PubMed Health⌕ Search

Biomedical subjects

Elena Lazzeri

Publications and source records attributed to Elena Lazzeri.

At least 19 recordsLinked to original sources
PubMed2007

PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion.

PF-4/CXCL4 is a member of the CXC chemokine family, which is mainly produced by platelets and known for its pleiotropic biological functions. Recently, the proteic product of a nonallelic variant gene of CXCL4 was isolated from human platelets and named as CXCL4L1. CXCL4L1 shows only 4.3% amino acid divergence in the mature protein, but exhibits a 38% amino acid divergence in the signal peptide region. We hypothesized that this may imply a difference in the cell type in which CXCL4L1 is expressed or a difference in its mode of secretion. In different types of transfected cells, CXCL4 and CXCL4L1 exhibited a distinct subcellular localization and a differential regulation of secretion, CXCL4 being stored in secretory granules and released in response to protein kinase C activation, whereas CXCL4L1 was continuously synthesized and secreted through a constitutive pathway. A protein kinase C-regulated CXCL4 secretion was observed also in lymphocytes, a cell type expressing mainly CXCL4 mRNA, whereas smooth muscle cells, which preferentially expressed CXCL4L1, exhibited a constitutive pathway of secretion. These results demonstrate that CXCL4 and CXCL4L1 exhibit a distinct subcellular localization and are secreted in a differentially regulated manner, suggesting distinct roles in inflammatory or homeostatic processes.

Cells, Cultured↗
PubMed2006

Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys.

Regenerative medicine represents a critical clinical goal for patients with ESRD, but the identification of renal adult multipotent progenitor cells has remained elusive. It is demonstrated that in human adult kidneys, a subset of parietal epithelial cells (PEC) in the Bowman's capsule exhibit coexpression of the stem cell markers CD24 and CD133 and of the stem cell-specific transcription factors Oct-4 and BmI-1, in the absence of lineage-specific markers. This CD24+CD133+ PEC population, which could be purified from cultured capsulated glomeruli, revealed self-renewal potential and a high cloning efficiency. Under appropriate culture conditions, individual clones of CD24+CD133+ PEC could be induced to generate mature, functional, tubular cells with phenotypic features of proximal and/or distal tubules, osteogenic cells, adipocytes, and cells that exhibited phenotypic and functional features of neuronal cells. The injection of CD24+CD133+ PEC but not of CD24-CD133- renal cells into SCID mice that had acute renal failure resulted in the regeneration of tubular structures of different portions of the nephron. More important, treatment of acute renal failure with CD24+CD133+ PEC significantly ameliorated the morphologic and functional kidney damage. This study demonstrates the existence and provides the characterization of a population of resident multipotent progenitor cells in adult human glomeruli, potentially opening new avenues for the development of regenerative medicine in patients who have renal diseases.

AC133 Antigen↗
PubMed2006

Nuclear medicine imaging of bone infections.

The inflammation and infection of bone include a wide range of processes that can result in a reduction of function or in the complete inability of patients. Apart from the inflammation, infection is sustained by pyogenic microorganisms and results mostly in massive destruction of bones and joints. The treatment of osteomyelitis requires long and expensive medical therapies and, sometimes, surgical resection for debridement of necrotic bone or to consolidate or substitute the compromised bones and joints. Radiographs and bone cultures are the mainstays for the diagnosis but often are useless in the diagnosis of activity or relapse of infection in the lengthy management of these patients. Imaging with radiopharmaceuticals, computed tomography and magnetic resonance are also used to study secondary and chronic infections and their diffusion to soft or deep tissues. The diagnosis is quite easy in acute osteomyelitis of long bones when the structure of bone is still intact. But most cases of osteomyelitis are subacute or chronic at the onset or become chronic during their evolution because of the frequent resistance to antibiotics. In chronic osteomyelitis the structure of bones is altered by fractures, surgical interventions and as a result of bone reabsorption produced by the infection. Metallic implants and prostheses produce artefacts both in computed tomography and magnetic resonance images, and radionuclide studies should be essential in these cases. Vertebral osteomyelitis is a specific entity that can be correctly diagnosed by computed tomography or magnetic resonance imaging at the onset of symptoms but only with radionuclide imaging is it possible to assess the activity of the disease after surgical stabilization or medical therapy. The lack of comparative studies showing the accuracy of each radiopharmaceutical for the study of bone infection does not allow the best nuclear medicine techniques to be chosen in an evidence-based manner. To this end we performed a meta-analysis of peer reviewed articles published between 1984 and 2004 describing the use of nuclear medicine imaging for the study of the most frequent causes of bone infections, including prosthetic joint, peripheric post-traumatic bone infections, vertebral and sternal infections. Guidelines for the choice of the optimal radiopharmaceuticals to be used in each clinical condition and for different aims is provided.

