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1.
Cancer Immunol Immunother ; 62(6): 1041-52, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23591981

ABSTRACT

BACKGROUND: Anti-tumor vaccination is a new frontier in cancer treatment applicable to immunogenic neoplasms such as prostate and renal cancers. GX301 is a vaccine constituted by four telomerase peptides and two adjuvants, Montanide ISA-51 and Imiquimod. OBJECTIVE: The aim of this study was to analyze safety and tolerability of GX301 in an open-label, phase I/II trial. Immunological and clinical responses were also evaluated as secondary endpoints. EXPERIMENTAL DESIGN: GX301 was administered by intradermally injecting 500 µg of each peptide (dissolved in Montanide ISA-51) in the skin of the abdomen. Imiquimod was applied as a cream at the injection sites. The protocol included 8 administrations at days 1, 3, 5, 7, 14, 21, 35, 63. Eligible patients were affected with stage IV prostate or renal cancer resistant to conventional treatments. Patients were clinically and immunologically monitored up to 6 months from the first immunization. RESULTS: No grade 3-4 adverse events were observed. Evidence of vaccine-specific immunological responses was detected in 100 % of patients. Disease stabilization occurred in 4 patients. Prolonged progression-free survival and overall survival were observed in patients showing a full pattern of vaccine-specific immunological responses. CONCLUSION: GX301 demonstrated to be safe and highly immunogenic. Further studies are needed to determine its clinical efficacy.


Subject(s)
Cancer Vaccines/administration & dosage , Kidney Neoplasms/immunology , Kidney Neoplasms/therapy , Peptides/administration & dosage , Prostatic Neoplasms/immunology , Prostatic Neoplasms/therapy , Adjuvants, Immunologic , Aged , Aged, 80 and over , Aminoquinolines/immunology , Antigens, Neoplasm/chemistry , Antigens, Neoplasm/immunology , Cancer Vaccines/adverse effects , Cancer Vaccines/immunology , Cell Proliferation , Combined Modality Therapy , Cytotoxicity, Immunologic , Humans , Imiquimod , Interferon-gamma/metabolism , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Male , Mannitol/analogs & derivatives , Mannitol/immunology , Middle Aged , Neoplasm Staging , Oleic Acids/immunology , Peptides/adverse effects , Peptides/immunology , Phenotype , Prostatic Neoplasms/mortality , Prostatic Neoplasms/pathology , Telomerase/chemistry , Telomerase/immunology , Treatment Outcome
2.
Clin Exp Med ; 22(1): 9-25, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34100160

ABSTRACT

Sjögren's syndrome is a chronic autoimmune disease characterized by ocular and oral dryness resulting from lacrimal and salivary gland dysfunction. Besides, a variety of systemic manifestations may occur, involving virtually any organ system. As a result, the disease is characterized by pleomorphic clinical manifestations whose characteristics and severity may vary greatly from one patient to another. Sjögren's syndrome can be defined as primary or secondary, depending on whether it occurs alone or in association with other systemic autoimmune diseases, respectively. The pathogenesis of Sjögren's syndrome is still elusive, nevertheless, different, not mutually exclusive, models involving genetic and environmental factors have been proposed to explain its development. Anyhow, the emergence of aberrant autoreactive B-lymphocytes, conducting to autoantibody production and immune complex formation, seems to be crucial in the development of the disease. The diagnosis of Sjögren's syndrome is based on characteristic clinical signs and symptoms, as well as on specific tests including salivary gland histopathology and autoantibodies. Recently, new classification criteria and disease activity scores have been developed primarily for research purposes and they can also be useful tools in everyday clinical practice. Treatment of Sjögren's syndrome ranges from local and symptomatic therapies aimed to control dryness to systemic medications, including disease-modifying agents and biological drugs. The objective of this review paper is to summarize the recent literature on Sjögren's syndrome, starting from its pathogenesis to current therapeutic options.


Subject(s)
Autoimmune Diseases , Sjogren's Syndrome , Xerostomia , Autoantibodies , Autoimmune Diseases/diagnosis , Humans , Salivary Glands , Sjogren's Syndrome/complications
3.
Clin Immunol ; 139(3): 249-57, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21419712

ABSTRACT

Aim of the study has been to understand the relationship between TH17 and Treg cell subsets in patients affected with systemic sclerosis (SSc). Phenotypes and functions of Th17 and Treg cell subsets were analyzed in a series of 36 SSc patients. Th17 cell concentration in the peripheral blood was found to be increased in SSc patients with respect to healthy controls independently from type or stage of disease. After PBMC stimulation with a polyclonal stimulus or Candida albicans antigens the frequency of Th17 T cell clones was significantly higher in SSc patients with respect to controls suggesting the skewing of immune response in SSc patients toward Th17 cell generation/expansion. Concerning the Treg compartment, both CD4+CD25+ and CD8+CD28- Treg subsets showed quantitative and qualitative alteration in the peripheral blood of SSc patients. Collectively, these data highlight the existence of an imbalanced ratio between Th17 and Treg cell subsets in SSc patients.


