Biomedical subjects

F B Aiello

Publications and source records attributed to F B Aiello.

At least 19 recordsLinked to original sources

PubMed2005

Retroviral transduction of IL-7Ralpha into IL-7Ralpha-/- bone marrow progenitors: correction of lymphoid deficiency and induction of neutrophilia.

Defects in the gene for the IL-7 receptor (R) alpha chain are one cause of severe combined immunodeficiency disease (SCID) based on a strict requirement for IL-7 in T lymphoid development and survival. We tested the feasibility and potentially undesirable consequences of IL-7Ralpha gene transfer as a therapy for this genetic defect. The murine IL-7Ralpha gene was introduced into IL-7Ralpha(-/-) bone marrow progenitors using retrovirus and transplanted into Rag(-/-) recipient mice. Both alphabeta and gammadelta T cells were reconstituted in thymus and spleen showing proof of principle. B-cell development was also restored in some mice, but their numbers were much lower than in the T-cell compartment. Splenomegaly was observed due to an increase in neutrophils. We showed that hematopoietic progenitors, after transfection with IL-7Ralpha, could respond to IL-7 in vitro by a striking production of neutrophils and other myeloid cells. These data indicate that although IL-7 is a critical lymphopoietin, ectopic expression of its receptor on multipotential progenitors can also induce production of myeloid cells, presumably through survival and proliferation signals that are not restricted to lymphoid cells. This supports the stochastic model of progenitor differentiation, in which cytokines give permissive and not instructive signals.

Animals↗

PubMed2000

Flavonoids apigenin and quercetin inhibit melanoma growth and metastatic potential.

Flavonoids are a class of polyphenolic compounds widely distributed in the plant kingdom, which display a variety of biological activities, including chemoprevention and tumor growth inhibition. Our aim was to investigate the effects of several polyphenols on the growth and metastatic potential of B16-BL6 melanoma cells in vivo. Intraperitoneal administration of quercetin, apigenin, (-)-epigallocathechin-3-gallate (EGCG), resveratrol, and the anti-estrogen tamoxifen, at the time of i.m. injection of B16-BL6 cells into syngeneic mice, resulted in a significant, dose-dependent delay of tumor growth, without toxicity. The relative descending order of potency was EGCG > apigenin = quercetin = tamoxifen > resveratrol > control. Furthermore, polyphenols significantly potentiated the inhibitory effect of a non-toxic dose of cisplatin. When tested for the ability to inhibit lung colonization, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the number of B16-BL6 colonies in the lungs in a dose-dependent manner, with quercetin and apigenin being more effective than tamoxifen. Interestingly, quercetin, apigenin, and tamoxifen (but not EGCG or resveratrol) significantly decreased the invasion of B16-BL6 cells in vitro, with quercetin and apigenin being more effective than tamoxifen. This suggests that anti-invasive activity is one of the mechanisms underlying inhibition of lung colonization by quercetin and apigenin. In conclusion, quercetin and apigenin inhibit melanoma growth and invasive and metastatic potential; therefore, they may constitute a valuable tool in the combination therapy of metastatic melanoma.

Animals↗

PubMed2000

Polymorphonuclear leukocyte apoptosis is inhibited by platelet-released mediators, role of TGFbeta-1.

Platelets regulate several polymorphonuclear leukocyte (PMN) functions. We have found that thrombin-stimulated platelets potently inhibited PMN apoptosis. Cell-free supernatant from increasing concentrations of stimulated platelets inhibited PMN apoptosis in a dose-dependent manner, with an effect similar to that of corresponding concentrations of platelets. At the plateau, platelet supernatant inhibited PMN apoptosis by 54.6 +/- 6.8%, the anti-apoptotic activity being higher than that of GM-CSF and comparable to that of LPS. Neither IL-1ra nor a combination of anti-IL1alpha + betamAb affected the activity of platelet supernatant. In contrast a mAb recognizing the active form of TGF-beta1 significantly decreased this activity. Moreover, exogenous TGF-beta1 inhibited PMN apoptosis in a dose-dependent manner. The active form of this cytokine was indeed present in the supernatant of stimulated platelets at a concentration able to elicit an anti-apoptotic effect. The p38 MAPK inhibitor SB203580 prevented the anti-apoptotic effect of TGF-beta1 in a dose-dependent manner. Interestingly, it also prevented the anti-apoptotic effect of IL-1alpha, but not that of GM-CSF, LPS and dexamethasone. In conclusion, we report for the first time that PMN apoptosis is potently inhibited by platelet-released mediators, that TGF-beta1 mediates an important part of this effect, and that p38 MAPK is involved in the TGF-beta1 signaling leading to its anti-apoptotic effect. These results provide novel evidence to support the central role of platelets in inflammation.

Apoptosis↗

PubMed1998

IL-10 synergizes with dexamethasone in inhibiting human T cell proliferation.

We have evaluated the effects of dexamethasone (Dex) alone or in combination with interleukin (IL)-10 or transforming growth factor-beta 1 (TGF-beta 1) on human T cell proliferation. Both IL-10 and TGF-beta 1 significantly decreased the Dex concentration needed to inhibit T cell proliferation by 50% (IC50). Dex in combination with IL-10 completely inhibited T cell proliferation, even when IL-10 alone was ineffective, as in the case of phytohemagglutinin-induced T cell proliferation. The evaluation of the results according to the isobole method displayed a potent synergistic activity between Dex and IL-10, whereas the combination of Dex with TGF-beta 1 was additive. IL-10, but not TGF-beta 1, enhanced the inhibitory effect of Dex on IL-2 production. IL-2 and IL-4 only partly antagonized the antiproliferative effect of the combinations. IL-4 was as effective as IL-2 in antagonizing the combination of Dex with TGF-beta 1, but significantly less effective against the combination of Dex with IL-10. IL-10 and TGF-beta 1 are thus able to potentiate the Dex inhibitory effect on T cell proliferation and could be regarded as potential agents for future immunosuppressive protocols.