Bone Diseases, Infectious↗
PubMed2006

Osteomyelitis: clinical update for practical guidelines.

Bone infections represent a diagnostic or therapeutic challenge for the infectivologist, orthopaedic surgeon, radiologist and nuclear medicine physician. Staphylococcus aureus is the major bacterium responsible for bone infections although Mycobacterium tuberculosis is emerging as an infectious agent in Italy because of immigration from Africa and Asia. Osteomyelitis requires long and expensive antibiotic treatment, including rifampicin administered parenterally for several weeks and the use of antimicrobial-impregnated cement in prosthesis substitution. Sometimes it is necessary to carry out surgical debridement of a necrotic bone or the consolidation of compromised bones and joint prosthesis implants. Radiographs and bone cultures are mainstays for the diagnosis of bone infections but are often useless in the lengthy management of these patients. Diagnosis of skeletal infections still includes conventional radiography but magnetic resonance imaging is essential in haematogenous and spinal infections. Bone scans are still useful in acute osteomyelitis whereas scintigraphy using labelled white blood cells is preferred in infections of peripheral bone segments or joint prosthesis. In the axial skeleton a combination of an agent for detecting inflammation ((67)Ga citrate) and a metabolic agent ((99m)Tc-methylene diphosphonate) enables an infection and an area of increased metabolic activity to be distinguished. [(18)F]Fluorodeoxyglucose positron emission tomography, where available, has a significant impact in the study of infections using radionuclides: high-resolution tomographic images represent an effective alternative to gallium in the assessment of inflammation of spine lesions but a comparison with morphological examinations (computed tomography or magnetic resonance imaging) is essential.

Humans↗
PubMed2005

Expression of the DNAM-1 ligands, Nectin-2 (CD112) and poliovirus receptor (CD155), on dendritic cells: relevance for natural killer-dendritic cell interaction.

In this study, we demonstrate the involvement of DNAM-1-triggering receptor and its ligands, poliovirus receptor (PVR) and Nectin-2, in natural killer (NK) cell-mediated lysis of dendritic cells (DCs). The surface expression of both ligands was up-regulated in DCs as compared to monocytes. It reached maximal densities after DC maturation induced by different stimuli including lipopolysaccharide (LPS), poly I:C, flagellin, and CD40L. Both immunohistochemical analysis and confocal microscopy revealed expression of DNAM-1 ligands by DCs in lymph nodes in which they were localized in the parafollicular T-cell region and surrounded the high endothelial venules. Remarkably, in cytolytic assays, DNAM-1 cooperated with NKp30 in the NK-mediated killing of both immature and mature DCs and the degree of contribution of DNAM-1 appeared to correlate with the surface densities of its specific ligands PVR and Nectin-2.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2005

CD14+CD34low cells with stem cell phenotypic and functional features are the major source of circulating endothelial progenitors.

