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Biomedical subjects

G Del Prete

Publications and source records attributed to G Del Prete.

At least 19 recordsLinked to original sources
PubMed2002

Investigation of environmental and host-related risk factors for tuberculosis in Africa. I. Methodological aspects of a combined design.

Host-related and environmental factors for tuberculosis have usually been investigated separately using different study designs. Joint investigation of the genetic, immunologic, and environmental factors at play in susceptibility to tuberculosis represents an innovative goal for obtaining a better understanding of the pathogenesis of the disease. In this paper, the authors describe methods being used to investigate these points in a West African study combining several designs. Patients with newly diagnosed smear-positive cases of tuberculosis are recruited. The effect of host-related factors is assessed by comparing each case with a healthy control from the case's household. The role of environmental factors is estimated by comparing cases with randomly selected community controls. The frequencies of candidate gene variants are compared between cases and community controls, and results are validated through family-based association studies. Members of the households of cases and community controls are being followed prospectively to determine the incidence of "secondary" tuberculosis and to evaluate the influence of geographic and genetic proximity to the index case. This type of design raises important methodological issues that may be useful to consider in studies investigating the natural history of infectious diseases and in attempts to disentangle the effects of environmental and genetic factors in response to infection.

Africa, Western↗
PubMed2002

Investigation of environmental and host-related risk factors for tuberculosis in Africa. II. Investigation of host genetic factors.

In an accompanying paper (Am. J. Epidemiol. 2002;155:1066-73), the authors describe the design of a large multicenter study being carried out in three West African countries for investigation of the roles of environmental and host-related factors in the development of tuberculosis. In this paper, the authors review some evidence that host genetic factors play a role in susceptibility to tuberculosis. They describe the three components of the study that are designed to investigate the effect of host genetic factors on the development of tuberculosis: case-control and family-based association studies of candidate genes and analysis of affected relative pairs to screen the human genome for areas of linkage to the disease. The authors also address a number of methodological issues that arise, such as the effects of consanguinity, half-siblings, and nonpaternity. Lastly, they review opportunities to assess gene-environment interaction in the framework of the study, in light of current methodological knowledge. Consideration of these issues may be useful in the design of other studies of genetic susceptibility to infectious diseases, particularly those to be carried out in developing countries.

Africa, Western↗
PubMed2001

Neonatal bacillus Calmette-Guérin vaccination induces adult-like IFN-gamma production by CD4+ T lymphocytes.

The immaturity of the neonatal immune system in mice is associated with defective IFN-gamma production and Th2-biased immune responses. In this study, infants vaccinated at birth with BCG produced similar concentrations of IFN-gamma in response to PPD and showed similar frequencies of IFN-gamma-producing lymphocytes as compared to immune adults. Infants and adults produced only low concentrations of IL-4 and IL-5. CD4+ T lymphocytes were the main source of IFN-gamma. Similar proportions of Th1 and Th0 PPD-specific T cell clones were observed in infants and adults. This study demonstrates that the human neonatal immune response to BCG is not biased towards Th2 and is characterized by the predominant production of IFN-gamma by CD4+ T lymphocytes.

Adolescent↗
PubMed2001

Preferential Th1 profile of T helper cell responses in X-linked (Bruton's) agammaglobulinemia.

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency of the B-cell compartment caused by a defective gene encoding for the tyrosine kinase (btk) essential for B cell differentiation. Affected males undergo recurrent pyogenic infections and deficient immunoglobulin production. Peripheral blood T cells from 6 XLA patients and 6 matched healthy controls were stimulated with either PHA or tetanus toxoid (TT) and T cell clones obtained were compared for their cytokine profile. In the series of PHA-induced or TT-specific CD4(+) T cell clones derived from XLA patients, the Th1 profile was predominant (63 and 65 %, respectively). Upon stimulation with TT, the proportion of activated T cells from XLA that expressed the IFN-gamma -associated LAG-3 activation molecule was higher than in control T cells (51 vs. 25 %), whereas the expression of the IL-4-associated CD30 molecule was lower (5 vs. 21 %). In a cohort of 31 XLA patients, plasma levels of soluble (s)LAG-3 and sCD30, chosen as indirect indicators of the Th1 / Th2 activity in vivo, were significantly higher and lower, respectively, than those measured in 31 healthy controls. Likewise, plasma levels of interferon-inducible protein 10 and of macrophage-derived chemokine in XLA patients were significantly higher and lower, respectively, than in healthy controls.

