tissues were treated for several months with oral mebendazole (50-60 mg kg-1 day-1), in divided doses after fat-rich meals, either without surgery (WS), post-surgery (PS) or pre- and post-surgery (PPS). Long-term follow-up, possible for 52 of the patients, showed that WS, PS and PPS patients have so far remained disease-free following treatment for (means +/- standard deviations) 65.5 +/- 37.7, 82.5 +/- 37.0 and 84.1 +/- 28.3 months, respectively. Ultrasound and computed tomography scans were similar in WS and PPS patients post-treatment. Blood eosinophil levels, which were sometimes elevated initially, returned to normal in all patients and this decrease indicated cyst degeneration before this was evident on the scans. Treatment of patients with cystic echinococcosis may no longer require surgery.

Increased levels of NF-κB inhibitors (IκBα and IκBγ) in the intestinal mucosa of Crohn's disease patients during infliximab treatment

The treatment with infliximab is employed successfully in Crohns disease (CD) but predictors of efficacy are lacking. Activation of the transcription factor NF-kB has been demonstrated in CD and its inhibition is one of the mechanisms by which anti-inflammatory agents exert their effects. We evaluated the production of TNFα by peripheral blood mononuclear cells (PBMC) and the levels of NF-κB family molecules in the intestinal mucosa during infliximab therapy in 12 patients. TNFα was assayed on supernatants of PBMC culture stimulated with PHA or LPS. Immunohistochemistry was also done on intestinal biopsies. In six patients, Western blot analysis of the NF-kB subunit Rel-A, and its inhibitors IκBα and IκBγ was performed on intestinal biopsies and PBMC. The TNFα production by LPS stimulated PBMC showed mild changes, while it was increased by PHA–stimulated PBMC after treatment. The number of inflammatory cells in the intestinal mucosa was reduced (p<0.002) by the treatment. In five out of six cases we detected an increase of the IκBα and IκBγ inhibitor levels in intestinal biopsies after treatment. An increase of IκB inhibitors levels could be one of the mechanisms by which infliximab decreases NF-κB activity and exerts its anti-inflammatory effects.

Immune parameters in a populatio of institutionalized elderly subjects: influence of depressive disorders and endocrinological correlations

Twenty-six institutionalized elderly subjects, selected as healthy according to the SENIEUR protocol, were compared to adult controls to establish correlations between affective disorders and immune abnormalities and to investigate underlying neuroendocrine mechanisms. After an extensive psychodiagnostic examination, 35% of the aged subjects were classified as depressed. Cutaneous delayed hypersensitivity tests showed reduced responses in the aged, but no correlation was found with the psychological status. Examination of the peripheral blood lymphocyte subsets revealed no imbalance in the percentages of CD3+, CD4+, CD8+ cells in the aged. A slight reduction in the CD4+/CD8+ cell ratio could however be detected in the non-depressed aged, as compared to adult controls. The CD4+/CD45R+ cell subset was reduced in non-depressed aged. The percentage of B lymphocytes was reduced in the aged, mostly in the non-depressed subjects. No changes were detected in the percent of OKDR+ cells. The percentage of CD16+ cells was found unchanged, while that of Leu7+ cells was significantly higher in the aged than in the adults and in the non-depressed than in the depressed aged. Leu7+ cell levels were negatively correlated with the depression score. On double labelling, the percent of CD16+/Leu7+ cells appears increased in the subgroup of depressed aged and positively correlated with age. Plasmatic and urinary cortisol levels were both positively correlated with depression score. Urinary cortisol level was higher in the depressed aged. These parameters, as well as plasmatic ACTH, beta-endorphin and urinary catecholamines, were not correlated with immune responses. Based on these findings, we recommend that the neuroendocrinological conditions should be taken into account when healthy subjects are examined in studies of immune senescence.

Latent Coagulation Disorders Evaluated by the Assay of Plasma Thrombin-Antithrombin III Complexes in a Large Series of ‘Solid Tumours’

Coagulation disorders are frequently detected in patients affected by different tumours even though clinical symptoms occur in a very small percentage of such subjects. Coagulation processes are probably involved in the mechanism of metastatic spread. We assayed the plasma levels of thrombin-antithrombin III (TAT) complexes in a group of 276 patients with several tumours in different stages in order to achieve a better understanding of the complex interactions between coagulation disorders and either tumour growth or metastatic spread. High levels of TAT complexes were found in 51% of localized, 66.3% of metastatic and 58.3% of patients with no evidence of disease; a statistically significant difference was observed comparing metastatic cancer either with localized (p < 0.00015) or with free-of-disease (p < 0.004) groups. Gastrointestinal tract neoplasms showed higher levels of TAT complexes in the metastatic than in the localized group. No difference was seen between small-cell and non-small-cell lung-localized cancer. Our results confirm the frequent coexistence of cancer and subclinical blood coagulation disorders. The evidence of higher levels of TAT complexes in metastatic cancer than in the other groups could be related to the mechanisms involved in tumour spread.

Assay, isolation and characterization of circulating immune complexes from serum of gastrointestinal cancer, stage III and IV melanoma and chronic inflammatory bowel disease patients

Circulating immune complexes (CIC) have been detected in several autoimmune diseases, and studies have also suggested that CIC provide a useful tool as tumor markers. In order to identify differences or similarities in antigenic composition, CIC from 23 patients with gastrointestinal (GI) tumors, from 20 patients with stage III and IV melanoma and from 6 patients with inflammatory bowel disease (IBD) were studied. Serum from all GI, melanoma and IBD patients showed higher levels of CIC than controls. SDS/PAGE electrophoresis under reducing conditions revealed some differences between cancer and IBD patients as far as the CIC protein composition was concerned. In melanoma patients, two fast-migrating bands, in the regions of 71-74 and 30-49 kD, were found, consistent with previously isolated and characterized antigens described in the literature.

Non-Hodgkin Lymphoma Associated with Double Monoclonal Immunoglobulin

We describe an unusual case displaying the features of double monoclonal gammapathy (IgM-kappa plus IgG-lambda) associated with non-Hodgkin lymphoma (NHL). In the last years monoclonal gammapathies have been sometimes found to be associated with NHLs; it is a very peculiar occurrence the association between a different class double monoclonal gammapathy and NHL, as the case reported in this paper.

Soluble immunosuppressor factors in human cancer

An effective immunologic destruction of tumors does not take place in most cases, despite the fact that many cancers display antigenic properties and, generally, the host immune system is affected by a complex functional defect. One of the postulated mechanisms of immune suppression in cancer patients is the presence, in body fluids, of soluble factors with inhibitory activity on immune functions. Many different substances have been claimed as soluble immunosuppressor factors in cancer, and most of them have been incompletely characterized. Soluble immunosuppressor factors could be roughly classified according to their origin, if determined (the tumor itself or the host cells) by their mode of action (tumor specific or non-specific suppressors) and nature.