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Biomedical subjects

G Candore

Publications and source records attributed to G Candore.

At least 55 records · Page 3Linked to original sources
PubMed1996

Major histocompatibility complex regulation of cytokine production.

This review describes the phenomenon of the major histocompatibility complex (MHC) control of cytokine production both in experimental animals and in humans. H-2 (mouse MHC) regulates which type of cytokine is selectively produced in response to the hapten trinitrophenyl (TNP). T cells from TNP-immune H-2k mice produce interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-3, IL-5, tumor necrosis factor-alpha (TNF-alpha), IL-10, and very low levels of IL-4 on reexposure to the specific antigen in vitro. By contrast, T cells from H-2d mice produce IL-3, TNF-alpha, IL-10, and IL-4 but very low levels of IL-2, IL-5 and IFN-gamma. As MHC-congenic matched strains (BALB/k and BALB/c) are used, this makes it unlikely that non-MHC genes influence the class of response observed. A similar pattern of haplotype regulation of cytokine production is observed in humans. In fact, peripheral blood mononuclear cells from HLA-B8,DR3-positive and negative individuals differ in their ability to produce IL-2, IL-5, and IFN-gamma on stimulation with the mitogen phytohemagglutinin while producing similar amounts of IL-4, IL-6, and IL-10. The following main considerations emerge from these observations. The MHC/peptide complex generated after antigen immunization, indicates which class of cytokine production is preferentially induced and, therefore, the outcome of the immune response. Furthermore, MHC genotype may affect cytokine production (and then immune responses) by completely different mechanism(s), that is, by an antigen-nonspecific control that does not depend on the ability of MHC molecules to bind in different ways the different peptides. Accurate control of the functional repertoire of an immune response is a critical parameter in response to infections as well as in immunopathology. MHC control of the class of the immune response at the level of cytokine production is a sophisticated way in which this occurs. This control might be involved in adaptive immune responses to infections as well as in immunopathology.

Animals↗
PubMed1995

T-cell activation in HLA-B8, DR3-positive individuals. Early antigen expression defect in vitro.

The HLA-B8, DR3 haplotype is overrepresented in several autoimmune diseases, implying that genes predisposing to these disorders are linked to this haplotype. In the patients affected by these diseases, as well as in healthy HLA-B8, DR3 individuals, various dysfunctions reflecting an impairment of T-cell activation have been found. To better characterize T-cell impairment of HLA-B8, DR3-positive healthy individuals, we analyzed the surface expression of early (CD69) and late (CD71) activation phenotypes. MNC cultures were stimulated with PHA and used for T-cell phenotyping by flow cytometry analysis. The results showed that the percentage of CD69+ T cells was significantly decreased in MNC from HLA-B8, DR3+ subjects. This defect was detected in cell cultures from all subjects studied, but it attained significance only in females in the early hours after stimulation. The difference in CD69 expression between HLA-B8, DR3-positive individuals and -negative ones was not due to differences in CD4 and CD8 ratios in the HLA-B8, DR3 cells that underwent activation, as following activation the pattern of CD4 and CD8 antigen expression was the same in both groups of subjects. Concerning the late antigen CD71, no significant difference in percentage was observed between T lymphocytes from HLA-B8, DR3+ and HLA-B8, DR3- subjects at all the times studied. The analysis of the requirements for CD69 expression has suggested that sustained PKC activation and an increase of intracellular CA2+ could be responsible for TCR/CD3-mediated CD69 induction. Thus, present data suggest a defect in the signal transduction pathway of the TCR/CD3 complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

In vitro impairment of interleukin-5 production in HLA-B8, DR3-positive individuals implications for immunoglobulin A synthesis dysfunction.

Healthy subjects carrying the HLA-B8,DR3 haplotype may show a large number of immune dysfunctions. Concerning T-cell dysfunctions, the most intriguing is a defect of the early phases of T-cell activation, responsible for the impairment of in vitro mitogen-stimulated cytokine production. Regarding B-cell dysfunctions, one the most fascinating topics is the association between this haplotype and IgA deficiency in healthy blood donors. Accordingly, HLA-B8,DR3-positive healthy subjects show significantly lower values of serum IgA than HLA-B8,DR3-negative ones. Because IL-5 is a stimulating factor for the secretion of IgA by committed B cells, we have analyzed the in vitro mitogen-stimulated IL-5 production by MNCs from healthy HLA-B8,DR3-positive individuals to study whether they display an impaired production of IL-5. The results clearly demonstrate that MNCs from HLA-B8,DR3-positive individuals display significant reduction of IL-5 production, suggesting that IgA synthesis dysregulation observed in HLA-B8,DR3-positive subjects could be due to an impairment of IL-5 production.