Adolescent↗
PubMed2001

Atopy, intestinal helminth infection and total serum IgE in rural and urban adult Gambian communities.

BACKGROUND: The rarity of atopy in traditional societies has been attributed to high parasite-driven blocking IgE concentrations. Information is lacking on the relationship between atopy, IgE and intestinal helminth infection in African populations. OBJECTIVE: To determine the prevalence of atopy and intestinal helminth infection and to relate these to wheeze history and serum total IgE in a community sample of adults from an urban (Banjul) and a rural (Farafenni) area of the Gambia. METHODS: Six hundred and ninety-three adults were interviewed about respiratory symptoms using a modified version of the IUTLD questionnaire, and had skin prick testing using four allergens. Stools were examined after formol-ether concentration. Total serum IgE concentration was measured in a subset of participants. RESULTS: The prevalence of atopy (mean weal diameter > or = 3 mm) in the urban and rural area was 35.3% and 22.5% (P = 0.05); D. pteronyssinus and Mold mix being the common sensitizing allergens. Prevalence of wheeze in the previous 12 months was 4.4% and 3.5% for the urban and rural areas, respectively. Wheezing was not significantly associated with atopy. Seventeen per cent of urban and 8.2% of rural subjects had helminths detected in stools. There was an inverse association between atopy and intestinal helminth infection; 7% of atopic subjects had helminths, compared to 13% of non-atopic subjects (unadjusted odds ratio 0.51, 95%CI 0.24-1.1, P = 0.09; adjusted odds ratio 0.37, 95%CI 0.15-0.92, P = 0.03). Non-atopics had total serum IgE concentrations about 2.5 times the upper limit of the reference range in non-atopic Western populations. Geometric mean total serum IgE concentration was significantly higher among atopic subjects (570 IU/mL, IQR 91-833) than non-atopic subjects (259 IU/mL, IQR 274-1303) (P < 0.001). IgE concentration was not associated with the presence of helminth infection. CONCLUSION: Further studies are needed to clarify why asthma is still relatively uncommon in spite of the prevalence of atopy in Gambian adults. Our data are also compatible with the idea that atopy might protect against helminth infection.

Adolescent↗
PubMed2001

H(+),K(+)-atpase (proton pump) is the target autoantigen of Th1-type cytotoxic T cells in autoimmune gastritis.

BACKGROUND & AIMS: The proton pump H(+),K(+)-adenosine triphosphatase (H(+),K(+)-ATPase) of parietal cells is the major humoral autoantigen in both human and experimental autoimmune gastritis (AIG) characterized by an inflammatory infiltrate in the gastric mucosa and loss of parietal cells. The aim of this study was to detect H(+),K(+)-ATPase-specific T cells in the gastric mucosa of patients with AIG and to define their functional properties. METHODS: In vivo-activated T cells from the infiltrates of the gastric mucosa of 5 patients with AIG were isolated and cloned. The ability of gastric T-cell clones to proliferate and to produce cytokines in response to H(+),K(+)-ATPase, as well as their expression of B-cell help, perforin-mediated cytotoxicity, and Fas-Fas ligand-mediated apoptosis in target cells, were assessed. RESULTS: A proportion (25%) of the CD4(+) clones from the gastric corpus of AIG patients proliferated in response to porcine H(+),K(+)-ATPase. Most of these clones (88%) showed a Th1 profile, whereas a few secreted both Th1 and Th2 cytokines. Virtually all of the H(+),K(+)-ATPase-specific clones produced tumor necrosis factor alpha and provided substantial help for B-cell immunoglobulin production, and most of them expressed perforin-mediated cytotoxicity against antigen-presenting cells and induced Fas-Fas ligand-mediated apoptosis in target cells. CONCLUSIONS: Activation of proton pump-specific Th1 cytotoxic/proapoptotic T cells in the gastric mucosa can represent an effector mechanism for the target cell destruction in AIG.

