Lavori pubblicati su PUBMED

Curr Pharm Des. 2006;12(32):4255-62.

Toll-like receptor-positive cells and recognition of pathogens: how human myeloid dendritic cells respond to in vitro infection with Leishmania infantum.

Pepe M, Altamura M, Spinelli R Calvello R, Saccia M, Cavallo P, Covelli V, Jirillo E, Brandonisio O.

Department of Internal Medicine, Immunology and Infectious Diseases, University of Bari, Bari, Italy.

Dendritic cells (DCs), instructed by the priming signals from microbial factors, can produce interleukin (IL)-12p70 and promote T helper (Th)1 proliferation and interferon (IFN)-gamma production. This event seems to be critical for the containment of infections caused by intracellular pathogens, even including Leishmania infection. In the present in vitro study we have investigated: 1) phagocytic capacities and IL-12 production by human monocyte-derived DCs and macrophages (MOs), infected with Leishmania infantum promastigotes; 2) IFN-gamma production by human CD4+ T cells co-incubated with DCs or macrophages pulsed with live promastigotes. Monocyte-derived myeloid DCs and MOs from healthy donors were infected with live metacyclic Leishmania infantum (MON-1) promastigotes, previously opsonized with 5% autologous serum, at 1:4 cell/parasite ratio. Percentage and index of phagocytosis were calculated after 2, 24 and 48 h of incubation. IL-12 production was evaluated by an ELISA in supernatants from 48 h Leishmania-infected or lipopolysaccharides (LPS)-stimulated DCs and MOs, also in the presence of phytohemagglutinin-activated or inactivated CD4+ T cells. For IFN-gamma production, CD4+ T cells were repeatedly stimulated with DCs or MOs, pulsed with live Leishmania promastigotes or activated with LPS. The number of IFN-gamma-secreting cells was evaluated by an ELISpot assay. Results showed that MOs have a higher phagocytic capacity towards L. infantum promastigotes than DCs. Moreover, unlike MOs, Leishmania-infected DCs were able to release IL-12p70; this production significantly increased in the presence of activated CD4+ T cells. Finally, DCs pulsed with live parasites and added to autologous CD4+ T cells induced a higher number of IFN-gamma-secreting cells than MOs, thus indicating their ability to polarize Th cells toward the Th1 subset. These data indicate that DCs are able to promote protective Th1 immune responses in our experimental model of Leishmania infantum infection, thus representing the grounds for initiating immunoterapeutic and vaccinal strategies.

Publication Types:

• Research Support, Non-U.S. Gov’t

PMID: 17100627 [PubMed – in process]

Curr Pharm Des. 2006;12(10):1195-200.

Involvement of the transforming growth factor beta in the pathogenesis of hereditary hemorrhagic telangiectasia.

Jirillo E, Amati L, Suppressa P, Cirimele D, Guastamacchia E, Covelli V, Tafaro E, Sabba C.

National Institute of Gastroenterology, Castellana Grotte, Bari, Italy. jirillo@midim.uniba.it

Hereditary hemorrhagic telangiectasia (HHT) is characterized by vessel alterations such as dilatation of postcapillary venules and arterio-venous communications, which account for the major clinical manifestations of the disease. Two types of HHT have been characterized HHT-1 and HHT-2, respectively, depending the former on endoglin mutations and the latter on activin receptor-like kinase 1 (ALK-1) mutations. Both endoglin and ALK-1 bind to the transforming growth factor (TGF) superfamily which, physiologically, regulates the activities of endothelial cells and also those related to the extracellular matrix. In this review, the salient features of TGF-beta will be outlined with special reference to its activity on the immune system and on tumorigenesis. Furthermore, the involvement of TGF-beta in the pathogenesis of some gastrointestinal diseases will be discussed and, in particular, in the course of liver disease, Helicobacter pylori infection and inflammatory bowel disease. In the light of these data and of animal model of HHT, the potential risk of developing other diseases in HHT patients will be discussed.

Publication Types:

• Research Support, Non-U.S. Gov’t
• Review

PMID: 16611100 [PubMed – indexed for MEDLINE]

Curr Med Chem. 2006;13(3):325-33.

Taking advantage of viral immune evasion: virus-derived proteins represent novel biopharmaceuticals.

Amati L, Passeri ME, Lippolis A, Lio D, Caruso C, Jirillo E, Covelli V.

National Institute for Digestive Diseases, Castellana Grotte-Bari, Italy.