Subject(s)
Scleroderma, Systemic/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology , Aged , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Proliferation , Cytokines/blood , Cytokines/immunology , Female , Flow Cytometry , Humans , Immunophenotyping/methods , Male , Middle Aged , Statistics, Nonparametric
4.
J Autoimmun ; 35(3): 176-80, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20638239

ABSTRACT

The mechanisms that lead to loss of tolerance in autoimmune disease have remained both elusive and diverse, including both genetic predisposition and generic dysregulation of critical mononuclear cell subsets. In primary biliary cirrhosis (PBC), patients exhibit a multilineage response to the E2 component of pyruvate dehydrogenase involving antibody as well as autoreactive CD4 and CD8 responses. Recent data from murine models of PBC have suggested that a critical mechanism of biliary destruction is mediated by liver-infiltrating CD8 cells. Further, the number of autoreactive liver-infiltrating CD4 and CD8 cells is significantly higher in liver than blood in patients with PBC. Based on this data, we have studied the frequencies and phenotypic characterization of both CD4 and CD8 regulatory T cell components in both patients with PBC and age-sex matched controls. Our data is striking and indicate that CD8 Treg populations from PBC patients, but not controls, have significant phenotypic alterations, including increased expression of CD127 and reduced CD39. Furthermore, in vitro induction of CD8 Tregs by incubation with IL10 is significantly reduced in PBC patients. Importantly, the frequencies of circulating CD4+CD25+ and CD8+ and CD28- T cell subpopulations are not significantly different between patients and controls. In conclusion, these data identify the CD8 Treg subset as a regulatory T cell subpopulation altered in patients with PBC.


Subject(s)
Antigens, CD/biosynthesis , Apyrase/biosynthesis , CD8-Positive T-Lymphocytes/metabolism , Interleukin-7 Receptor alpha Subunit/biosynthesis , Liver Cirrhosis, Biliary/immunology , T-Lymphocytes, Regulatory/metabolism , Adult , Aged , Antigens, CD/genetics , Antigens, CD/immunology , Apyrase/genetics , Apyrase/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/pathology , Cell Count , Cell Movement , Cells, Cultured , Female , Humans , Immunophenotyping , Interleukin-10/immunology , Interleukin-10/metabolism , Interleukin-7 Receptor alpha Subunit/genetics , Interleukin-7 Receptor alpha Subunit/immunology , Liver/immunology , Liver/pathology , Liver Cirrhosis, Biliary/pathology , Liver Cirrhosis, Biliary/physiopathology , Lymphocyte Activation , Male , Middle Aged , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/pathology
5.
Transfusion ; 50(3): 547-55, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19906035

ABSTRACT

BACKGROUND: Numerous mechanisms have been proposed to explain the beneficial action of intravenous immune globulin (IVIG) in autoimmune and systemic inflammatory disorders. Among others' data, an in vitro increase of intracellular TGF-beta expression when culturing CD4+ T lymphocytes in the presence of IVIG has been reported. As IVIG infusion involves administration of soluble contaminants likewise all hemoderivative preparations, we hypothesized that, besides several other immunomodulatory proposed mechanisms, the clinical effects of IVIG therapy might be, at least partly, due to contaminating soluble HLA Class I (sHLA-I) molecules capable to exert pleiotropic immunomodulatory effects among which TGF-beta(1) modulation. STUDY DESIGN AND METHODS: Ex vivo and in vitro transcriptional and posttranscriptional modulation of TGF-beta(1) in CD8+ T lymphocytes and neutrophils after IVIG infusion was analyzed. RESULTS: Ex vivo analysis of cells drawn from 10 enrolled IVIG recipients pointed out a significant increase of TGF-beta(1) mRNA and intracellular TGF-beta(1) molecules in both leukotypes. In vitro comparable results were obtained incubating CD8+ T lymphocytes and neutrophils from healthy donors with IVIG. The immunodepletion of sHLA-I and/or soluble Fas ligand (sFasL) abolished TGF-beta(1) modulation in both leukotypes. Coculture with human immunoglobulin (Ig)M monoclonal antibody or chimeric IgG (MabThera, Roche), whose manufacturing excludes "contamination," did not exert any mRNA modulation. Finally, IgM or MabThera plus purified sHLA-I molecules enhanced TGF-beta(1) mRNA in both white blood cells to levels comparable to those obtained with IVIG incubation. CONCLUSION: On the whole, these data lead us to speculate that the ability of IVIG administration to modulate TGF-beta(1) might be related to the immunomodulatory activities of sHLA-I and sFasL molecules on activated CD8+ T lymphocytes and neutrophils.