Adult↗
PubMed2001

Polarization of PPD-specific T-cell response of patients with tuberculosis from Th0 to Th1 profile after successful antimycobacterial therapy or in vitro conditioning with interferon-alpha or interleukin-12.

The T helper (Th) 1/Th2 balance in the T-lymphocyte response to purified protein derivative (PPD) was evaluated at the clonal level in six Italian and five Gambian patients with pulmonary tuberculosis (TB) before and after antimycobacterial therapy, as well as in five Gambian and four Italian healthy immune control subjects. In untreated patients, most PPD-specific clones derived from either peripheral blood or pleural effusions showed a Th0 cytokine profile (production of both interferon [IFN]-gamma and interleukin [IL]-4/IL-5). After 6 mo of therapy and clinical healing, most PPD-specific clones showed a polarized Th1 profile (production of IFN-gamma but not IL-4/IL-5) in both Italian and Gambian patients. The Th1 polarization was less marked in Gambian than in Italian patients and failed to occur in another group of four Italian patients who experienced treatment failure. The cytokine profile observed after successful therapy in patients with TB was similar to that found in healthy control subjects. T-cell clones of undefined specificity generated from PPD-stimulated cultures showed a similar Th0/Th2 bias in Gambian individuals and Italian patients with treatment failure. The Th0/Th2-biased responses in Gambian patients before therapy could be modulated in vitro by IFN-alpha or IL-12, which induced a Th1 polarization of both PPD-specific and bystander T cells. Our data show that active TB associates with a predominant Th0 response to mycobacterial antigens that could play a role in the pathogenesis of the disease. Adjunctive immunotherapy using Th1-polarizing cytokines could increase host defense against mycobacteria and accelerate healing.

Adult↗
PubMed2000

Defective recruitment and activation of ZAP-70 in common variable immunodeficiency patients with T cell defects.

We have previously identified a subset of common variable immunodeficiency (CVID) patients with defective T cell function associated with impaired activation of the TCR-dependent tyrosine phosphorylation cascade. Here we have assessed the structural and functional integrity of the principal components involved in coupling the TCR/CD3 complex to intracellular tyrosine kinases in two of these patients. We show that ZAP-70 fails to bind the signaling-competent CD3zeta tyrosine phosphorylation isoform and to become activated following TCR engagement, suggesting that defective recruitment of ZAP-70 might underlie the TCR signaling dysfunction in these patients. Determination of the nucleotide sequences encoding the intracellular domains of the CD3/zeta subunits and ZAP-70 did not reveal any mutation. Furthermore, ZAP-70 from these patients could interact in vitro with recombinant phospho-zeta, ruling out genetic defects at the immunoreceptor tyrosine-based activation motif/SH2 domain interface responsible for ZAP-70 recruitment to the activated TCR. No defect was found in expression, activity or subcellular localization of Lck, which is thought to be primarily responsible for CD3zeta phosphorylation. Hence, while the T cell defect in these CVID patients can be pinpointed to the interaction between ZAP-70 and CD3zeta, the integrity in the components of the signaling machinery involved in this process suggests that additional components might be required for completion of this step.

Animals↗
PubMed2000

[Reconstruction of the aortic root: midterm results].

