PubMed Health⌕ Search

Biomedical subjects

A Cerutti

Publications and source records attributed to A Cerutti.

At least 37 records · Page 2Linked to original sources
PubMed1997

Interleukin-15 triggers activation and growth of the CD8 T-cell pool in extravascular tissues of patients with acquired immunodeficiency syndrome.

The impairment of interleukin-2 (IL-2) production occurs very early after human immunodeficiency virus (HIV) infection as a consequence of the quantitative depletion of Th1 cells. Despite the shift in cytokine production, most individuals develop an oligoclonal expansion of major histocompatibility complex restricted, HIV-specific CD8+ cytotoxic T lymphocytes (CTL) in different organs, suggesting that other cytokines replace IL-2 in initiating the tissue infiltration of CD8+ T cells. In this study we show that IL-15, a product of monocyte-macrophages and non-T cells and which has overlapping biological activities with IL-2, is involved in local cell networks accounting for the activation and expansion of CD8+ T-cell pools in a highly affected organ, ie, the lung. IL-15 induced proliferation of T cells obtained from the lower respiratory tract of HIV-infected patients with T-cell alveolitis and severe depletion of CD4+ T cells. Lung lymphocytes were CD45R0+/CD8+ T cells spontaneously expressing activation markers (CD69 and HLA-DR) and equipped with the receptorial subunits which bind IL-15, notably the beta and gamma chains of the IL-2 receptor (IL-2R) and the recently identified IL-15 binding-protein termed IL-15R alpha. Similar phenotypic findings were obtained after incubation of normal T cells with IL-15, which induced CD8+ T cells to express activation markers and to proliferate. The block of the IL-2R beta/IL-2R gamma complex with specific monoclonal antibodies abolished the T-cell stimulatory activity of IL-15 while the combination of IL-15 and tumor necrosis factor-alpha upregulated the proliferative response of lung T lymphocytes. The hypothesis that the tissue growth of lung CD8+ lymphocytes may involve cytokines produced from cells other than T lymphocytes was confirmed by the evidence that pulmonary macrophages expressed high levels of IL-15 and that anti-IL-15 antibodies inhibited the accessory function of alveolar macrophages on mitogen-induced CD8+ T-cell proliferation. Together, these results suggest that macrophage-derived cytokines produced at sites of T-cell infiltration play a role in the activation of HIV-specific CD8+ T-cell-mediated immune response.

AIDS-Related Opportunistic Infections↗
PubMed1997

Thrombopoietin levels in patients with primary and reactive thrombocytosis.

Human c-mpl ligand or thrombopoietin (TPO) has been proved to be a critical cytokine in the physiological regulation of thrombopoiesis. Previous evidence suggested that TPO production is constitutive and TPO plasma levels are regulated by the platelet-megakaryocyte mass through c-mpl receptor-mediated uptake and metabolism. To evaluate whether this mechanism of TPO level regulation is also operative in subjects with an elevated platelet count, we evaluated serum TPO in 32 patients with thrombocytosis due to essential thrombocythaemia (ET) or polycythaemia vera (PV) and in 70 subjects with reactive thrombocytosis; 32 healthy subjects were also studied. TPO levels were significantly higher in the ET and PV groups (median 246.2 pg/ml, range 93.5-4596) and reactive thrombocytosis patients (median 287 pg/ml, range 82.7-1960.0) than in normal subjects (median 156.7 pg/ml, range 62.2-352.7). No significant difference was found between the two groups of patients, indicating that serum TPO levels cannot differentiate between primary and reactive thrombocytosis. No significant correlation was found between platelet count and TPO levels in either ET-PV or reactive thrombocytosis, whereas a trend toward a correlation between acute-phase reactants and TPO was observed in patients with reactive thrombocytosis. These results indicate that TPO clearance by platelets-megakaryocytes is not fully operative or is not the only mechanism of TPO level regulation in primitive and reactive thrombocytosis.