Subject(s)
CD8-Positive T-Lymphocytes/metabolism , Histocompatibility Antigens Class I , Immunoglobulins, Intravenous , Immunologic Factors , Neutrophils/metabolism , Transcription, Genetic/drug effects , Transforming Growth Factor beta1/biosynthesis , Antibodies, Monoclonal/pharmacology , Cells, Cultured , Fas Ligand Protein/administration & dosage , Fas Ligand Protein/pharmacology , Female , Histocompatibility Antigens Class I/administration & dosage , Histocompatibility Antigens Class I/pharmacology , Humans , Immunoglobulins, Intravenous/administration & dosage , Immunoglobulins, Intravenous/pharmacology , Immunologic Factors/administration & dosage , Immunologic Factors/pharmacology , Lymphocyte Activation/drug effects , Male , RNA, Messenger/biosynthesis
6.
Am J Respir Crit Care Med ; 179(5): 408-13, 2009 Mar 01.
Article in English | MEDLINE | ID: mdl-19096004

ABSTRACT

RATIONALE: Interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) is associated with increased morbidity and mortality. Gastroesophageal reflux (GER) is considered a contributing factor in the pathogenesis of ILD. OBJECTIVES: To characterize GER (acid and nonacid) in patients with SSc with and without ILD. METHODS: Patients with SSc underwent pulmonary high-resolution computer tomography (HRCT) scan and 24-hour impedance-pH monitoring off-proton pump inhibitor therapy. The presence of pulmonary fibrosis was assessed using validated HRCT-scores. Reflux monitoring parameters included number of acid and nonacid reflux episodes, proximal migration of the refluxate, and distal esophageal acid exposure. Unless otherwise specified, data are presented as median (25th-75th percentile). MEASUREMENTS AND MAIN RESULTS: Forty consecutive patients with SSc (35 female; mean age, 53 yr; range, 24-71; 15 patients with diffuse and 25 with limited SSc) were investigated; 18 (45%) patients with SSc had pulmonary fibrosis (HRCT score >or= 7). Patients with SSc with ILD had higher (P < 0.01) esophageal acid exposure (10.3 [7.5-15] vs. 5.2 [1.5-11]), higher (P < 0.01) number of acid (41 [31-58] vs. 19 [10-23]) and nonacid (25 [20-35] vs. 17 [11-19]) reflux episodes, and higher (P < 0.01) number of reflux episodes reaching the proximal esophagus (42.5 [31-54] vs. 15 [8-22]) compared with patients with SSc with normal HRCT scores. Pulmonary fibrosis scores (HRCT score) correlated well with the number of reflux episodes in the distal (r(2) = 0.637) and proximal (r(2) = 0.644) esophagus. CONCLUSIONS: Patients with SSc with ILD have more severe reflux (i.e., more reflux episodes and more reflux reaching the proximal esophagus). Whether or not the development of ILD in patients with SSc can be prevented by reflux-reducing treatments needs to be investigated.


Subject(s)
Gastroesophageal Reflux/complications , Pulmonary Fibrosis/complications , Scleroderma, Systemic/complications , Adult , Aged , Case-Control Studies , Electric Impedance , Esophageal pH Monitoring , Esophagus/pathology , Esophagus/physiopathology , Female , Gastroesophageal Reflux/pathology , Gastroesophageal Reflux/physiopathology , Humans , Male , Middle Aged , Prospective Studies , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/physiopathology , Respiratory Function Tests , Scleroderma, Systemic/pathology , Scleroderma, Systemic/physiopathology , Tomography, X-Ray Computed , Young Adult
7.
Clin Immunol ; 133(2): 238-44, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19762282

ABSTRACT

We have reported that serum level of soluble HLA-A, -B, -C (sHLA-A,-B,-C) antigens is elevated in HIV-infected subjects and decreases after antiretroviral therapy (HAART). In this study, we measured the levels of soluble HLA-G (sHLA-G) antigens in a cohort of HIV-infected patients before and during HAART. sHLA-G and sHLA-A, -B, -C levels were significantly elevated in HIV-infected subjects as compared with controls before antiretroviral treatment and significantly decreased after 36 months of HAART. sHLA-G levels were correlated with sHLA-A, -B, -C levels, the decrease of plasma HIV-RNA level, the increase of CD4+ T-lymphocyte number and the decrease of CD8+ T-lymphocyte number. These results suggest that the measurement of sHLA-G and sHLA-A, -B, -C antigen serum levels might represent a useful surrogate marker to monitor virological response and immune reconstitution in HIV-positive subjects undergoing HAART treatment.