BACKGROUND: The aim of this study was to assess mid-term results of aortic reconstruction. METHODS: According to Dr. David's technique, 20 patients (17 males, 3 females, median age 63 years) were examined, who underwent surgery between September 1996 and August 1999. Indications for operation were aortic insufficiency with ascending aorta aneurysm in 19 patients, and acute Stanford type A dissection in 1 patient. In every patient the native valve was preserved and suspended inside a tubular prosthesis on which the coronaries were reimplanted. RESULTS: No patient died in hospital. Follow-up (mean 13 months) was complete for all patients. One patient died of extracardiac causes. Seventeen of 19 survivors are in NYHA functional class I, the remaining 2 in class II. Nineteen patients underwent echocardiography which showed moderate aortic regurgitation in 1, mild in 6 and absent or trivial in 12. There were no instances of thromboembolism. CONCLUSIONS: These results are encouraging and have brought us to consider aortic reconstruction a valid alternative to traditional aortic root replacement. Dr. David's technique is reproducible and reliable in the long term.

Adult↗
PubMed2000

[Dilated thyrotoxic cardiomyopathy].

We report a case of reversible, dilated cardiomyopathy due to thyrotoxicosis, which occurred in a young male without any underlying heart disease. The patient presented a clinical picture of cardiogenic shock related to severe left ventricular dilation and dysfunction and with new-onset atrial fibrillation and very high ventricular rate. In spite of vigorous medical therapy, there was only a mild improvement of clinical and hemodynamic status and ventricular rate persisted inappropriately elevated. Subsequently, laboratory test results allowed for recognition of thyrotoxicosis (secondary to Graves's disease) and then specific thyrostatic treatment was added. There was a prompt clinical improvement and parallel, progressive reversal of left ventricular dysfunction. The patient could be converted to normal sinus rhythm and one week later was discharged in good condition. We discuss the pathophysiological mechanism for the induction of this rare form of thyrotoxic cardiomyopathy and emphasize that awareness of this possible presentation of hyperthyroidism is essential to identify patients with potentially reversible dilated cardiomyopathy.

Adult↗
PubMed1999

Phenotype and cytokine profile of Schistosoma mansoni specific T cell lines and clones derived from schistosomiasis patients with distinct clinical forms.

It is essential to distinguish the role of T lymphocytes on the physiopathology associated to more severe forms of schistosomiasis and on the immunomodulation that evolves in the majority of infected people. In this study, we generated Schistosoma mansoni-specific T cell lines and clones from patients with the acute and chronic (intestinal and hepatosplenic forms) phases of disease, from former ones, and from uninfected individuals sensitized to parasite soluble antigens. T cell lines derived from nontreated acute infected donors were capable of producing IL-4 and IL-5, while cells from treated patients secreted IFN-gamma. Lines from intestinal chronic and antigen-sensitized donors preferentially produced IFN-gamma, while those from hepatosplenic patients secreted all three cytokines. The cytokine analysis of CD4+ T cell clones revealed a Th2/Th0 pattern (clones producing IL-4 and IL-5 and clones producing all three cytokines) for those derived from infected patients, while cells from antigen-sensitized donors exhibited an opposite Th1/Th0 pattern (clones producing IFN-gamma and clones producing all three cytokines). The possible role of these T cell populations on human schistosomiasis mansoni is discussed.

Acute Disease↗
PubMed1999

Impaired T-cell regulation of B-cell growth in Helicobacter pylori--related gastric low-grade MALT lymphoma.

BACKGROUND & AIMS: Neoplastic B cells of the Helicobacter pylori-related low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma are responsive to T helper cells and sensitive to withdrawal of H. pylori-induced T-cell help. METHODS: The clonal progeny of T cells from the gastric mucosa of 5 patients with MALT lymphoma was compared with that of T-cell clones obtained from 5 H. pylori-infected patients with chronic gastritis. RESULTS: T-cell clones were assessed for specificity to H. pylori, cytokine profile, help for B-cell proliferation, and perforin- or Fas-mediated cytotoxic regulation of B-cell growth. Twenty-eight of 165 CD4(+) gastric clones from MALT lymphoma and 33 of 178 CD4(+) clones from chronic gastritis recognized H. pylori antigens. Cytokine production was similar in the 2 series of clones. All MALT lymphoma-derived clones dose-dependently increased their B-cell help, whereas clones from chronic gastritis lost helper activity at T-to-B-cell ratios greater than 1 because of concomitant cytolytic killing of B cells. T-cell clones from MALT lymphoma had both reduced perforin-mediated cytotoxicity and poor ability to induce Fas-mediated apoptosis. These defects were limited to gastric T cells. CONCLUSIONS: H. pylori-induced T cell-dependent B-cell activation and deficient cytotoxic control of B-cell growth may link H. pylori infection, local T-cell response, and genesis of low-grade gastric MALT lymphoma.

