Biomedical subjects

G Matarese

Publications and source records attributed to G Matarese.

33 records · Page 2Linked to original sources

PubMed1999

Leptin protects mice from starvation-induced lymphoid atrophy and increases thymic cellularity in ob/ob mice.

Thymic atrophy is a prominent feature of malnutrition. Forty-eight hours' starvation of normal mice reduced the total thymocyte count to 13% of that observed in freely fed controls, predominantly because of a diminution in the cortical CD4(+)CD8(+) thymocyte subpopulation. Prevention of the fasting-induced fall in the level of the adipocyte-derived hormone leptin by administering exogenous recombinant leptin protected mice from these starvation-induced thymic changes. The ob/ob mouse, which is unable to produce functional leptin because of a mutation in the obese gene, has impaired cellular immunity together with a marked reduction in the size and cellularity of the thymus. We found that ob/ob mice had a high level of thymocyte apoptosis resulting in a ratio of CD4(+)CD8(+) (cortical) to CD4(-)CD8(-) (precursor) thymocytes that was 4-fold lower than that observed in wild-type mice. Peripheral administration of recombinant leptin to ob/ob mice reduced thymocyte apoptosis and substantially increased both thymic cellularity and the CD4(+)CD8(+)/CD4(-)CD8(-) ratio. In contrast, a comparable weight loss in pair-fed PBS-treated ob/ob mice had no impact on thymocyte number. In vitro, leptin protected thymocytes from dexamethasone-induced apoptosis. These data indicate that reduced circulating leptin concentrations are pivotal in the pathogenesis of starvation-induced lymphoid atrophy.

Animals↗

PubMed1998

Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression.

Nutritional deprivation suppresses immune function. The cloning of the obese gene and identification of its protein product leptin has provided fundamental insight into the hypothalamic regulation of body weight. Circulating levels of this adipocyte-derived hormone are proportional to fat mass but maybe lowered rapidly by fasting or increased by inflammatory mediators. The impaired T-cell immunity of mice now known to be defective in leptin (ob/ob) or its receptor (db/db), has never been explained. Impaired cell-mediated immunity and reduced levels of leptin are both features of low body weight in humans. Indeed, malnutrition predisposes to death from infectious diseases. We report here that leptin has a specific effect on T-lymphocyte responses, differentially regulating the proliferation of naive and memory T cells. Leptin increased Th1 and suppressed Th2 cytokine production. Administration of leptin to mice reversed the immunosuppressive effects of acute starvation. Our findings suggest a new role for leptin in linking nutritional status to cognate cellular immune function, and provide a molecular mechanism to account for the immune dysfunction observed in starvation.

Adult↗

PubMed1998

Serum concentrations of soluble human leukocyte class I antigens and of the soluble intercellular adhesion molecule-1 in endometriosis: relationship with stage and non-pigmented peritoneal lesions.

Serum concentrations of soluble human leukocyte class I antigens (sHLA-I) and of the intercellular adhesion molecule-1 (sICAM-1) are increased in the early inflammatory stages of several immune-related diseases. These soluble molecules also exert immunomodulatory activity, including regulation of natural killer (NK) cell cytotoxicity. The aim of this study was to verify whether sHLA-I and sICAM-1 serum concentrations are related to the various stages of pelvic endometriosis, which is an immune-related disorder associated with impaired in-vitro NK cell activity. Serum sHLA-I and sICAM-1 concentrations were similar in patients and in healthy donors. However, when evaluated according to disease stage, sHLA-I and sICAM-1 concentrations were higher in patients with endometriosis stage I-II (revised American Fertility Society classification), or with non-pigmented peritoneal lesions. In conclusion, studies on sHLA-I and sICAM-1 may help to clarify the pathogenic mechanisms of endometriosis, and their serum concentrations may serve as additional markers for the early detection of recurrence of the disease during the monitoring of treatment outcome.

Adult↗

PubMed1998

T cell activation deficiency associated with an aberrant pattern of protein tyrosine phosphorylation after CD3 perturbation in Down's syndrome.

Children affected by Down's syndrome (DS) have an increased susceptibility to viral or bacterial infections and leukemia, associated with several abnormalities of the immune system. We investigated whether the T cell defect was qualitative in nature and associated with abnormalities of the early events occurring during cell activation. The proliferative response of lymphocytes from DS individuals after CD3 cross-linking was clearly depressed, as already reported. In contrast, phorbol ester and ionomycin were able to induce cell cycle progression in DS, suggesting a defect in the early stages of the signal transduction through a T cell receptor/CD3 (TCR/CD3) complex upstream of protein kinase C activation. The functional impairment in DS was not related either to a decrease of circulating mature-type CD3+ cells, which express high levels of surface of CD3 molecules, or to a decrease of the CD4+ subpopulation. The analysis of phosphotyrosine-containing proteins after the cross-linking of CD3 molecules in DS lymphocytes revealed a partial signaling, characterized by increased phosphorylation of proteins of 42-44 kD, comparable to that observed in control subjects, but not of proteins of 70 and 21 kD. Moreover, although the "anti-anergic" gamma element of IL-2, IL-4, IL-7, and IL-15 receptors was normally tyrosine-phosphorylated during cell activation, the CD3 zeta-associated protein kinase (ZAP-70) was not. Our results indicate that in DS there is a T cell activation defect, characterized by partial signal transduction through a TCR/CD3 complex, and associated with a selective failure of ZAP-70 tyrosine phosphorylation.

Adolescent↗

PubMed1996

The role of CD4-Lck in T-cell receptor antagonism: evidence for negative signaling.

Small changes in the complex between a peptide and a molecule of the major histocompatibility complex generate ligands able to partially activate (partial agonist) or even inhibit (antagonist) T-cell functions. T-cell receptor engagement of antagonist complex results in a partial zeta chain phosphorylation without activation of the associated ZAP-70 kinase. Herein we show that, despite a strong inhibition of both inositol phospholipid hydrolysis and extracellular increasing antagonist concentrations increased the activity of the CD4-Lck kinase. Addition of anti-CD4 antibody to culture medium prevented inhibitory effects induced by antagonist ligand. We propose that CD4-Lck activation triggered by antagonist complexes may act in a dominant negative mode, thus overriding stimulatory signals coming from agonist ligand. These findings identify a new T-cell signaling profile that may explain the ability of some T-cell receptor variant ligands to inhibit specific biological activities or trigger alternative activation programs.

Amino Acid Sequence↗

PubMed1987