Endothelial progenitor cells (EPCs) seem to be a promising tool for cell therapy of acute myocardial infarction, but their nature is still unclear. We show here that EPCs obtainable from peripheral blood (PB) derive from the adhesion-related selection in culture of a subset of CD14+ cells, which, when assessed by the highly-sensitive antibody-conjugated magnetofluorescent liposomes (ACMFL) technique, were found to express CD34. These CD14+CD34low cells represented a variable proportion at individual level of CD14+ cells, ranging from 0.6% to 8.5% of all peripheral-blood leukocytes, and constituted the dominant population among circulating KDR+ cells. By using the ACMFL technique, virtually all CD14+ cells present in the bone marrow were found to be CD14+CD34low double-positive cells. EPCs, as well as purified circulating CD14+CD34low cells, exhibited high expression of embryonic stem cell (SC) markers Nanog and Oct-4, which were downregulated in a STAT3-independent manner when they differentiated into endothelial cells (ECs). Moreover, circulating CD14+CD34low cells, but not CD14+CD34- cells, proliferated in response to SC growth factors, and exhibited clonogenicity and multipotency, as shown by their ability to differentiate not only into ECs, but also into osteoblasts, adipocytes, or neural cells. The results of this study may reconcile apparently contradictory data of the literature, showing the generation of PB-derived EPCs from either CD34+ or CD14+ cells. We suggest that the use of this previously unrecognized population of circulating CD14+CD34low cells, which exhibit both phenotypic and functional features of SCs, may be useful in improving cell-based therapies of vascular and tissue damage.

Antigens, CD↗
PubMed2005

High CXCL10 expression in rejected kidneys and predictive role of pretransplant serum CXCL10 for acute rejection and chronic allograft nephropathy.

BACKGROUND: Several experimental models have shown that CXCL10 is required for initiation and development of graft failure caused by both acute and chronic rejection. METHODS: CXCL10 expression and distribution was investigated in tissue specimens obtained from 22 patients suffering from acute rejection (AR) or chronic allograft nephropathy (CAN) by using in situ hybridization. Furthermore, pretransplantation sera of 316 cadaveric kidney-graft recipients were tested retrospectively for serum CXCL10 levels by a quantitative sandwich immunoassay. RESULTS: Bioptic specimens obtained from patients with CAN were characterized by wide CXCL10 expression not only at level of infiltrating inflammatory cells but also of vascular, tubular, and glomerular structures. In addition, assessment of pretransplant serum CXCL10 levels in 316 graft recipients and stratification of patients in three groups according to serum CXCL10 levels (<100 pg/mL, n=163; 100-150 pg/mL, n=69; >150 pg/mL, n=84) showed highly significant differences in 5-year survival rates for the two extreme groups (95.7% vs. 79.7%, P=0.0002). Accordingly, patients who developed severe, early AR (277.14+/-65.08 p=0.004) and those who developed CAN also showed increased pretransplant serum CXCL10 levels (193.2+/-36.9, P=0.03). Multivariate analysis demonstrated that among the analyzed variables, CXCL10 (relative risk [RR] 2.801) and delayed graft function (RR 3.728) had the highest predictive power of graft loss. CONCLUSIONS: These results suggest that pretransplant serum CXCL10 levels greater than 150 pg/mL confer an increased risk of early, severe, AR and subsequent CAN, finally resulting in renal-allograft failure. This finding might be used for the individualization of immunosuppressive therapies.

Biomarkers↗
PubMed2005

Elevated serum interferon-gamma-inducible chemokine-10/CXC chemokine ligand-10 in autoimmune primary adrenal insufficiency and in vitro expression in human adrenal cells primary cultures after stimulation with proinflammatory cytokines.