In healthy individuals, natural and adaptive immune responses are able to control virus entry into the host. In particular, CD8(+)-mediated cytotoxicity, sustained by the intervention of CD4+ cells, represents the major key event leading to virus eradication. On the other hand, viruses are able to evade from host immune response via several mechanisms, and special emphasis will be placed on hepatitis C virus and chronic Epstein-Barr infections also in view of personal data. Virokines, viroreceptors, and serpins greatly contribute to viral immune escape, and, among virokines, interleukin (IL)-10 has been object of intensive studies. Finally, all these products have been used as biopharmaceuticals, and, for instance, viral IL-10, chemokine-binding proteins, and serpins exhibit in animal models immunosuppressive, anti-inflammatory, and antiatherogenic activities. As far as their use in human trials is concernded, many cautions are required in order to avoid deleterious side effects and, in particular, the purity of the product, its route and frequency of administration, as well as the immune status of the patient should be taken into serious account.

Publication Types:

• Research Support, Non-U.S. Gov’t
• Review

PMID: 16475940 [PubMed – indexed for MEDLINE]

Curr Pharm Des. 2006;12(32):4247-54.

Toll-like receptor signaling mechanisms involved in dendritic cell activation: potential therapeutic control of T cell polarization.

Amati L, Pepe M, Passeri ME, Mastronardi ML, Jirillo E, Covelli V.

National Institute for Digestive Diseases, Castellana Grotte, Bari, Italy.

Dendritic cells (DCs) represent a bridge between innate and adaptive immunity, being the maturation process dependent on the binding of pathogen-associated molecular patterns (PAMPs) to Toll-Like Receptors (TLRs) expressed on their surface. TLRs associated to adaptor proteins, following binding to PAMPs, are able to skew specific immune responses towards the T helper (h)(1)- or the Th(2)-type according to the antigenic stimulation involved. Of note, other receptors different from TLRs are expressed on DCs which are also able to recognize PAMPs. Among them, one should mention the DC-specific ICAM-3-grabbing nonintegrin, the mannose receptor, Dectin-1 (the major beta-glucan receptor) and NOD2. Finally, the possibility to interfere therapeutically with the TLR-dependent and -independent signaling pathways in DCs is reviewed. According to current literature, DC activation, their antigen uptake capacity and migration can be enhanced with different experimental procedures whose use in humans is still under evaluation. However, just recently a probiotic cocktail VSL3, successfully used in patients with pouchitis, seems to act on DCs, promoting abundant release of Interleukin-10 in the gut. These novel therapeutic strategies based on the modulation of the signaling pathways in DCs seem to be encouraging for the treatment of inflammatory and autoimmune diseases.

PMID: 17100626 [PubMed – in process]

Curr Med Chem. 2005;12(15):1801-9.

Drug targets in stress-related disorders.

Covelli V, Passeri ME, Leogrande D, Jirillo E, Amati L.

Division of Neurology, Polyclinic Hospital, Bari Italy.