Acute-Phase Reaction↗
PubMed1997

Retinal vascular network architecture in low-birth-weight men.

BACKGROUND: Low birth weight is associated with hypertension and increased cardiovascular mortality, but the mechanism of this association is not known. Hypertension is accompanied by abnormalities of the microvasculature including rarefaction. OBJECTIVE: To test the hypothesis that low birth weight is associated with an alteration in microvascular architecture. DESIGN: A stratified random sample of 100 men aged 64-74 years was selected from a cohort of men whose birth weights were known. They were of relatively high or low birth weight ('high' > or = 3700 g, 'low' < or = 3200 g) and high or low systolic blood pressure (high > or = 160 mmHg, low < or = 140 mmHg). METHODS: Retinal arteriolar geometry was defined in terms of arteriolar bifurcation angles and junction exponents (a measure of the relative diameters of parent and daughter vessels), measured from photographic diapositives using operator-directed image analysis. RESULTS: Members of low-birth-weight groups had significantly narrower bifurcation angles than did members of high-birth-weight groups (74 +/- 1 degree versus 78 +/- 1 degree, P= 0.017 by analysis of variance). There was no significant difference between angles in members of groups with high and low blood pressures. Neither birth weight nor blood pressure grouping affected junction exponents. CONCLUSIONS: Narrower bifurcation angles are associated with increased circulatory energy costs and may be related to a lower than normal microvascular density. Our finding of differences in retinal microvascular architecture might reflect a persistent alteration in vascular architecture as a result of an impairment of foetal development and could provide a mechanistic link between low birth weight and subsequently increased cardiovascular risk.

Aged↗
PubMed1997

Selection of T lymphocytes bearing limited TCR-Vbeta regions in the lung of hypersensitivity pneumonitis and sarcoidosis.

Hypersensitivity pneumonitis (HP) and sarcoidosis are interstitial lung disorders (ILD) characterized by a lymphocytic alveolitis that, in the active phase of the disease, is sustained by different T-cell subsets, i.e., CD8+ cells in HP and CD4+ lymphocytes in sarcoid patients. To address the question of whether a bias in T-cell selection occurs in the lung of patients with HP and sarcoidosis, we analyzed the T-cell receptor beta chain variable region (TCR-Vbeta) repertoire by flow cytometry and polymerase chain reaction (PCR) analyses in blood and lung lymphocytes of 14 HP and 25 sarcoid patients. To verify whether these cells can be activated in vitro through the TCR, blood and lung lymphocytes were also assessed for their responsiveness to different superantigenic stimuli represented by staphylococcal enterotoxins, including SEA, SEB, SEC1, SEC2, SED, and SEE. Flow cytometry and PCR analyses demonstrated an overexpression of cells bearing Vbeta2, Vbeta3, Vbeta5, Vbeta6, and Vbeta8 gene segments in the lung of HP patients as compared with the peripheral blood. In sarcoid patients cells bearing Vbeta2, Vbeta5, and Vbeta6 gene segments in the lung of HP patients as compared with the peripheral blood. In sarcoid patients cells bearing Vbeta2, Vbeta5, and Vbeta6 gene segments were overrepresented in the lung rather than in the blood. Both in HP and sarcoid patients almost all T cells bearing the dominant Vbeta segment belonged to the T-cell subset that sustains the alveolitis, i.e., CD8 in HP patients and CD4 in sarcoid subjects. Follow-up studies demonstrated that the recovery of the alveolitis was characterized by the disappearance of cells bearing a limited T-cell repertoire. Interestingly, T-lymphocyte response to different superantigens demonstrated that the proliferation elicited by different staphylococcal toxins was more pronounced in the lung than in the blood. Taken together, our findings indicate a compartmentalization of cells bearing discrete Vbeta gene products in the pulmonary microenvironment and suggest that the expansion of specific Vbeta region subsets occurring in the lung might result from triggering by a specific antigen. In fact, the removal from exposure in HP patients or specific treatment in sarcoidosis resulted in the decrease of the overrepresented cell population accounting for the lymphocytic alveolitis.