Chemokines are a large family of cytokines involved in the pathogenesis of inflammatory and autoimmune diseases. Among CXC chemokines, CXC chemokine ligand 10 (CXCL10) has been identified to play an important role in several endocrinological autoimmune diseases, such as Hashimoto's thyroiditis, Graves' disease, and type 1 diabetes mellitus. Although the mechanisms leading to glandular autoimmune process may be at least in part shared by different endocrine organs, the role of CXCL10 in autoimmune adrenal insufficiency is unknown. The aim of this study was to evaluate the role of CXCL10 in Addison's disease (AD). Serum CXCL10 levels were assayed in 64 patients with clinically evident autoimmune AD, 20 patients with autoimmune subclinical AD, nine patients with nonautoimmune AD, and 48 healthy volunteers. Clinically evident and subclinical AD, but not nonautoimmune AD patients, showed a significant increase in serum CXCL10 levels compared with healthy subjects: 119.9 pg/ml (range, 39.8-427.6) and 124.0 pg/ml (range, 37.0-384.7) vs. 75.6 pg/ml (range, 22.4-164.0; P < 0.001 for both groups). Comparable serum CXCL10 levels were found between patients with an isolated form of AD and patients with other autoimmune conditions associated with AD, suggesting a specific influence of the adrenal autoimmune process in determining elevated CXCL10 concentrations in such patients. No relationship was found between serum CXCL10 levels and anti-21-hydroxylase or adrenal cortex autoantibody titers or between CXCL10 levels and duration of disease. The role of CXCL10 in the adrenal gland was also evaluated in vitro in human zona fasciculata cells (hZFC). CXCL10, although not basally detected in cultured hZFC, was strongly induced by interferon-gamma and synergistically increased by TNF-alpha addition. Hydrocortisone or ACTH alone had no effect on CXCL10 secretion in hZFC, but they both significantly inhibited cytokine-induced CXCL10 secretion. Taken together, these data suggest a potential role of hZFC, through the production of CXCL10, in regulating the recruitment of specific subsets of activated lymphocytes in autoimmune AD.

Addison Disease↗
PubMed2005

CXCR3-mediated opposite effects of CXCL10 and CXCL4 on TH1 or TH2 cytokine production.

BACKGROUND: Two variants of the CXCR3 receptor exist, one (CXCR3-A) reactive with CXCL9, CXCL10, and CXCL11 and the other (CXCR3-B) also reactive with CXCL4. Both variants are contemporarily expressed by human T cells. OBJECTIVE: We sought to investigate the in vitro effects of CXCL10 and CXCL4 on the production of TH1 or TH2 cytokines. METHODS: The cytokine profile of antigen-specific human CD4+ T-cell lines obtained in the absence or presence of CXCL10 or CXCL4 was evaluated by means of quantitative RT-PCR, flow cytometry, and ELISA. RESULTS: CXCL10 upregulated IFN-gamma and downregulated IL-4, IL-5, and IL-13 production, whereas CXCL4 downregulated IFN-gamma and upregulated TH2 cytokines. Similar effects were also observed on polyclonally activated pure naive CD4+ T cells. The opposite effects of CXCL10 and CXCL4 on TH1 and TH2 cytokine production were inhibited by an anti-CXCR3 antibody able to neutralize both CXCR3-A and CXCR3-B and were apparently related to the activation of distinct signal transduction pathways. Moreover, CXCL10 upregulated mRNA levels of T-box expressed in T cells and downregulated GATA-3 expression, whereas CXCL4 downregulated T-box expressed in T cells and upregulated GATA-3. Finally, CXCL4, but not CXCL10, induced direct activation of IL-5 and IL-13 promoters. CONCLUSION: CXCL10 and CXCL4 exert opposite effects on the production of human TH1 and TH2 cytokines, likely through their respective interaction with CXCR3-A or CXCR3-B and the consequent activation of different signal transduction pathways. This might represent an internal regulatory pathway of TH cell responses and might contribute to the modulation of chronic inflammatory reactions, including allergy.

CD4-Positive T-Lymphocytes↗
PubMed2005

Nephrotic syndrome and renal failure after allogeneic stem cell transplantation: novel molecular diagnostic tools for a challenging differential diagnosis.

BACKGROUND: Sudden onset of nephrotic syndrome after allogeneic stem cell transplantation is rare and has been associated mostly with membranous glomerulonephritis related to chronic graft-versus-host disease (cGVHD). We report a case of nephrotic syndrome and rapidly progressive renal failure occurring in a young woman 3 years after allogeneic stem cell transplantation from her HLA-identical brother. In the renal biopsy, a diffuse mononuclear cell infiltrate was observed. Furthermore, histological analysis, immunofluorescence, and electron microscopy of the kidney specimen defined the diagnosis as minimal change disease, a T-cell-mediated glomerulopathy associated with lymphoproliferative disorders, but that has never been described as an isolated manifestation of cGVHD. METHODS: The differential diagnosis was performed by using immunohistochemistry and laser capture microdissection combined with Taq-Man quantitative polymerase chain reaction. RESULTS: Infiltrating mononuclear cells in renal tissue consisted of T cells expressing DNA levels of a Y chromosome-specific gene quantitatively similar to those observed in a male subject, showing that these cells derived from the transplant donor and definitely excluding leukemia relapse. However, the large number of infiltrating T cells allowed the possibility that in this patient, minimal change disease could be related to an atypical form of GVHD. CONCLUSION: This is the first study to use molecular techniques to show the differential diagnosis of nephrotic syndrome after allogeneic stem cell transplantation. This novel method approach might represent a key tool to characterize kidney infiltrate after allogeneic stem cell transplantation.