Nervous and immune systems mutually cooperate via release of mediators of both neurological and immunological derivation. Adrenocorticotropin hormone (ACTH) is a product of the hypothalamus-pituitary adrenal axis (HPAA) which stimulates secretion of corticosteroids from adrenals. In turn, corticosteroids modulate the immune response in virtue of their anti-inflammatory activity. On the other hand, catecholamines, products of the sympathetic nervous system (SNS), regulate immune function by acting on specific beta-adrenergic receptors. Conversely, cytokines released by monocytes/macrophages and lymphocytes, upon antigenic stimulation, are able to cross the blood-brain-barrier, thus modulating nervous functions (e.g., thermoregulation, sleep, and appetite). However, cytokines are locally produced in the brain, especially in the hypothalamus, thus contributing to the development of anorexic, pyrogenic, somnogenic and behavioural effects. Besides pathogens and/or their products, the so-called stressors are able to activate both HPAA and SNS, thus influencing immune responses. In this respect, many studies conducted in medical students taking exams have evidenced an array of stress-induced immune alterations. Phobic disorders and migraine without aura (MWA) represent examples of stress-related disorders in which phagocytic immune deficits, endotoxemia and exaggerated levels of proinflammatory cytokines [Tumor Necrosis Factor-alpha (TNF- alpha), and interleukin- 1 beta] have been detected. Quite interestingly, administration of a thymic hormone could ameliorate clinical symptoms in phobic patients. In MWA patients, a beta-blocker, propranolol, could mitigate migraine, whose cessation coincided with a drop of TNF-alpha serum concentration. In phobic disorders and in MWA, benzodiazepines are very often administered and, in this respect, some of them, such as diazepam, inhibit immune functions, while others, e.g., alprazolam, enhance immune responses. Alprazolam could improve clinical symptoms in MWA patients. Chronic Fatigue Syndrome (CFS) is a disorder whose etiology and pathogenesis are still unknown. In this syndrome both abnormalities of nervous and immune systems have been reported. Despite many immune parameters evaluated in CFS no specific biomarkers of disease have been found. Our own data are in agreement with current literature in that we found decreased levels of serum (IFN)-gamma in these patients, thus indicating a predominance of T helper (h)1 response in CFS. Also leptin, a hormone which regulates food intake, fluctuates within normal ranges in CFS individuals. Quite interestingly, in depressed patients, used as controls, leptinaemia was more elevated than in CFS. Finally, in a series of recent therapeutic trials several immunomodulating agents have been used, such as staphypan Berna, lactic acid bacteria, kuibitang and intravenous immunoglobulin. In conclusion, it seems that major drug targets in stress-related disorders are immune cells in terms of inhibition of proinflammatory cytokines and modulation of Th responses. In particular, according to recent evidences, antidepressants seem to exert beneficial effects in experimental autoimmune neuritis in rats by decreasing IFN- beta release or augmenting NK activity in depressed patients.

Publication Types:

• Research Support, Non-U.S. Gov’t
• Review

PMID: 16029148 [PubMed – indexed for MEDLINE]

Curr Pharm Des. 2003;9(24):1951-5.

A point of view: The need to identify an antigen in psyconeuroimmunological disorders.

Covelli V, Pellegrino NM, Jirillo E.

Division of Neurology, Azienda Policlinico, Bari, Italy. nm.pellegrino@midim.uniba.it

Several lines of evidence support a mutual relationship between the nervous system and the immune system. Therefore, it is not surprising that some neuropsychiatric disorders are also characterized by immune abnormalities. In patients with phobic disorders and in patients with migraine without aura some common immune abnormalities have been detected and, in particular, natural immunity deficits, exaggerated release of proinflammatory cytokines and circulating bacterial endotoxins have been found. In other neurological disease, some etiologic factors have been detected as in the case of Guillain-Barre syndrome in which molecular mimicry between Campylobacter jejuni endotoxin and GM1 ganglioside may cause an acute inflammatory polyneuropathy. On the other hand, attempts to identify an antigen have been made in patients with Alzheimer’s disease and schizophrenia. Finally, the chronic fatigue syndrome, an old illness in search for an antigen, risk factors and precipitating agents have been described but evidence for a specific antigen is still lacking.

Publication Types:

• Review

PMID: 12871180 [PubMed – indexed for MEDLINE]

Immunopharmacol Immunotoxicol. 2001 Feb;23(1):1-11.

In vitro effects of naloxone on T-lymphocyte-dependent antibacterial activity in hepatitis C virus (HCV) infected patients and in inflammatory bowel disease (IBD) patients.

Amati L, Caradonna L, Magrone T, Manghisi C, Leandro G, Caccavo D, Covelli V, Sciorsci RL, Minoia P, Jirillo E.

Istituto Gastroenterologico, Castellana Grotte Bari, Italy.

Naloxone acts as an opioid antagonist, displacing opioid drugs from cellular receptors. Among opioid substances, beta-endorphins are able to bind to several cell receptors, even including those expressed by immune cells. In this respect, evidence has been provided that in the course of viral infections, as well as in patients with ulcerative colitis high levels of beta-endorphins are detectable. Here, peripheral blood lymphocytes (PBL) from 21 HCV infected patients and 14 patients with IBD, respectively, were incubated with Naloxone and Naloxone + Ca2+ in order to evaluate a putative modulation of PBL-mediated antibacterial activity. In fact, previous studies have demonstrated a reduction of this T-cell activity in HCV and IBD patients. In general terms, the above treatment led to a recovery of the depressed antibacterial activity. In some cases, increase in T lymphocyte function was obtained with Naloxone alone, while in other cases the combination Naloxone + Ca2+ gave rise to a restorative effect. Of note, in some instances, lymphocytes were unresponsive to pharmacological modulation. The overall results suggest that beta-endorphins may down modulate T-cell antibacterial response in HCV and in IBD patients by saturating peripheral receptors on immune cells. Therefore, it is likely that Naloxone and/or Naloxone + Ca2+ may displace opioid drugs, thus antagonizing their effects.