Subject(s)
Antiretroviral Therapy, Highly Active , HIV Infections/blood , HIV-1/genetics , HLA Antigens/blood , HLA-A Antigens/blood , HLA-B Antigens/blood , HLA-C Antigens/blood , Histocompatibility Antigens Class I/blood , Adult , Biomarkers/blood , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes/cytology , Female , HIV Infections/diagnosis , HIV Infections/drug therapy , HLA-G Antigens , Humans , Lymphocyte Count , Male , Middle Aged , RNA, Viral/blood , RNA, Viral/genetics , Sex Characteristics , T-Lymphocyte Subsets/cytology
8.
Recenti Prog Med ; 100(11): 512-6, 2009 Nov.
Article in Italian | MEDLINE | ID: mdl-20066883

ABSTRACT

Interstitial lung disease represents the main cause of morbidity and mortality in patients with systemic sclerosis. The mechanisms leading to interstitial lung disease are poorly understood and thus current strategies have little effect on this progressive and fatal disease. Therefore, it appears relevant the importance to assess the possible risk factors involved in its pathogenesis. Previous studies in vivo and in vitro suggested that pulmonary fibrosis can occur after repeated aspiration of small amounts of gastric contents over long periods of time. Recently, our group observed that patients with systemic sclerosis and pulmonary fibrosis have a more severe degree of gastroesophageal reflux with a greater number of reflux events and a higher percentage of reflux episodes reaching the proximal esophagus, causing an increasing risk of microaspiration, compared to patients with systemic sclerosis without lung involvement. Further larger controlled studies are necessary to evaluate whether or not the development of interstitial lung disease in systemic sclerosis patients can be prevented by treating gastroesophageal reflux.


Subject(s)
Gastroesophageal Reflux/complications , Pulmonary Fibrosis/etiology , Scleroderma, Systemic/complications , Age Factors , Aged , Animals , Disease Models, Animal , Esophageal pH Monitoring , Gastroesophageal Reflux/diagnosis , Gastroesophageal Reflux/therapy , Humans , Lung Diseases, Interstitial/etiology , Middle Aged , Pulmonary Fibrosis/complications , Risk Factors , Scleroderma, Systemic/mortality
9.
Clin Exp Med ; 19(3): 357-366, 2019 Aug.
Article in English | MEDLINE | ID: mdl-30989453

ABSTRACT

Vasculopathy is a crucial feature of systemic sclerosis (SSc), and Raynaud's phenomenon (RP) and digital ulcers (DU) have a deep impact on the quality of patients' life. The management of vascular disease can be challenging for the clinician because of the suboptimal tolerability of the treatments and lack of consensus on the best therapeutic approach. Intravenous iloprost, a synthetic analogue of prostacyclin, is broadly used for the treatment of RP and ischemic ulcers secondary to SSc. However, no standardized protocol on iloprost use is currently available and, consequently, the management of this treatment is largely based on the experience of each single center. The PROSIT project is an observational, multicenter study aiming to investigate the current treatments for SSc vasculopathy, the use of prostanoids, with special regard to iloprost, and the perception of the treatment from a patient's perspective. The study was conducted on a cohort of 346 patients from eight Italian centers and included a structured survey addressed to physicians, data collected from patient's medical records and two patient-administered questionnaires assessing the level of satisfaction, tolerability and perception of the efficacy of Iloprost. PROSIT data confirmed that in the contest of SSc iloprost represents the first-line choice for the management of severe RP and DU. Moreover, it is a well-tolerated treatment as reported by patients' experience. Although a standard protocol for the treatment of SSc-related vasculopathy is lacking, PROSIT study identified different therapeutic approaches largely supported by tertiary Italian centers. Further studies are needed in order to optimize the best treatment for SSc vascular diseases, in particular to improve the best iloprost schedule management.


Subject(s)
Disease Management , Iloprost/therapeutic use , Peripheral Vascular Diseases/drug therapy , Peripheral Vascular Diseases/pathology , Scleroderma, Systemic/complications , Scleroderma, Systemic/drug therapy , Vasodilator Agents/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Italy , Male , Middle Aged , Retrospective Studies , Tertiary Care Centers , Treatment Outcome , Young Adult
10.
Am J Gastroenterol ; 103(5): 1257-62, 2008 May.
Article in English | MEDLINE | ID: mdl-18422815

ABSTRACT

OBJECTIVES: After the skin, the gastrointestinal tract is the second most common target of systemic sclerosis (SSc). AIM: Our aims were to investigate orocecal transit time (OCTT) and the presence of small intestinal bacterial overgrowth (SIBO) in SSc as a cause of intestinal symptoms. METHODS: Fifty-five SSc patients and 60 healthy controls, sex and age matched, entered the study. Enrolled subjects completed a questionnaire for intestinal symptoms and a global symptomatic score (GSS) was calculated. OCTT and the presence of SIBO were assessed by a lactulose breath test (LBT). Patients with SIBO were treated with rifaximin 1,200 mg/day for 10 days. Finally, a second questionnaire and LBT were performed 1 month after the end of therapy. RESULTS: The prevalence of SIBO was higher in SSc patients compared with controls (30/54 vs 4/60, respectively, P < 0.001). OCTT was significantly slower in SSc patients compared with controls (150 min, 25-75th percentile 142.5-165 vs 105 min, 25-75th percentile 90-135, respectively, P < 0.001). In patients with SIBO, the median GSS score was 8 (25-75th percentile 3.25-10.75). Eradication of SIBO was achieved in 73.3% of patients, with a significant reduction of symptoms in 72.7% of them (GSS score 2, 25-75th percentile 1-3, P < 0.05). CONCLUSIONS: These data suggest that SIBO occurs more frequently in SSc patients than in controls. Intestinal symptoms in these patients may be related to this syndrome and its eradication seems useful to improve clinical features. OCTT is significantly delayed in SSc patients, suggesting an impairment of intestinal motility, a further risk factor for the development of SIBO.