Acute Kidney Injury↗
PubMed2004

Clinical feasibility of two-step streptavidin/111In-biotin scintigraphy in patients with suspected vertebral osteomyelitis.

PURPOSE: Streptavidin accumulates at sites of inflammation and infection as a result of increased capillary permeability. In addition to being utilised by bacteria for their own growth, biotin forms a stable, high-affinity non-covalent complex with avidin. The objective of this investigation was to determine the diagnostic performance of two-step streptavidin/111In-biotin imaging for evaluating patients with suspected vertebral osteomyelitis. METHODS: We evaluated 55 consecutive patients with suspected vertebral osteomyelitis (34 women and 21 men aged 27-86 years), within 2 weeks after the onset of clinical symptoms. Thirty-two of the patients underwent magnetic resonance imaging (MRI) and 24, computed tomography (CT). DTPA-conjugated biotin was radiolabelled by incubating 500 microg of DTPA-biotin with 111 MBq of 111In-chloride. Two-step scintigraphy was performed by first infusing 3 mg streptavidin intravenously, followed 4 h later by 111In-biotin. Imaging was begun 60 min later. RESULTS: Streptavidin/111In-biotin scintigraphy was positive in 32/34 patients with spinal infection (94.12% sensitivity). The study was negative in 19/21 patients without infection (95.24% specificity). The corresponding results for MRI and CT were 54.17% and 35.29% (sensitivity), and 75% and 57.14% (specificity), respectively. All statistical parameters of diagnostic performance (Youden's J index, kappa measure of agreement with correct classification, accuracy, sensitivity, specificity, positive likelihood and negative likelihood) were clearly better for streptavidin/111In-biotin scintigraphy than for either MRI or CT. CONCLUSION: Streptavidin/111In-biotin scintigraphy is highly sensitive and specific for detecting vertebral osteomyelitis in the first 2 weeks after the onset of clinical symptoms, and is potentially very useful for guiding clinical decisions on instituting appropriate therapy.

Adult↗
PubMed2004

High pretransplant serum levels of CXCL10/IP-10 are related to increased risk of renal allograft failure.

In experimental models, the chemokine CXCL10/IP-10 is required for graft failure owing to both acute and chronic rejection. In the present study, pretransplantation sera from 316 cadaver kidney graft recipients were tested for serum CXCL10 and CCL22/MDC levels by an ELISA assay. Kidney graft recipients with normally functioning grafts showed significantly lower serum CXCL10 levels than patients who experienced graft failure, whereas no differences for serum CCL22 levels were observed. After the assignment of all patients to four groups according to serum CXCL10 levels, the death-censored survival rates of grafts were 97.5%, 93.6%, 89.7%, 78.7% (p = 0.0006) at 5 years, while no influence was observed on patient survival. Accordingly, patients with the highest CXCL10 levels showed an increased frequency and severity of rejection episodes. Serum C-reactive protein (CRP) level was also assayed in the same samples. Increase of serum CRP levels represented a predictive parameter for death, but not for graft failure. Multivariate analysis demonstrated that among the analyzed variables, CXCL10 had the highest predictive power of graft loss (RR 2.787). Thus, measurement of pretransplant serum CXCL10 levels might represent a clinically useful parameter to identify subjects who are at high risk of severe rejection and graft failure.

Adult↗
PubMed2003

Human CD8+CD25+ thymocytes share phenotypic and functional features with CD4+CD25+ regulatory thymocytes.