Publication Types:

• Comparative Study
• Evaluation Studies
• In Vitro
• Research Support, Non-U.S. Gov’t

PMID: 11322642 [PubMed – indexed for MEDLINE]

Immunopharmacol Immunotoxicol. 2001 Feb;23(1):1-11.

In vitro effects of naloxone on T-lymphocyte-dependent antibacterial activity in hepatitis C virus (HCV) infected patients and in inflammatory bowel disease (IBD) patients.

Amati L, Caradonna L, Magrone T, Manghisi C, Leandro G, Caccavo D, Covelli V, Sciorsci RL, Minoia P, Jirillo E.

Istituto Gastroenterologico, Castellana Grotte Bari, Italy.

Naloxone acts as an opioid antagonist, displacing opioid drugs from cellular receptors. Among opioid substances, beta-endorphins are able to bind to several cell receptors, even including those expressed by immune cells. In this respect, evidence has been provided that in the course of viral infections, as well as in patients with ulcerative colitis high levels of beta-endorphins are detectable. Here, peripheral blood lymphocytes (PBL) from 21 HCV infected patients and 14 patients with IBD, respectively, were incubated with Naloxone and Naloxone + Ca2+ in order to evaluate a putative modulation of PBL-mediated antibacterial activity. In fact, previous studies have demonstrated a reduction of this T-cell activity in HCV and IBD patients. In general terms, the above treatment led to a recovery of the depressed antibacterial activity. In some cases, increase in T lymphocyte function was obtained with Naloxone alone, while in other cases the combination Naloxone + Ca2+ gave rise to a restorative effect. Of note, in some instances, lymphocytes were unresponsive to pharmacological modulation. The overall results suggest that beta-endorphins may down modulate T-cell antibacterial response in HCV and in IBD patients by saturating peripheral receptors on immune cells. Therefore, it is likely that Naloxone and/or Naloxone + Ca2+ may displace opioid drugs, thus antagonizing their effects.

Publication Types:

• Comparative Study
• Evaluation Studies
• In Vitro
• Research Support, Non-U.S. Gov’t

PMID: 11322642 [PubMed – indexed for MEDLINE]

Immunopharmacol Immunotoxicol. 1998 May;20(2):199-209.

Stress, neuropsychiatric disorders and immunological effects exerted by benzodiazepines.

Covelli V, Maffione AB, Nacci C, Tato E, Jirillo E.

II Faculty of Medicine, University of Naples, Italy.

Psychoneuroimmunology is a growing scientific field which deals with the mutual interplay between nervous and immune systems. In this framework, many data have demonstrated that cytokines (CKs) derived from the periphery are able to cross the blood brain barrier and act upon the central nervous system (CNS) [e.g., the hypothalamic-pituitary-adrenal axis (HPAA)], thus regulating several physiological functions (thermoregulation, sleep, appetite) or damaging the nervous tissue, when released in exaggerated amounts. On the other hand, nervous cells, such as astrocytes and microglial cells also generate proinflammatory CKs which may be detrimental for the CNS. The neuromodulating CK network can be triggered by microorganisms and/or their products (i.e. bacterial endotoxins), but also stressful life events may activate the HPAA, thus affecting the immune system function. This review will place emphasis on some clinical conditions, such as phobia and migraine without aura (MWA), characterized by anxiety disorders. Patients affected by these neuropsychiatric alterations exhibit multiple functional deficits of phagocytes and T lymphocytes which allow penetration of various pathogens into the host. This is also supported by the detection of circulating bacterial endotoxins and the evidence of both spontaneous and induced exaggerated release of proinflammatory CKs in phobic and MWA patients. The possible iatrogenic effects of benzodiazepines (BDZ) on the immune system have been evaluated by in vitro and in vivo studies. In this respect, it emerges that diazepam exerts an inhibitory function on the immune system, while alprazolam behaves as an immunoenhancer. The presence of central and/or peripheral BDZ receptors on immune cells seems to be the key mechanism responsible for the immunomodulation exerted by these drugs.

PMID: 9653667 [PubMed – indexed for MEDLINE]

Eur J Pharmacol. 1998 Mar 5;344(2-3):143-7.

Dopamine receptors in the striatum of rats exposed to repeated restraint stress and alprazolam treatment.