Subject(s)
Blind Loop Syndrome/drug therapy , Scleroderma, Systemic/complications , Adult , Aged , Anti-Infective Agents/therapeutic use , Blind Loop Syndrome/epidemiology , Blind Loop Syndrome/etiology , Breath Tests , Cross-Sectional Studies , Female , Gastrointestinal Transit , Humans , Intestine, Small , Lactulose , Male , Middle Aged , Prospective Studies , Rifamycins/therapeutic use , Rifaximin , Scleroderma, Systemic/epidemiology , Treatment Outcome
11.
Hum Immunol ; 69(7): 409-13, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18573288

ABSTRACT

Allergic rhinitis (AR) is characterized by a T-helper (Th)-2 (Th2) polarized immune response. Soluble human leukocyte antigen (sHLA) molecules play an immunomodulatory role. Specific immunotherapy is the only causal treatment for AR and is able to shift the immune response to Th1 polarization. The aim of this study was to evaluate the relationship between sHLA-G and sHLA-A,-B,-C serum levels and interferon-gamma (IFN-gamma) production in AR patients with pollen allergy before and after a preseasonal course of sublingual immunotherapy (SLIT). A total of 40 AR patients with pollen allergy were enrolled and given a course of preseasonal SLIT for 3 months. Serum sHLA-G and sHLA-A,-B,-C levels were determined by enzyme-linked immunoabsorbent assay, and cell production of IFN-gamma was evaluated by enzyme-linked immunoabsorbent spot assay at baseline and 3 months after the end of the SLIT course. There was a significant relationship between sHLA-G serum level change and IFN-gamma increase as well as between sHLA-A,-B,-C level change and IFN-gamma increase after SLIT. The present study provides the first published evidence that the reduction of sHLA molecules serum levels and the increased IFN-gamma production after SLIT in AR patients with pollen allergy are significantly related phenomena.


Subject(s)
Desensitization, Immunologic , HLA Antigens/blood , HLA-A Antigens/blood , HLA-B Antigens/blood , HLA-C Antigens/blood , Histocompatibility Antigens Class I/blood , Interferon-gamma/biosynthesis , Pollen , Rhinitis, Allergic, Seasonal/blood , Rhinitis, Allergic, Seasonal/therapy , Administration, Sublingual , Adult , Allergens/administration & dosage , Female , HLA Antigens/immunology , HLA-A Antigens/immunology , HLA-B Antigens/immunology , HLA-C Antigens/immunology , HLA-G Antigens , Histocompatibility Antigens Class I/immunology , Humans , Interferon-gamma/immunology , Male , Middle Aged , Rhinitis, Allergic, Seasonal/immunology
12.
Hum Immunol ; 69(11): 745-50, 2008 Nov.
Article in English | MEDLINE | ID: mdl-18832002

ABSTRACT

Among the different regulatory T lymphocyte (Treg) subpopulations, non-antigen-specific CD8+CD28- Treg (CD8+CD28- Treg) have been characterized for being involved in the pathogenesis of autoimmune diseases and cancer. A better phenotypic and functional characterization of this regulatory T-cell subset could help in identifying modulators of their activity with therapeutic finalities. The results of the present work show that Foxp3, a transcriptional marker of natural CD4+CD25+ Treg, is not expressed by CD8+CD28- Treg, thus indicating different origin and pathways of function for the latter with respect to the former regulatory cell type. Moreover, the results underline that the glucocorticoid induced TNF receptor is involved in generation processes but not in suppressor function of CD8+CD28- Treg. Phenotypic analyses demonstrate that, during their commitment from circulating nonregulatory CD8+CD28- T lymphocytes to Treg (an interleukin-10-dependent process), these cells downmodulate the IL7-receptor, thus differentiating them from long-lived, memory CD8+ T lymphocytes. Interestingly, CD8+CD28- Treg have been found to be resistant to the inhibitory effects of methylprednisolone, one of the most frequently administered corticosteroid drug used in therapy for immunosuppressive purposes.