Adult↗
PubMed1996

The CD5/CD72 receptor system is coexpressed with several functionally relevant counterstructures on human B cells and delivers a critical signaling activity.

The CD5 molecule is expressed on T cells and, at a lower density, on a minor B cell subset (CD5+ B cells). The pan-B Ag CD72 was recently identified as the CD5 counterstructure, and several data suggest the involvement of this ligand pair in T-B cell cognate interaction. However, the functional role of CD5 and CD72 molecules within the B cell compartment is still unknown. In this work we studied umbilical cord blood CD5+ B cells (B-1a), adult splenic CD5- B cells (B-2), and CD5+ B cells from patients with chronic lymphocytic leukemia. Flow cytometry analysis and proliferation assays were used to determine 1) the ability of B-1a and B-2 cells to coexpress functionally relevant counterligands other than CD5 and CD72, and 2) the signaling capacity of CD5 and CD72 in terms of B cell activation and proliferation. To this purpose, freshly isolated or preactivated normal and neoplastic B cells were cultured with agonistic anti-CD5 or anti-CD72 mAbs in the presence or the absence of cytokines equipped with B cell activity. Our data demonstrate that CD5 and CD72 molecules are coexpressed with other ligand pairs usually involved in T-B cell cognate interaction on B-1a cells, but not on B-2 cells. CD5 and/or CD72 engagement delivers critical costimulatory signals in B-1a, B-2, and B cells from patients with chronic lymphocytic leukemia, but with different requirements and patterns. Besides suggesting the potential involvement of B-1a lymphocytes in B-B cell interactions during T-independent B cell responses, our results indicate that CD5 and CD72 counterstructures play a functional role in the B cell compartment.

Adult↗
PubMed1996

Role of IL-15, IL-2, and their receptors in the development of T cell alveolitis in pulmonary sarcoidosis.

Recent data suggest that the newly discovered cytokine IL-15 cooperates with IL-2 in driving T cell-mediated immune responses. The aim of this study was to determine the role of IL-15 in the regulatory networks leading to the development of T cell alveolitis in the lung of patients with sarcoidosis. We demonstrated that alveolar macrophages (AMs) isolated from the bronchoalveolar lavage of patients with active sarcoidosis expressed IL-15 mRNA and membrane and cytoplasmic IL-15, while AMs from healthy subjects and patients with inactive sarcoidosis did not. Pulmonary CD4+ T cells from sarcoid patients were equipped with the IL-2R subunits, which are able to bind IL-15, i.e., the IL-2R beta/IL-2R gamma complex, and proliferated in response to IL-15. Interestingly, the T cell proliferation elicited by IL-15 was comparable with that determined by IL-2. Following the addition of graded amounts of IL-15, IL-2-pulsed T cells showed a significant increase in their stimulation. TNF-alpha up-regulated the IL-15-mediated proliferative response of bronchoalveolar lavage T lymphocytes. Following the block of the IL-2R beta- and gamma-chains with specific mAbs, the stimulatory activity of IL-15 was abolished. The evaluation of the IL-2R on sarcoid AMs demonstrated the constitutive expression of alpha- and gamma-chain mRNA and proteins. Taken together, these findings demonstrate that IL-15 triggers the growth of sarcoid T cells through the IL-2R beta/IL-2R-gamma complex and raise the possibility that AMs may deliver proliferative signals for the development of the T cell alveolitis. Modulation of IL-2R on AMs could represent a critical variable in regulating local inflammatory responses.

Adult↗
PubMed1996

Interleukin-15 promotes the growth of leukemic cells of patients with B-cell chronic lymphoproliferative disorders.