CD8+CD25+ cells, which expressed high levels of Foxp3, glucocorticoid-induced tumor necrosis factor receptor (GITR), CCR8, tumor necrosis factor receptor 2 (TNFR2), and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) mRNAs, were identified in the fibrous septa and medullary areas of human thymus. Activated CD8+CD25+ thymocytes did not produce cytokines, but most of them expressed surface CTLA-4 and transforming growth factor beta1 (TGF-beta1). Like CD4+CD25+, CD8+CD25+ thymocytes suppressed the proliferation of autologous CD25-T cells via a contact-dependent mechanism. The suppressive activity of CD8+CD25+ thymocytes was abrogated by a mixture of anti-CTLA-4 and anti-TGF-beta1 antibodies and it was mediated by their ability to inhibit the expression of the interleukin 2 receptor alpha chain on target T cells. These results demonstrate the existence of a subset of human CD8+CD25+ thymocytes sharing phenotype, functional features, and mechanism of action with CD4+CD25+ T regulatory cells.

Antigens, CD↗
PubMed2003

An alternatively spliced variant of CXCR3 mediates the inhibition of endothelial cell growth induced by IP-10, Mig, and I-TAC, and acts as functional receptor for platelet factor 4.

The chemokines CXCL9/Mig, CXCL10/IP-10, and CXCL11/I-TAC regulate lymphocyte chemotaxis, mediate vascular pericyte proliferation, and act as angiostatic agents, thus inhibiting tumor growth. These multiple activities are apparently mediated by a unique G protein-coupled receptor, termed CXCR3. The chemokine CXCL4/PF4 shares several activities with CXCL9, CXCL10, and CXCL11, including a powerful angiostatic effect, but its specific receptor is still unknown. Here, we describe a distinct, previously unrecognized receptor named CXCR3-B, derived from an alternative splicing of the CXCR3 gene that mediates the angiostatic activity of CXCR3 ligands and also acts as functional receptor for CXCL4. Human microvascular endothelial cell line-1 (HMEC-1), transfected with either the known CXCR3 (renamed CXCR3-A) or CXCR3-B, bound CXCL9, CXCL10, and CXCL11, whereas CXCL4 showed high affinity only for CXCR3-B. Overexpression of CXCR3-A induced an increase of survival, whereas overexpression of CXCR3-B dramatically reduced DNA synthesis and up-regulated apoptotic HMEC-1 death through activation of distinct signal transduction pathways. Remarkably, primary cultures of human microvascular endothelial cells, whose growth is inhibited by CXCL9, CXCL10, CXCL11, and CXCL4, expressed CXCR3-B, but not CXCR3-A. Finally, monoclonal antibodies raised to selectively recognize CXCR3-B reacted with endothelial cells from neoplastic tissues, providing evidence that CXCR3-B is also expressed in vivo and may account for the angiostatic effects of CXC chemokines.

Alternative Splicing↗
PubMed2003

The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C.

BACKGROUND AND AIMS: The chemokines CCL19 and CCL21 bind CCR7, which is involved in the organization of secondary lymphoid tissue and is expressed during chronic tissue inflammation. We investigated the expression of CCL21 and CCR7 in chronic hepatitis C. The effects of CCL21 on hepatic stellate cells (HSCs) were also studied. METHODS: Expression of CCL21 was assessed by in situ hybridization and immunohistochemistry. CCR7 on T cells was analyzed by flow cytometry. Cultured human HSCs were studied in their activated phenotype. RESULTS: In patients with chronic hepatitis C, expression of CCL21 and CCR7 was up-regulated. CCL21 was detected in the portal tracts and around inflammatory lymphoid follicles, in proximity to T lymphocytes and dendritic cells, which contributed to expression of this chemokine. Expression of CCR7 was also increased in patients with primary biliary cirrhosis. Intrahepatic CD8(+) T lymphocytes isolated from patients with chronic hepatitis C had a significantly higher percentage of positivity for CCR7 than those from healthy controls, and the expression of CCR7 was associated with that of CXCR3. Cultured HSCs expressed functional CCR7, the activation of which stimulated cell migration and accelerated wound healing in an in vitro model. Exposure of HSCs to CCL21 triggered several signaling pathways, including extracellular signal-regulated kinase, Akt, and nuclear factor kappaB, resulting in induction of proinflammatory genes. CONCLUSIONS: Expression of CCL21 during chronic hepatitis C is implicated in the recruitment of T lymphocytes and the organization of inflammatory lymphoid tissue and may promote fibrogenesis in the inflamed areas via activation of CCR7 on HSCs.