Subject(s)
CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/immunology , Cell Differentiation/immunology , Immunologic Memory , T-Lymphocyte Subsets/cytology , T-Lymphocyte Subsets/immunology , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , CD28 Antigens , CD8-Positive T-Lymphocytes/metabolism , Cell Differentiation/drug effects , Forkhead Transcription Factors/biosynthesis , Forkhead Transcription Factors/immunology , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Glucocorticoids/pharmacology , Humans , Immunologic Memory/drug effects , Immunosuppression Therapy , Interleukin-10/biosynthesis , Interleukin-10/immunology , Methylprednisolone/pharmacology , Neoplasms/immunology , Neoplasms/metabolism , Receptors, Interleukin-17/biosynthesis , Receptors, Interleukin-17/immunology , Receptors, Tumor Necrosis Factor/biosynthesis , Receptors, Tumor Necrosis Factor/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism
13.
Autoimmun Rev ; 17(4): 325-330, 2018 Apr.
Article in English | MEDLINE | ID: mdl-29427825

ABSTRACT

The autoimmune regulator gene (AIRE) is a transcription factor expressed both in the thymus, by medullary thymic epithelial cells, and in secondary lymphoid organs. AIRE controls the local transcription of organ- specific proteins typically expressed in peripheral tissues, thus allowing the negative selection of self- reactive T cells. The crucial role played by AIRE in central immune tolerance emerged in the studies on the pathogenesis of Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy, a rare inherited polyendocrine/autoimmune disease. Thereafter, several studies found evidences indicating that AIRE impairment might be pathogenically involved in several autoimmune diseases and in tumorigenesis. In this review, we focus on recent advances relative to AIRE's effect on T cell development in physiology and disease. In particular, we address the following issues: 1) AIRE function and mTECs biology, 2) the impact of AIRE gene mutations in autoimmune diseases, and 3) the role of AIRE gene in anti-tumor immune response.


Subject(s)
Transcription Factors/genetics , Cell Differentiation , Humans , Transcription Factors/metabolism , AIRE Protein
14.
Front Immunol ; 9: 2447, 2018.
Article in English | MEDLINE | ID: mdl-30459765

ABSTRACT

The pathogenesis of HIV immunodeficiency is mainly dependent on the cytopatic effects exerted by the virus against infected CD4+ T cells. However, CD4+ T cell loss cannot be the only pathogenic factor since severe opportunistic infections may develop in HIV infected patients with normal CD4+ T cell counts and since the recent START study indicated that absolute CD4+ T cell counts are not predictive for AIDS and non-AIDS events. Recently our group demonstrated that CD8+CD28-CD127lowCD39+ regulatory T lymphocytes, previously found highly concentrated within tumor microenvironment, circulate with elevated frequency in the peripheral blood of HIV infected patients. Here, we show that these cells, that at least in part are HIV specific, express the PD1 immune checkpoint. Based on these evidences and considerations, in this Perspective article we speculate on the opportunity to treat HIV infected patients with anti-PD1 immune checkpoint inhibitors as a way to counteract the T regulatory cell compartment and to unleash virus-specific immune responses. In order to potentiate the immune responses against HIV we also propose the potential utility to associate immune checkpoint inhibition with HIV-specific therapeutic vaccination, reminiscent of what currently applied in oncologic protocols. We suggest that such an innovative strategy could permit drug-sparing regimens and, perhaps, lead to eradication of the infection in some patients.


Subject(s)
AIDS Vaccines/immunology , Antibodies, Monoclonal/therapeutic use , HIV Infections/therapy , HIV-1/physiology , Immunotherapy/methods , Programmed Cell Death 1 Receptor/antagonists & inhibitors , T-Lymphocytes, Regulatory/immunology , Animals , CD8 Antigens/metabolism , Combined Modality Therapy , HIV Infections/immunology , Humans , Immunization , Neoplasms/immunology , Neoplasms/therapy , Programmed Cell Death 1 Receptor/immunology , Tumor Microenvironment , Vaccination
15.
Hum Immunol ; 68(11): 894-900, 2007 Nov.
Article in English | MEDLINE | ID: mdl-18082568

ABSTRACT

Human major histocompatibility complex class I antigens (HLA-A, -B, and -C) are heterodimeric molecules composed of a alpha heavy chain noncovalently associated with an invariant protein known as beta(2)-microglobulin. Beside being expressed on the membrane of the large majority of nucleated cells, HLA class I antigens are evident in serum (sHLA-I). We have previously detected a significant increase in the serum level of beta(2)-microglobulin-associated HLA-I antigens in human immunodeficiency virus (HIV)-infected patients compared with HIV-negative controls. The introduction of highly active antiretroviral therapy (HAART) modified the clinical course of the disease and decreased the acquired immunodeficiency syndrome-related morbidity and mortality. Therefore, we measured the levels of sHLA-I antigens in 64 HIV-infected patients before and during HAART treatment and correlated them with the immunological and virological response to antiretroviral treatment. Serum sHLA-I antigen level was elevated in all HIV-infected patients before and significantly decreased after 36 months of HAART treatment, correlating with the decrease of plasma HIV-RNA level and with the increase of CD4+ T-lymphocyte number. These results suggest that the measurement of sHLA-I antigens serum level might represent a useful surrogate marker to monitor HIV-positive patients undergoing HAART treatment.