The recently discovered cytokine, interleukin-15 (IL-15), has been demonstrated to share several biologic properties with IL-2 in different cell systems, including T-cell and natural killer (NK) cell compartments. As for B lymphocytes, IL-15 has been shown to provide stimulatory activities in normal preactivated B cells that are mainly transduced through IL- 2 receptor (IL-2R) complex components. Since leukemic B cells from patients with chronic lymphoproliferative disorders (CLD) bear IL-2R and grow in response to IL-2, we investigated whether IL-15 triggers the proliferation of malignant B cells obtained from 12 patients with B-cell chronic lymphocytic leukemia (B-CLL) and five patients with hairy cell leukemia (HCL). Enriched B cells recovered from five healthy subjects were also studied as controls. IL-15 stimulated the proliferation of freshly isolated leukemic B cells, but not resting normal B lymphocytes, the latter being able to grow in the presence of IL-15 only after in vitro preactivation with phorbol myristate acetate. The proliferation elicited by IL-2 on leukemic cells was comparable to that determined by IL-15. Following addition of graded concentrations of IL-15 to low/intermediate-dose IL-2, resting leukemic B cells showed a higher stimulatory rate than that observed using the two cytokines separately. In normal resting B lymphocytes, this cumulative effect was not observed. The role of different IL-2R subunits in IL-15-driven growth of malignant B cells was investigated both by their expression on leukemic cells and by the block of different IL-2R subunits (p55, p75, and p64) with specific monoclonal antibodies (MoAbs). Using flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses we demonstrated that both B-CLL and HCL leukemic B cells express the beta and gamma chains of the IL-2R system. The stimulatory activity achieved by IL-15 decreased significantly, blocking the beta and gamma chains of the IL-2R. Taken together, these findings demonstrate that IL-15 triggers the growth of leukemic B cells through IL-2R system subunits, pointing to the role of this novel cytokine in regulating the neoplastic proliferation in CLD.

Adult↗
PubMed1996

IL-12 is involved in the activation of CD3+ granular lymphocytes in patients with lymphoproliferative disease of granular lymphocytes.

We investigated the effects of Il-12 on functional properties of CD3+ CD8+ granular lymphocytes (GL) of of patients with lymphoproliferative disease of granular lymphocytes (LDGL). To this aim, in 10 cases with clonal CD3+ GL proliferation (nine cases with an associated TCR alpha/beta receptor and one case with a TCR gamma/delta receptor) we studied the proliferative and cytotoxic activities of resting and alpha CD3 monoclonal antibody (mAb) activated cells in the presence of rIL-12 and anti-IL-12 blocking antibodies. Specific mRNA for IL-12 p40 subunit was also investigated. Our results showed that rIL-12 increased the proliferation of alpha CD3 pre-stimulated GL (2 to 6 times). Further, anti-IL-12 antibodies partially inhibited alpha CD3-induced cell growth, suggesting a role for this cytokine in the alpha CD3-mediated GL activation. The addition of antibodies blocking the p55 and p75 chains of IL-2 receptor (IL-2R) did not inhibit the rIL-12-mediated cell proliferation, indicating that the activity of rIL-12 is dependent of IL-2 in the in vivo expanded GL of patients under study. Concerning the cytotoxic activity, rIL-12 increased the alpha CD3-mediated NK activity against K-562 target cells and alpha CD3 redirected cytotoxicity against P815 target cells. Molecular analysis pointed out that, following alpha CD3 stimulation, patients' GL increased the expression of specific mRNA for the p40 subunit of IL-12 as compared to baseline conditions. Our data indicate that IL-12 is involved in the mechanisms of activation of clonal CD3+ GL in patients with LDGL; these features are consistent with the possibility that this discrete subset of GL might represent in vivo primed cytotoxic T lymphocytes.

Antibodies, Monoclonal↗
PubMed1996

Skewing of the T-cell receptor repertoire in the lung of patients with HIV-1 infection.