Giardino L, Zanni M, Pozza M, Bettelli C, Covelli V.

Inst. of Otolaryngology II, University of Milano, Italy. cefisnmo@mbox.vol.it

Stress-related behaviors are accompanied by modification of a large number of neurotransmitters in the brain. Moreover, the binding to GABA(A) receptors does not account for all the effects of benzodiazepines. In this study we investigated the effect of repeated restraint stress and alprazolam treatment (1 mg/day os) on dopamine receptors (Bmax and Kd) in the striatum of adult rats by means of quantitative receptor autoradiography. After chronic restraint stress dopamine D1 receptors (Bmax value) decreased in the accumbens nucleus, whereas dopamine D2 receptors were not modified in any investigated area. After alprazolam treatment, a considerable increase in both dopamine D1 and D2 receptors in the striatum was observed. Chronic immobilization stress together with alprazolam treatment re-established dopamine D1 receptor density to control values in the accumbens nucleus and olfactory tubercle, whereas it resulted in an increase in dopamine D2 receptors comparable to that elicited by alprazolam treatment alone.

PMID: 9600648 [PubMed – indexed for MEDLINE]

Immunopharmacol Immunotoxicol. 1997 May;19(2):147-64.

Pathogenetic role of phagocytic abnormalities in human virus immunodeficiency infection: possible therapeutical approaches. A review.

Covelli V, Pece S, Giuliani G, De Simone C, Jirillo E.

II Faculty of Medicine, University of Napoli, Italy.

Polymorphonuclear cells (PMN) and monocytes/macrophages (M/M) represent the first defence line against invading microorganisms. Both phagocytic cell functions are precociously compromised in human immunodeficiency virus (HIV)-infected subjects, thus leading to infectious and neurological complications in the late stages of disease. Among intracellular pathogens, emerging bacteria such as Bartonella henselae and Rhodococcus equi can cause peculiar clinical pictures, i.e. the bacillary parenchimal angiomatosis and a classical pyogranulomatous broncopneumonia, respectively. On the other hand, overproduction of proinflammatory cytokines (CKs) and, in particular, tumor necrosis factor-alpha under HIV or lipopolysaccharide stimulation may cause neural damage in terms of demyelination and subsequent development of acquired immunodeficiency syndrome (AIDS) dementia complex. Some therapeutical attempts have been made with colony stimulating factors in order to increase the number and potentiate the function of PMN and M/M. On the other hand, the use of drugs able to reduce exaggerated release of CKs by M/M is suggested in AIDS patients in order to prevent a further aggravation of the clinical condition.

Publication Types:

• Research Support, Non-U.S. Gov’t
• Review

PMID: 9130002 [PubMed – indexed for MEDLINE]

Ann N Y Acad Sci. 1994 Nov 25;741:263-70.

Hypothalamic-pituitary-adrenal axis in neuropsychiatric disorders.

Merola B, Longobardi S, Colao A, Di Somma C, Ferone D, Rossi E, Covelli V, Lombardi G.

Department of Molecular and Clinical Endocrinology, University of Naples, Italy.

Publication Types:

• Review

PMID: 7825814 [PubMed – indexed for MEDLINE]

Ann N Y Acad Sci. 1994 Nov 25;741:216-22.

Neuroendocrine axis and behavioral stress.

Lombardi G, Savastano S, Valentino R, Selleri A, Tommaselli AP, Rossi R, Gigante M, Covelli V.

Department of Endocrinology, University Federico II School of Medicine, Naples, Italy.

Publication Types:

• Review

PMID: 7825809 [PubMed – indexed for MEDLINE]

Ann N Y Acad Sci. 1994 Nov 25;741:212-5.

What is stress? How does it correlate with the immune system?

Covelli V.

Department of Neurology, University Federico II of Naples Medical School, Italy.

Publication Types:

• Review

PMID: 7825808 [PubMed – indexed for MEDLINE]

Ann N Y Acad Sci. 1994 Nov 25;741:174-84.

Endotoxins, cytokines, and neuroimmune networks with special reference to HIV infection.

Jirillo E, Covelli V, Maffione AB, Greco B, Pece S, Fumarola D, Antonaci S, De Simone C.

Facolta di Medicina, Universita di Bari, Italy.

Publication Types:

• Research Support, Non-U.S. Gov’t
• Review

PMID: 7825803 [PubMed – indexed for MEDLINE]