Adult↗
PubMed1994

In vitro cytokine production by HLA-B8,DR3 positive subjects.

It is well known that healthy subjects carrying the HLA-B8,DR3 haplotype may show an impairment of immune system, the T cells being the most affected. To gain insight into the mechanism(s) of the impairment displayed by these subjects, efforts have been centered on the study of in vitro cytokine production because of the pivotal role played by these mediators in the activation and control of several immune functions. The available results indicate that the ability to several immune functions. The available results indicate that the ability to produce interleukin-1 (IL-1), IL-2 and the soluble form of its receptor (sIL-2R) is impaired in HLA-B8,DR3 positive healthy subjects. To better characterize the cytokine production capacity of HLA-B8,DR3 positive subjects, we have investigated the pattern of in vitro production of IL-2, sIL-2R, IL-4. IL-6 and gamma-interferon (gamma-IFN) by mononuclear cells from HLA-B8, DR3 positive subjects after phytohaemoagglutinin stimulation. A significant decrease of IL-2, sIL-2R and gamma-IFN production by HLA-B8,DR3 positive subjects was observed. No significant difference was instead found between the HLA-B8,DR3 positive subjects and the negative ones as regards IL-4 and IL-6 production. We suggest that this imbalanced cytokine production may well account for the pattern of immune response that may observed in HLA-B8,DR3 positive subjects, i.e. a normal or increased humoral response in face of a low T cell immune responsiveness.

Adult↗
PubMed1994

Viral antibody titers are influenced by HLA-DR2 phenotype.

Antibody serum levels against herpes simplex type 1 virus, cytomegalovirus, viral capsid antigens of Epstein-Barr virus, and rubella virus were evaluated in a sample of the Sicilian population. Results demonstrated that HLA-DR2-positive individuals showed a significant increase in antibody titers, when compared to HLA-DR2-negative individuals. These observations seem to be in contrast with the reported association of the HLA-DR2 phenotype with an ineffective immune response against several infectious pathogens. On the other hand, an increased humoral response to viral antigens need not be interpreted as a marker for effective control of virus infections. In fact, the response to virus infections is related to the T-cell-mediated immune response restricted by class-I- or class-II-encoded proteins. Thus, the above-mentioned HLA-DR2-related susceptibility to certain viral infections could be associated with a preferential induction of an increased (although ineffective) antibody synthesis against viral antigens.

Adult↗
PubMed1993

Natural killer and lymphokine-activated killer activity in HLA-B8,DR3-positive subjects.

The haplotype HLA-B8,DR3 is over-represented in several autoimmune diseases, implying that genes predisposing people to these disorders are linked to this haplotype. In these diseases, various dysfunctions reflecting an impairment of the immune system have been found. Several reports indicate also that in HLA-B8,DR3-positive healthy subjects similar disorders may be demonstrated. In the present work, we have evaluated NK and LAK activity in these subjects. The study has been performed on monocyte-depleted peripheral blood MNCs by using, the K-562 cell line as a target for NK activity and the HL-60 cell line for as a target LAK activity. LAK cells were obtained by incubating MNCs for 3 days with 100 U/ml of rIL-2. The results of our experiments demonstrate that NK cell activity is significantly decreased in healthy subjects bearing the HLA-B8,DR3 haplotype. Since the number of circulating CD16+ cells is not significantly different between HLA-B8,DR3-positive subjects and negative ones, it is unlikely that this defect is due to a decreased number of NK cells in effector cell preparations. The observation that the treatment with rIL-2 can restore the killer activity of MNCs from these subjects suggests instead that the reduced NK activity may be due at least in part to the imbalance of cytokine network that has been demonstrated in HLA-B8,DR3-positive subjects. Finally, since a decreased NK activity has been reported in the autoimmune diseases linked to this haplotype, our results support the suggestion that immunologic changes observed in autoimmune diseases reflect systemic regulatory disorders that have a genetic basis.

Adult↗
PubMed1993

HLA-B8,DR3 phenotype and the antibody response against Epstein-Barr virus.

Antibodies against the viral capsid antigen (VCA) and nuclear antigens (EBNAs) of the Epstein-Barr virus (EBV) were determined in a sample of Sicilian population. A significant correlation was observed between HLA-B8,DR3 phenotype and reduced titres of antibodies to EBNAs, whereas HLA-B8,DR3 positive individuals displayed levels of antibodies to VCA comparable to those of HLA-B8,DR3 negative ones. These results further strengthen the suggestion that HLA-B8,DR3 positive subjects are low responders and that the depth of immune response depends on the fashion of antigenic challenge.