Aged↗
PubMed1998

Expression of the T-cell-specific tyrosine kinase Lck in normal B-1 cells and in chronic lymphocytic leukemia B cells.

Src family kinases play a key role in mitogenesis. The exquisitely tissue-specific distribution of different Src family members suggests that a fine tuning of their expression might be a key prerequisite for cell homeostasis. We tested B cells from patients affected by B-cell chronic lymphocytic leukemia (B-CLL) for expression of Src family kinases. The T-cell-specific tyrosine kinase Lck was found to be expressed at significant levels in CLL B-cells. This finding could be accounted for either by ectopic expression of Lck in B-CLL or by specific expression of this kinase in normal B-1 cells, which are believed to be the normal counterpart of CLL B cells. To answer this question B cells from different sources, characterized by a different size of the B-1 subpopulation, were tested for Lck expression. The results show that Lck expression is a feature of CD5(+), B-1 cells, suggesting a potential role for Lck in the self-renewal capacity of this B-cell subpopulation and supporting the notion that B-1 cells are the subset undergoing oncogenic transformation in B-CLL. Furthermore, we show that the CD5(-), B-2 subpopulation, while normally lacking Lck expression, acquires the capacity to express Lck ectopically upon transformation by EBV.

B-Lymphocyte Subsets↗
PubMed1998

Defective Th1 and Th2 cytokine synthesis in the T-T cell presentation model for lack of CD40/CD40 ligand interaction.

In this study, T or NK cell clones used as antigen-presenting cells (T- or NK-APC) were shown to be significantly less efficient than professional APC in inducing Th1 and Th2 cytokines by antigen-specific T cell clones. This phenomenon was not related to a limited engagement of TCR by T-APC, since comparable thresholds of TCR down-regulation were shown when antigen was presented by either T-APC or professional APC. Rather, the stimulatory T-APC weakness was due to their inability, because they are CD40-, to provide the appropriate co-stimuli to responder T cells both indirectly via IL-12, and partially via direct CD40L triggering on T cells. Indeed, the simultaneous addition of IL-12 and reagents directly engaging CD40L on responder T cells restored T cell cytokine synthesis when antigen was presented by T-APC. In addition, either IL-12 production or blocking of T cell cytokine synthesis by anti-IL-12 p75 antibodies was evident only when professional APC were used in our antigen-specific system. The down-regulation of cytokine synthesis in the system of T-T cell presentation could represent a novel mechanism of immune regulation, which may intervene to switch off detrimental Th1- or Th2-mediated responses induced by antigen presentation among activated T cells infiltrating inflamed tissues.

Antigen-Presenting Cells↗
PubMed1998

Human Th1 and Th2 T-cell clones are equally susceptible to infection and immortalization by human T-lymphotropic virus type I.

Human CD4+ Th1 and Th2 clones were infected with human T-lymphotropic virus type I (HTLV-I) and followed up for a 12 month period in culture. PCR analysis showed that proviral DNA and viral mRNA were present in both Th1 and Th2 infected clones, throughout the entire culture period. Thus, HTLV-I exhibited neither preferential tropism nor exerted differential immortalizing activity in Th1 versus Th2 cells. All the infected clones immediately lost their antigen dependency for growth and continuously proliferated in IL-2-conditioned medium without need for additional stimulation. Infected Th1 and Th2 clones equally showed high expression of CD25, HLA-DR, CD44, CD30 and CD45RO. Infection with HTLV-I altered the cytokine profile in Th1 and Th2 clones. Both types of clones produced IL-6 and TNF-alpha. Th1 infected clones retained their ability to secrete IFN-gamma, but lost IL-2 gene expression. Th2 infected clones lost IL-4 gene expression, retained the ability to produce small amounts of IL-5 and acquired IFN-gamma expression.