Cell Movement↗
PubMed2002

Phenotype, localization, and mechanism of suppression of CD4(+)CD25(+) human thymocytes.

Phenotypic markers, localization, functional activities, and mechanisms of action in vitro of CD4(+)CD25(+) T cells, purified from postnatal human thymuses, were investigated. These cells showed poor or no proliferation in mixed lymphocyte culture (MLC), and suppressed in a dose-dependent fashion the proliferative response to allogeneic stimulation of CD4(+)CD25(-) thymocytes. Virtually all CD4(+)CD25(+) thymocytes constitutively expressed cytoplasmic T lymphocyte antigen (CTLA)-4, surface tumor necrosis factor type 2 receptor (TNFR2), and CCR8. They prevalently localized to perivascular areas of fibrous septa and responded to the chemoattractant activity of CCL1/I-309, which was found to be produced by either thymic medullary macrophages or fibrous septa epithelial cells. After polyclonal activation, CD4(+)CD25(+) thymocytes did not produce the cytokines interleukin (IL)-2, IL-4, IL-5, IL-13, interferon gamma, and only a very few produced IL-10, but all they expressed on their surface CTLA-4 and the majority of them also transforming growth factor (TGF)-beta1. The suppressive activity of these cells was contact dependent and associated with the lack of IL-2 receptor (IL-2R) alpha-chain (CD25) expression in target cells. Such a suppressive activity was partially inhibited by either anti-CTLA-4 or anti-TGF-beta1, and was completely blocked by a mixture of these monoclonal antibodies, which were also able to restore in target T cells the expression of IL-2R alpha-chain and, therefore, their responsiveness to IL-2. These data demonstrate that CD4(+)CD25(+) human thymocytes represent a population of regulatory cells that migrate in response to the chemokine CCL1/I-309 and exert their suppressive function via the inhibition of IL-2R alpha-chain in target T cells, induced by the combined activity of CTLA-4 and membrane TGF-beta1.

Abatacept↗
PubMed2002

Expression of IP-10/CXCL10 and MIG/CXCL9 in the thyroid and increased levels of IP-10/CXCL10 in the serum of patients with recent-onset Graves' disease.

Both mRNA and protein expression of the chemokines IP-10/CXCL10 and Mig/CXCL9, as well as of their receptor, CXCR3, were assessed in the thyroid glands of 16 patients suffering from Graves' disease (GD). In addition, IP-10/CXCL10 levels were measured in the serum of 50 GD patients. Expression of IP-10/CXCL10, Mig/CXCL9, and CXCR3 was poor or absent in normal thyroid tissue from patients undergoing thyroidectomy because of primary localized thyroid tumors, while both the chemokines and their receptor were present in most thyroid glands of patients affected by GD. IP-10/CXCL10 and Mig/CXCL9 localized to infiltrating lymphocytes and macrophages, as well as to resident epithelial follicular cells, whereas CXCR3 was mainly found at the level of infiltrating inflammatory cells and endothelial cells from large and small vessels. Of note, maximal expression of IP-10/CXCL10 and Mig/CXCL9 was found in the thyroid gland of patients with recent-onset GD and was correlated with interferon (IFN)-gamma. Accordingly, high levels of IP-10/CXCL10 could be measured in the serum of patients with short-duration GD. Taken together, the results of this study demonstrate that the CXCR3-binding chemokines IP-10/CXCL10 and Mig/CXCL9 play an important role in the recruitment of cells and in the amplification of inflammation in GD. They also suggest that the production of these chemokines by resident follicular epithelial cells may contribute to the recruitment of CXCR3-expressing type 1 T-helper cells in the initial phases of GD.

Adult↗