Subject(s)
Antiretroviral Therapy, Highly Active , HIV Infections/drug therapy , HIV Infections/immunology , Histocompatibility Antigens Class I/blood , Adult , CD4 Lymphocyte Count , Female , HIV/isolation & purification , HIV Infections/virology , Histocompatibility Antigens Class I/immunology , Humans , Male , Middle Aged , RNA, Viral/blood , Receptors, Tumor Necrosis Factor, Type II/blood , Treatment Outcome , Viral Load , beta 2-Microglobulin/blood
16.
Ann N Y Acad Sci ; 1108: 121-6, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17893978

ABSTRACT

Accelerated atherosclerosis is an emerging problem in patients with systemic lupus erythematosus (SLE). We planned an observational study to determine whether in patients with SLE carotid intima-media thickness (IMT) represents an early sign of accelerated atherosclerosis and to confirm that SLE adds to the traditional cardiovascular Framingham risk factors. Thirty females with SLE (age 18-65 years) underwent anamnestic, clinical, and laboratory evaluation and B-mode ultrasonography of carotid arteries, which provides a direct and noninvasive assessment of subclinical atherosclerosis. IMT measurements were performed on the right and left common carotid arteries 1.0 cm proximal to the carotid bulb and the mean IMT value was calculated with a dedicated software. The Framingham Point Score was also calculated for each subject. SLE patients showed a mean IMT value of 0.73 +/- 0.12 (SD) mm. This value is significantly (P < 0.05) higher than that reported for an age-matched healthy female control population (0.66 +/- 0.11 SD mm). A preliminary evaluation of the Framingham Point Score, estimating the 10-year risk for women to develop cardiovascular events, indicated an increased risk of early cardiovascular events in SLE patients. In our study we have shown that patients with SLE have an increased mean IMT value compared with a healthy females control. Moreover, the evaluation of the Framingham Point Score suggests that SLE is an additional risk factor for cardiovascular disease.


Subject(s)
Atherosclerosis/complications , Carotid Arteries/pathology , Lupus Erythematosus, Systemic/complications , Tunica Intima/pathology , Tunica Media/pathology , Adolescent , Adult , Aged , Atherosclerosis/pathology , Female , Humans , Lupus Erythematosus, Systemic/pathology , Middle Aged , Risk Factors , Ultrasonography
17.
Ann N Y Acad Sci ; 1110: 99-111, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17911425

ABSTRACT

DNA vaccination is a strategy of immunization based on the injection of a gene encoding for a target protein with the goal of eliciting a potentially protective immune response in the host. Compared to traditional immunization procedures, DNA vaccination offers several advantages: increased availability of antigenic peptides because of the endogenous and long-term synthesis of the gene product, improved antigen processing and presentation, possibility of antigen structure modeling through molecular engineering, coexpression of immunologically relevant agents, and low cost of vaccine production. Although the choice of the most appropriate vector for gene transfer may still be controversial, the application of DNA vaccination to the treatment of autoimmune diseases in different experimental animal models has demonstrated the great potential of this procedure for therapeutic purposes. DNA vaccination has been successful in protecting mice from the development of organ-specific autoimmunity (experimental allergic encephalomyelitis (EAE), autoimmune diabetes, experimental arthritis, experimental uveitis) as well as systemic autoimmune disease (systemic lupus erythematosus (SLE), antiphospholipid syndrome). The protection appears to be highly influenced by the capacity of DNA vaccination to modulate immune responses affecting the Th1, Th2 and, importantly, the T cell immunoregulatory arms. We review here the experimental evidence and most recent data supporting the use of DNA vaccination in the induction of immune tolerance.


Subject(s)
Immune Tolerance/genetics , Immune Tolerance/immunology , Vaccination , Animals , Autoimmune Diseases/genetics , Autoimmune Diseases/immunology , Drug-Related Side Effects and Adverse Reactions , Humans , Vaccination/adverse effects , Vaccines, DNA/adverse effects , Vaccines, DNA/genetics , Vaccines, DNA/immunology
18.
Clin Exp Med ; 17(3): 257-267, 2017 Aug.
Article in English | MEDLINE | ID: mdl-27334977