Antigens, CD↗
PubMed1998

The concept of type-1 and type-2 helper T cells and their cytokines in humans.

In both mice and humans, functionally distinct helper T (Th)-cell subsets, known as Th1 and Th2 cells, are characterized by the patterns of cytokines they produce. These two polarized forms of the specific cellular immune response provide a useful model for explaining not only the different types of protection, but also the pathogenic mechanisms of several immunopathological disorders. The development of polarized Th1 or Th2 responses depends on either environmental factors, including dose of antigen, nature of immunogen and cytokines (IL-12 and interferons or IL-4) at the time of antigen presentation, or other undefined factors in the individual genetic background, mainly at level of the so-called "natural immunity". Th1-dominated responses are potentially effective in eradicating infectious agents, including those hidden within the host cells. When the Th1 response is poorly effective or exhaustively prolonged, it may result in host damage. In contrast, Th2 responses are apparently insufficient to protect against the majority of infectious agents, but can provide some protection against parasites. Th2 cells are able to make unpleasant the life of parasites in the host and tend to limit potentially harmful Th1-mediated responses. Thus, Th2 cells may be regarded as a part of down regulatory (or suppressor) mechanism for exaggerated and/ or inappropriate Th1 responses. The Th1/Th2 paradigm applied to the study of chronic inflammatory disorders or autoimmune diseases allowed to understand that a number of diseases are mediated by Th1 cells, the two clearest examples being multiple sclerosis and thyroid autoimmunity. In other disorders, Th1/Th2 polarization is less prominent, or rather Th2 responses tend to predominate, such as in systemic lupus erythematosus, progressive systemic sclerosis or allergic diseases. It is of note that in experimental models in animals, a number of diseases can be prevented by switching immune responses from Th1 to Th2 or from Th2 to Th1. Moreover, the Th1/Th2 concept suggests that modulation of the relative contribution of Th1- or Th2-type cytokines makes possible to regulate the balance between protection and immunopathology, as well as the development and/or the severity of some immunologic disorders.

CD4-Positive T-Lymphocytes↗
PubMed1997

Expression and role in apoptosis of the alpha- and beta-chains of the IFN-gamma receptor on human Th1 and Th2 clones.

The mRNA and protein expression of the alpha- and beta-chains of IFN-gammaR were evaluated on a panel of human Th1 and Th2 clones. When cultured in IL-2-conditioned medium, both types of clones expressed mRNA for the alpha- and beta-chains, and both chains were present in the cytoplasm. Membrane expression of the alpha-chain was higher on Th2 than on Th1, whereas the beta-chain was poorly expressed on both types but increased following IL-2 withdrawal or PHA stimulation. In addition, both types of clones overexpressed MHC class I glycoproteins following IFN-gammaR triggering by exogenous IFN-gamma, although the kinetics was slower in Th1, and this exposure induced mRNA for IRF-1. When their TCR was triggered in the absence of APC, Th1 only underwent apoptosis. This activation-induced apoptosis was prevented by blocking of the alpha-chain or by IFN-gamma neutralization. Addition of IFN-gamma triggered the apoptosis of Th2 clones. Apoptosis of both types of clones was mediated by autocrine or exogenous IFN-gamma through the up-regulation of Fas-L expression, since anti-IFN-gammaR alpha mAb inhibited its expression on Th1 and exogenous IFN-gamma increased its expression on Th2. These results indicate that activated human Th1 and Th2 lymphocytes express IFN-gammaR alpha- and beta-chains and are both sensitive to signals provided by IFN-gamma. Data also suggest that IFN-gamma is critical for switching off their responses.

Apoptosis↗