OBJECTIVES: A bias of the use of T-cell receptor (TCR) V beta regions has been reported both in peripheral blood and in several tissues in patients with AIDS, including lymph nodes, spleen and salivary glands. Although the disease is frequently characterized by an infiltration of T cells in the lung interstitium, no information is presently available on the configuration of the TCR repertoire in this microenvironment. This study was performed to address the question of whether a bias in T-cell selection occurs in the lung of patients with AIDS. METHODS: TCR beta-chain variable region (TCR-V beta) repertoire was analysed by flow cytometry and polymerase chain reaction (PCR) analyses in blood and lung lymphocytes of 13 patients with HIV-1 infection at different stages of the disease. Blood and lung lymphocytes were also assessed for their responsiveness to different superantigenic stimuli represented by staphylococcal enterotoxins (SEA, SEB, SEC1, SEC2, SED and SEE). RESULTS: Flow cytometry analysis in AIDS patients demonstrated an overexpression of cells bearing V beta 2 and V beta 3 gene segments in the lung compared with peripheral blood of the same subjects, as well as to lung and blood lymphocytes of normal controls. PCR analysis performed in AIDS patients extended these observations and demonstrated a significant bias also in the use of T cells bearing V beta 7 and V beta 9 gene regions in the lung compartment with respect to the blood. Virtually all T cells bearing the overrepresented V beta segment belong to the CD8 subset. Interestingly, T-lymphocyte response to different superantigens demonstrated a low proliferative rate in the lung with respect to the blood in HIV-1-infected patients. CONCLUSIONS: These findings indicate a compartmentalization of cells bearing discrete V beta gene products in the pulmonary microenvironment of patients with AIDS and suggest that the expansion of specific-V beta region subsets occurring in the lung might result from triggering by a superantigen.

Adult↗
PubMed1996

Expression of tumor necrosis factor-receptor superfamily members by lung T lymphocytes in interstitial lung disease.

Recently, a novel receptor superfamily has been identified whose members interact with a parallel family of ligands showing homology to tumor necrosis factor (TNF). To investigate the role of these receptor structures in the pulmonary environment, we evaluated the expression of some members of the TNF-receptor (CD27, CD30, CD40, CD95/Fas, CD120a, and CD120b) and TNF-ligand (CD40L, CD70/CD27L, CD30L, and mTNFalpha) superfamilies by bronchoalveolar lavage (BAL) T cells recovered from healthy subjects and patients with interstitial lung disease (ILD). Lung T lymphocytes recovered from control subjects showed a slight expression of CD27 but did not bear CD30, CD40, CD120a, or CD120b antigens. CD27 expression was restricted to normal CD4+ cells. Fas antigen (CD95), which is involved in activation-driven T-cell suicide, and the ligand for CD27 (CD70) were weakly expressed by normal BAL T-cell subpopulations. In patients with sarcoidosis, the majority of pulmonary T lymphocytes were CD4+ cells that expressed low levels of CD27 antigen and an upregulation of CD95 and CD70 molecules. When we characterized lymphocytes accumulating in the lung of patients with HIV infection and hypersensitivity pneumonitis, we demonstrated that T cells accounting for the CD8 alveolitis bore TNF-receptor type 2 (CD120b) at high density and were CD70+ while CD40L, CD30L, or mTNF-alpha expression were not found. The discrete surface expression of the TNF-receptors and TNF-ligands on alveolar T-cell subsets suggests that these molecules play a role in the immune regulatory mechanisms that ultimately lead to the alveolitis in the pulmonary microenvironment of interstitial lung disease.

Adult↗
PubMed1995

Analysis of the T cell receptor in the lymphoproliferative disease of granular lymphocytes: superantigen activation of clonal CD3+ granular lymphocytes.