Adult↗
PubMed1993

gamma-Interferon, interleukin-4 and interleukin-6 in vitro production in old subjects.

It is well known that ageing is associated with various alterations of the lymphoid cell functions. Although both B and T cell are affected, the last appear to be more sensitive to ageing process. During the past years, to gain insight into thé mechanism(s) of this impairment, effort has been centered on the helper T cells specifically engaged in the production of interleukin-2 (IL-2) because of the pivotal role played by this cytokine in the activation of several immune functions. The results have demonstrated that the ability to produce IL-2 declines with age. In this paper we report the results of a study performed to determine the influence of age on the capacity to produce gamma-interferon (gamma-IFN), interleukin-4 (IL-4) and interleukin-6 (IL-6). Mononuclear cells from young and old subjects were assessed for cytokine producing capacity in response to phytohaemagglutinin stimulation. A significant decrease of gamma-IFN production by old subjects has been observed. No significant difference was instead observed between the old subjects and the young ones as regards IL-4 and IL-6 production. We suggest that this imbalanced cytokine production may well account for the pattern of immune response which may be observed in elderly, i.e. a normal or increased humoral response in face of a low T cell immune responsiveness.

Adult↗
PubMed1992

The effect of age on mitogen responsive T cell precursors in human beings is completely restored by interleukin-2.

It is well known that the function of T lymphocytes is significantly impaired by advancing age. In the present study, attempts have been made to further characterize the T cell impairment of elderly subjects. Thus, we have performed limiting dilution microculture analysis to evaluate the precursor frequency of T lymphocytes responding to a mitogenic stimulus in old and young subjects. Furthermore we have evaluated the activity of recombinant interleukin-2 (rIL-2) on these cells. The results demonstrate that in older subjects the frequency of these precursors is significantly decreased. The in vitro treatment with rIL-2 increased the frequency of mitogen responsive T lymphocyte precursors in both groups so that the difference between the two groups was not significant. Thus present results extend the findings demonstrating that older subjects display an impairment of T cell functions and that IL-2 treatment may correct these alterations. In particular, they confirm the hypothesis that age-associated functional changes are more likely due to diminished numbers of reactive cells, than to a decline in the activity of all cells.

Adult↗
PubMed1992

Blood antiphospholipid antibody levels are influenced by age, sex and HLA-B8,DR3 phenotype.

Antiphospholipid antibodies (APA) are known to be associated with a number of seemingly heterogeneous pathological conditions that are part of the antiphospholipid syndrome, formerly called anticardiolipin syndrome. Recent studies on the mechanism of action of these autoantibodies suggest that we are dealing with a new autoimmune syndrome which may occur either in a primary form or in the context of other autoimmune diseases, mainly systemic lupus erythematosus (SLE). Moreover, increased levels of APA have been found in elderly subjects, who are known to display increased frequency of autoimmune phenomena. It is well known that many autoimmune diseases, including SLE, are associated with HLA antigens, particularly with HLA-B8,DR3 phenotype. In our study, APA serum levels were analyzed in 26 old subjects and in 56 young ones. The results demonstrate that HLA-B8,DR3-positive young females display significantly higher levels of APA than HLA-B8,DR3-negative ones. Interestingly, the same is true for elderly subjects on the whole with respect to young individuals. These data are consistent with previous findings demonstrating that HLA-B8,DR3-positive subjects (mainly female) as well as old subjects display (also in the absence of any clinical manifestation), multiple immune dysfunctions that may underlie the predisposition to autoimmunity.

Adult↗
PubMed1991

Soluble interleukin-2 receptor release defect in vitro in elderly subjects.

The evidence from several studies indicates that as individuals age, they may display immune dysfunctions, mostly T cell dysfunctions. Recently, a soluble form of the receptor for interleukin-2 (IL-2) (sIL-2R) has been demonstrated in human sera and in vitro stimulated culture supernatants from human T lymphocytes. In the present paper, we report in vitro sIL-2R production from peripheral blood mononuclear cells in elderly subjects. The results show that no difference exists for unstimulated cultures, whereas after mitogen stimulation the elderly subjects showed the lowest values compared with young ones. These findings suggest that sIL-2R may provide a new tool for the study of T lymphocyte dysfunctions in old age.

Aged↗
PubMed1991

HLA-B8,DR3 T cell impairment is completely restored by in vitro treatment with interleukin-2.