ABSTRACT

Antiphospholipid antibody syndrome (APS) is an autoimmune acquired thrombophilia characterized by recurrent thrombosis and pregnancy morbidity in the presence of antiphospholipid antibodies (aPL). APS can be primary, if it occurs in the absence of any underlying disease, or secondary, if it is associated with another autoimmune disorder, most commonly systemic lupus erythematosus. The exact pathogenetic mechanism of APS is unknown, but different, not mutually exclusive, models have been proposed to explain how anti-PL autoantibodies might lead to thrombosis and pregnancy morbidity. Diagnosis of APS requires that a patient has both a clinical manifestation (arterial or venous thrombosis and/or pregnancy morbidity) and persistently positive aPL, but the clinical spectrum of the disease encompasses additional manifestations which may affect every organ and cannot be explained exclusively by a prothrombotic state. Treatment for aPL-positive patients is based on the patient's clinical status, presence of an underlying autoimmune disease, and history of thrombotic events. In case of aPL positivity without previous thrombotic events, the treatment is mainly focused on reduction of additional vascular risk factors, while treatment of patients with definite APS is based on long-term anticoagulation. Pregnancy complications are usually managed with low-dose aspirin in association with low molecular weight heparin. Refractory forms of APS could benefit from adding hydroxychloroquine and/or intravenous immunoglobulin to anticoagulation therapy. Promising novel treatments include anti-B cell monoclonal antibodies, new-generation anticoagulants, and complement cascade inhibitors. The objective of this review paper is to summarize the recent literature on APS from pathogenesis to current therapeutic options.


Subject(s)
Anticoagulants/therapeutic use , Antiphospholipid Syndrome/drug therapy , Antiphospholipid Syndrome/physiopathology , Pregnancy Complications/drug therapy , Pregnancy Complications/physiopathology , Antiphospholipid Syndrome/epidemiology , Female , Humans , Male , Pregnancy , Pregnancy Complications/epidemiology , Sex Factors
19.
Ann N Y Acad Sci ; 1069: 377-85, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16855164

ABSTRACT

Mechanisms responsible for peripheral immune tolerance are currently under investigation in several laboratories, in order to define the role of immune homeostasis in physiological processes and pathologic conditions, such as autoimmunity and cancer. In this context, recent studies attributed a relevant role to the glucocorticoid-induced TNFR-related gene (GITR). GITR is expressed at high levels on CD4(+)CD25(+). T regulatory (Treg) cells, but only at low levels on resting responder T lymphocytes, and is upregulated after activation. GITR triggering induces both pro- and anti-apoptotic effects through different intracellular pathways, abrogates the suppressive activity of Treg cells, and co-stimulates responder T cells. These data hint that GITR triggering overstimulates the immune system. Indeed, in vivo studies demonstrated that GITR stimulation may both induce autoimmune diseases and strengthen anti-virus and anti-tumor immune responses. Therefore, the GITR-GITRL system appears crucial in regulating immunity. Currently, the majority of studies about GITR's role on regulatory cells are focused on CD4(+)CD25(+) Treg cells, while very little is known about the importance of this molecule in other Treg subtypes. We have recently characterized a subpopulation of CD8+ T suppressor lymphocytes able to inhibit both T cell proliferation and cytotoxicity. Preliminary data show that GITR is expressed on such CD8+ T suppressor cells and that its activation by a specific antibody inhibits generation, but not function, of these cells. These early results suggest the importance of GITR in human T suppressor lymphocytes other than CD4(+)CD25(+) Treg cells.


Subject(s)
Endocrine System/immunology , Glucocorticoids/pharmacology , Lymphocytes/drug effects , Lymphocytes/immunology , Receptors, Tumor Necrosis Factor/immunology , Animals , Antigens/immunology , Humans , Receptors, Tumor Necrosis Factor/classification , Receptors, Tumor Necrosis Factor/genetics
20.
Autoimmun Rev ; 15(2): 167-73, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26546717

ABSTRACT

The vasculitides form a heterogeneous group of systemic diseases that differ in etiology, histological patterns, and, consequently, clinical significance and prognosis but are traceable to the same pathological event, namely, vessel wall inflammation. The clinical heterogeneity among these diseases, together with yet unknown pathogenetic mechanisms for many of them, creates difficulties in the early diagnosis and correct management of affected patients. Therefore, several groups of investigators have elaborated nomenclatures to set some order in the definition and grouping of the vasculitides. The two main naming systems used for decades, i.e., the Fauci nomenclature and the 1994 Chapel Hill Consensus Conference (CHCC) nomenclature, were recently superseded by a revised CHCC nomenclature published in 2012. The aim of that revision was to update the names and definitions of the vasculitides and to include novel forms, considering the advances in knowledge made since the first consensus conference was held. Here, we critically discuss the 2012 CHCC nomenclature in light of the earlier naming systems and raise some concerns in how several vasculitides were grouped. On the basis of this analysis, we propose an integrated nomenclature that we believe will have a more direct impact in the clinic, perfectly aware that any redefinition may present contradictions.


Subject(s)
Vasculitis/diagnosis , Antibodies, Antineutrophil Cytoplasmic/immunology , Humans , Prognosis , Vasculitis/immunology
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