To investigate whether cell populations in CD3+ lymphoproliferative disease of granular lymphocytes (LDGLs) were skewed toward the use of specific V beta regions, we studied the repertoire of T-cell receptor (TCR) V beta gene products in 18 patients, as well as their relationship to the clonal bands in the Southern blot and the activation mediated by superantigens. Using a panel of monoclonal antibodies (mAbs) for conserved V beta segments and PCR, a dominant population expressing a specific V beta region was demonstrated in all patients. In five (27%) cases, granular lymphocytes (GLs) were found to express the V beta 13.1, while V beta 8 and V beta 6 were each expressed in three (17%) cases. The remaining cases were characterized by the proliferation of TCR V beta 2, V beta 3, V beta 4, V beta 9, V beta 12, V beta 16, and V beta 20. This finding indicates a biased usage of a limited TCR V beta in LDGLs, since nearly 60% of the cases utilized only three families of the TCR V beta genes. In all of the cases studied, we proved that the subset recognized by mAb and PCR was identical to that accounting for the extra band(s) of the Southern blot. This finding confirms the clonal nature of the population identified according to TCR V beta expression both by phenotype and PCR. On functional grounds, we evaluated whether GLs can be activated through the specific TCR using the superantigens recognizing discrete V beta families, such as staphylococcal proteins, including SEA, SEB, SEC1, SEC2, SED, and SEE. We demonstrated that the TCR-alpha/beta of clonal GLs in LDGL patients is functionally active in delivering cytotoxic and proliferative signals upon superantigen activation.

CD3 Complex↗
PubMed1995

Expression of TNF receptors by T cells and membrane TNF-alpha by alveolar macrophages suggests a role for TNF-alpha in the regulation of the local immune responses in the lung of HIV-1-infected patients.

High amounts of TNF-alpha are released by alveolar macrophages (AMs) in the lungs of patients with HIV-1 infection. To investigate the role of this cytokine in the local immune response, we studied the expression of surface receptors for TNF-alpha (TNF-Rs) and the presence of the transmembrane form of TNF-alpha (mTNF-alpha) on bronchoalveolar lavage (BAL) cells recovered from 14 patients with HIV-1 infection. The role of TNF-alpha both in the events leading to the T cell alveolitis and as a mediator of cytotoxicity was also evaluated. TNF-R expression was determined by flow cytometry on BAL CD8 lymphocytes and AMs (i.e., the cells that account for the alveolitis in HIV-1 infection). We found that CD8 cells express the 75-kDa (CD120a) but not the 55-kDa (CD120a) TNF-Rs, whereas AMs were devoid of TNF-R expression. More than 90% of BAL T cells efficiently bound TNF-alpha; when T cells were tested for their proliferative capacity, an up-regulation of the IL-2-mediated proliferation by TNF-alpha was observed, suggesting that this cytokine may drive the in situ proliferation of CD120b+ T cells. As shown by flow cytometry analysis and immunoprecipitation with anti-TNF-alpha Ab, mTNF-alpha expression was observed on AMs but not on alveolar T cells. Fixed AMs showed high levels of killing against TNF-sensitive targets. Taken together, our data demonstrate the selective expression of TNF-Rs and mTNF-alpha on cells accumulating within the alveolar spaces of patients with HIV-1 infection, pointing to the compound role of TNF-alpha in the local immune responses.

Adult↗
PubMed1995

Alveolar macrophages as a cell source of cytokine hyperproduction in HIV-related interstitial lung disease.