The activity of recombinant interleukin-2 (rIL-2) on the in vitro lymphocyte proliferative response to phytohemagglutinin mitogen was investigated in healthy HLA-B8,DR3 positive and negative subjects. The response to mitogen, significantly decreased in HLA-B8,DR3 positive subjects, was completely restored by adding rIL-2. Moreover, in HLA-B8,DR3 positive subjects the in vitro treatment with rIL-2 significantly increased the reduced frequency of mitogen responsive T lymphocyte precursors, as assessed by limiting dilution analysis. These data suggest that a decrease in the size of the pool of T cell precursors able to produce IL-2 is responsible for the impairment of T cell function observed in HLA-B8,DR3 positive subjects. Since in autoimmune diseases it is possible to show the same impairment(s) of T cell functions which can be observed in HLA-B8,DR3 positive subjects, these results could be of practical value for the understanding of pathogenetic mechanism(s) of autoimmune diseases and, in case, for therapeutical purposes.

Adult↗
PubMed1991

Immunoglobulin heavy-chain allotypes play a role in the clinical history of celiac disease.

We studied the role of the immunoglobulin heavy-chain allotypes in the evolution of celiac disease. Particularly the Gm(fb) phenotype was investigated since this phenotype is able to determine the breadth of immune response against alpha-gliadin antigen. The results show that weight percentiles and intestinal absorption as assessed by xylose test are influenced by Gm(fb) phenotype suggesting that Gm(fb) genes contribute to the determination of clinical aspects and evolution of celiac disease.

Adolescent↗
PubMed1991

Immunoglobulin heavy chain allotypes in a sample of Sicilian patients with celiac disease.

The authors have studied the immunoglobulin heavy chain allotypes in 14 Sicilian patients with celiac disease (CD) and in 75 healthy controls. No association has been found between CD and Gm or Km phenotypes. When the role of Gm phenotypes in immune response against gliadin was analyzed, fb-positive CD patients on gluten-free diet for 1 year showed an increased antigliadin IgG response. Comparing the values of fb-positive subjects with those of negative ones, a significant difference was observed. These data, demonstrating that the presence or absence of a phenotype is able to define the breadth of immune response against alpha-gliadin antigen, are indicative of the role played by Ig allotypes in CD.

Adolescent↗
PubMed1990

Markers of T lymphocyte activation in HLA-B8, DR3 positive individuals.

Many autoimmune diseases are associated in Caucasians with HLA-B8 and/or HLA-DR3 antigens. There is evidence that bearers of these antigens may display significant changes in immune parameters when compared to individuals not having these antigens. Recently, increased numbers of blood activated T lymphocytes have been reported in the majority of these diseases. The increase in activated blood T lymphocytes is paradoxically characterized by an in vitro impairment of T cell activation. Particularly, an inadequate production of interleukins has been observed. We have studied blood levels of activated T cells in HLA-typed, healthy subjects. The results show that the percentage of activated T cells, as recognized by monoclonal antibodies anti-CD25, anti-Ia and anti-MLR3, was more frequent in HLA-B8, DR3 positive individuals. On the other hand, in the 24 h, PHA stimulated cultures IL-2, IFN-gamma and the percentage of T cells CD25 positive were decreased. Thus, there was an apparent discrepancy between the increase of blood activated T cells and the in vitro impaired T cell activation. Since there is evidence that HLA-B8, DR3 positive subjects are genetically low responders, a possible reason for the discrepancy might be their relative inability to remove antigenic stimuli from the body. In this case, the increased number of activated blood T cells may reflect a cellular activation caused by persistent antigenic stimulation.

Adult↗
PubMed1990

Soluble interleukin-2 receptor secretion defect in vitro in HLA-B8, DR3 positive subjects.

Several studies have shown that HLA-B8,DR3 positive subjects may display T cell dysfunctions. Recently, a soluble form of the receptor for IL-2 (sIL-2R) has been demonstrated in human sera and in vitro-stimulated culture supernatant from human T lymphocytes. In the present paper we report sIL-2R serum levels and sIL-2R production from peripheral blood mononuclear cells in HLA-B8,DR3 positive subjects. We found that HLA-B8,DR3 positive subjects have the highest values of serum sIL-2R, but comparing the values of these subjects with those of negative ones no significant difference was observed. As regards the in vitro production of sIL-2R, no difference exists for unstimulated cultures, whereas after stimulation, the HLA-B8,DR3 positive subjects showed the lowest values compared with negative ones. It is noteworthy that these changes are observed in autoimmune diseases linked to this HLA phenotype.

Adolescent↗