Pulmonary macrophages play an important role in the pathogenesis of the acquired immunodeficiency syndrome (AIDS). They are known to be discrete target cells for human immunodeficiency virus (HIV), and compelling evidence is accumulating that alveolar macrophages (AMs) from HIV-infected patients behave as versatile secretory cells that, acting as antigen-presenting cells, release a great variety of cytokines. The secretory products of AMs, pivotal to their immune effects, may contribute to localized immune dysregulation as well as to primary lung damage and clinical disease. Pulmonary macrophages are also thought to facilitate retroviral spread by their direct infection, by presenting HIV antigens to uninfected T cells, and by secreting cytokines that transactivate HIV expression. This review briefly considers the events underlying the role of AMs in the pulmonary defense mechanisms against HIV and AIDS-related opportunistic infections. Following a brief overview of immune mechanisms taking place in the lungs of HIV-infected subjects, we describe the specific role of AMs in the immune mechanisms devoted to recognizing and removing HIV-infected cells and controlling the local growth of opportunists. The pathogenetic role envisaged for macrophages in lung damage are also reviewed in the context of the known biology of these cells. Finally, this review examines the relevance of the retroviral infection of AMs in terms of pathogenesis of the HIV-related interstitial lung disease.

Antigen-Presenting Cells↗
PubMed1995

Tumour-infiltrating lymphocytes bear the 75 kDa tumour necrosis factor receptor.

Tumour necrosis factor alpha (TNF-alpha) is a cytokine with a variety of immunological properties. The identification of two receptors for this molecule, i.e. the 75 kDa and the 55 kDa TNF receptors (TNF-R), recently clarified the mechanisms through which this cytokine provides its wide range of immunomodulatory activities. In this study we have investigated the expression and the functional properties of these receptors on tumour-infiltrating lymphocytes (TILs) recovered from 17 patients with solid cancers (melanoma, colorectal carcinoma and lung cancer). To this end, TIL lines and freshly isolated TILs were evaluated for (a) the expression and the functional role of TNF receptors following culture in the presence of interleukin 2 (IL-2) and (b) the production of TNF-alpha following culture with IL-2 and the role of this cytokine in IL-2-driven TIL proliferation. Flow cytometry analysis demonstrated that TILs bear the 75 kDa TNF-R. Moreover, TIL lines express detectable messages for TNF-alpha and release this cytokine. Functional in vitro studies have shown that anti-TNF-alpha, as well as anti-75 kDa TNF-R antibodies, are able to inhibit the IL-2-induced TIL proliferation. These data demonstrate that TILs are equipped with a fully functional TNF-R system and suggest a putative role for this receptor and its ligand in the activation and expression of TILs following immunotherapy with IL-2.

Antibodies, Monoclonal↗
PubMed1995

Vascular network changes in the retina with age and hypertension.

OBJECTIVE: To compare retinal arterial bifurcation geometry in normotensive and hypertensive subjects. DESIGN: A retrospective observational study. METHODS: Fluorescein angiograms of normotensive (n = 13) and hypertensive (n = 12) subjects aged 30-80 years with uni-ocular retinal pathology were compared. Quantification of diameters of the parent, larger daughter and smaller daughter vessels (d0, d1 and d2, respectively) and of bifurcation angles (the angle between the two daughter arterioles, omega) of arteriolar bifurcations was performed from digitized retinal angiograms of the uninvolved eye. The relative diameters of parent and daughter vessels at bifurcations were summarized by junction exponents (x) such that d1x + d2x = d0x. RESULTS: Junction exponents were similar for normotensives and hypertensives (means +/- SEM, 2.65 +/- 0.18 and 2.48 +/- 0.17), but analysis of covariance showed a parallel decrease in x in the two groups with age. A positive association was found between x and arteriolar microvascular density. Bifurcation angles were more acute in hypertensives (74 +/- 3 degrees) than in normotensives (84 +/- 3 degrees) and declined with increasing age in both groups. CONCLUSIONS: The present findings indicate that ageing and possibly hypertension are associated with disadvantageous branching geometry in the human retinal vasculature, implying increased power costs of blood transport, uneven distribution of shear forces throughout the vascular tree and microvascular rarefaction. The present findings may have important implications for our understanding of the pathogenesis of vascular disease in ageing and hypertension and offer the prospect of a novel sensitive diagnostic approach to the cardiovascular system.

Adult↗
PubMed1994

Expression and regulation of tumor necrosis factor, interleukin-2, and hematopoietic growth factor receptors in B-cell chronic lymphocytic leukemia.

Leukemic cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) express tumor necrosis factor (TNF) and interleukin-2 (IL-2) receptors, but only a low proliferative response can be elicited in vitro by TNF alpha and IL-2. To investigate the functional properties of IL-2 and TNF alpha on leukemic B cells, we evaluated (1) the regulation of expression of TNF receptors (TNF-R) and IL-2 receptors on leukemic B cells after culture with TNF alpha and IL-2; (2) the effect of the combination of TNF alpha and IL-2 in a proliferative in vitro assay; and (3) the expression and regulation by these cytokines of receptors for hematopoietic factors, including IL-3, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Flow cytometry analysis showed that freshly isolated leukemic cells from B-CLL patients bear the 75-kD TNF-R and the 55-kD IL-2R; TNF alpha was able to upregulate the 55-kD IL-2R but not the 75-kD TNF-R. On the other hand, IL-2 was not able to modify the expression of the above-mentioned receptors. Although each cytokine alone was unable to induce a relevant proliferation of leukemic cells, a synergistic proliferative effect was detected when these cytokines were used in combination. Leukemic B cells from B-CLL patients bear receptors for hematopoietic factors (IL-3, G-CSF, and GM-CSF) that were upregulated in vitro by IL-2 via the 55-kD IL-2R. On the contrary, TNF alpha was unable to affect the expression of the above-mentioned receptors. These results indicate (1) that IL-2 and TNF receptors are related to each other on leukemic cells in B-CLL and (2) that the IL-2R is involved in the regulation of other structures, ie, CSF receptors, thus pointing to another functional role of this receptor complex and the related cytokine in leukemic cells.

Aged↗
PubMed1994

Independent expression of p55 and p75 interleukin-2 receptors (IL-2R) during intravenous or subcutaneous administration of recombinant interleukin-2 (rIL-2) by T-lymphocytes and natural killer cells.

BACKGROUND: The effects of immunotherapy with recombinant interleukin-2 (rIL-2) on peripheral blood lymphocytes have been a matter of debate. In this study the authors addressed the issue of the biologic effects of two different schedules of rIL-2 administration (i.e., continuous intravenous infusion versus subcutaneous injection) on the expression of the p55 and p75 chains of interleukin-2 receptor (IL-2R). METHODS: Sixteen patients were studied: 6 patients with a previous diagnosis of acute leukemia entered the study at least +60 days (+63(-)+144 days) after autologous bone marrow transplantation and were treated with continuous rIL-2 infusion; 10 patients with advanced metastatic renal cancer were treated with subcutaneous rIL-2 therapy. In both groups of patients, therapy consisted of two cycles of 5-day rIL-2, and immunologic evaluation was performed two days after completion of the second cycle. RESULTS: Intravenous treatment was associated with a marked increase in CD56+ natural killer (NK) cells expressing the p75 but lacking the p55 IL-2R; however, the absolute number of CD3+ lymphocytes was unchanged, and they showed a low or absent expression of the p55 and negativity for the p75 IL-2R. After subcutaneous rIL-2 therapy, a slight increase in the percentage of NK cells expressing only the p75 IL-2R was shown. CD3+ lymphocytes still retained the p75 IL-2R negative phenotype, however, with a significant increase (> 15%) in p55 IL-2R expression. The absolute number of CD3+ lymphocytes was also significantly increased. Functional tests on the purified CD3+ population indicate that these cells exhibited low values of cytotoxic and proliferative activities in vitro. CONCLUSIONS: The authors' data point out that subcutaneous administration of rIL-2 during a 2-week period is associated with a marked increase in T-cells that bear the low affinity p55 IL-2R. These findings could be relevant considering the independent role of lymphokine modulation mediated by the p55 and p75 IL-2R on T- and NK cells.

Acute Disease↗