Dexamethasone↗

PubMed1997

Transforming growth factor beta 1, interleukin-8 and interleukin-1, in non-small-cell lung tumors.

A role in tumor progression has been proposed for transforming growth factor-beta 1 (TGF beta 1) and interleukin (IL)-8 as well as for IL-1, which itself induces the production of TGF beta 1 and IL-8 in many cell types. TGF beta 1 and IL-8 production and their regulation by IL-1 in five non-small-cell (NSC) lung tumor cell lines were evaluated. Moreover, their levels were evaluated in 29 NSC lung tumors. All cell lines constitutively produced TGF beta 1, and three produced IL-8. After IL-1 beta treatment, TGF beta 1 production was upregulated in two cell lines, whereas IL-8 production was markedly upregulated in two, induced in one, and unmodified in two. In tumors, the levels of TGF beta 1, IL-8, and IL-1 beta were higher than in normal counterparts (p < 0.001), and a positive correlation between IL-8 and IL-1 beta levels (p < 0.001) was found. TGF beta 1, IL-8, and IL-1 beta mRNA expression was examined in 12 tumors. TGF beta 1 mRNA was detected in all cases, IL-8 mRNA in 7, and IL-1 beta MRNA was undetectable. TGF beta 1, IL-8, and IL-1 beta immunoreactivity was then studied by immunohistochemistry. TGF beta 1 and IL-8 immunoreactivity was observed in neoplastic cells; IL-1 beta immunoreactivity was observed in mononuclear cells. In conclusion, in tumors IL-1 beta levels positively correlated with those of IL-8, and IL-1 beta as well as TGF beta 1 and IL-8 levels were significantly higher than in normal tissues.

Adenocarcinoma↗

PubMed1997

Interaction with type II estrogen binding sites and antiproliferative activity of tamoxifen and quercetin in human non-small-cell lung cancer.

The antiestrogen tamoxifen is thought to antagonize the effects of estrogens by competing with them for estrogen receptor (ER) binding. However, tarnoxifen can also reverse multidrug resistance, synergize with cisplatin cytotoxicity, and inhibit growth in ER-negative lung cancer cells. In addition to ERs, rat and human target tissues contain a second binding macromolecule termed the type II estrogen binding site (type II EBS). It has been shown that tamoxifen and flavonoids, a widely distributed class of natural substances with a variety of biologic actions, bind to type II EBS and inhibit the growth of several tumor cell types. At present, conflicting data about ERs and an absence of data about type II EBSs exist for lung tumors. We have tested non-small-cell lung carcinoma cell lines and primary tumor cells for the presence of ERs and type II EBSs and have evaluated the effects of tamoxifen and quercetin (pentahydroxyflavone) on the growth of these cells. Using a whole-cell assay and nuclear and cytosolic radiobinding experiments with [3H]estradiol as tracer, we have found that SK-LU1, SW900, ChaGo-K-1, H441, H661, and A549 cells, as well as primary tumors, bind estrogen specifically. This binding results mainly from the presence of a large number of type II EBSs, whereas ERs are absent or present at low concentrations. Type II EBSs bound tamoxifen and quercetin with similar affinity. Cell counts and a thymidine incorporation assay showed that both compounds inhibit cell growth in a concentration-dependent manner at concentrations ranging from 10 nM to 1 microM. Neither ipriflavone, an isoflavone, nor rutin, the 3-rhamnosylglucoside of quercetin, bound type II EBSs or inhibited cell growth. These findings suggest that tamoxifen and quercetin could regulate lung cancer cell growth through a binding interaction with type II EBSs. This mechanism could also be active in vivo, in that we have observed that nuclear and cytosolic type II EBSs were present in all primary lung cancers tested (n = 12), and that tamoxifen and quercetin were effective in inhibiting in vitro bromodeoxyuridine (BrdU) incorporation and proliferation-cell nuclear antigen expression by neoplastic cells in these cancers.

Aged↗

PubMed1996

Inactivation of the IL-6 gene prevents development of multicentric Castleman's disease in C/EBP beta-deficient mice.

Castleman's disease is a lymphoproliferative disorder thought to be related to deregulated production of IL-6. We have previously shown that mice lacking the trans-acting factor C/EBP beta, a transcriptional regulator of IL-6 and a mediator of IL-6 intracellular signaling, develop a pathology nearly identical to multicentric Castleman's disease, together with increasingly high levels of circulating IL-6. We describe here how the simultaneous inactivation of both IL-6 and C/EBP beta genes prevents the development of pathological traits of Castleman's disease observed in C/EBP beta-deficient mice. Histological and phenotypic analysis of lymph nodes and spleen of double mutant mice did not show either the lymphoadenopathy and splenomegaly or the abnormal expansion of myeloid, B and plasma cell compartments observed in C/EBP beta-/- mice, while B cell development, although delayed, was normal. Our data demonstrate that IL-6 is essential for the development of multicentric Castleman's disease in C/EBP beta-/- mice.

Animals↗

PubMed1996

Bronchoalveolar lavage, histological and immunohistochemical features in cryptogenic organizing pneumonia.

This study describes bronchoalveolar lavage (BAL), histological and immunohistochemical features in a series of 10 patients with cryptogenic organizing pneumonia (COP). The histological diagnosis was performed by transbronchial biopsy in seven cases and by open lung biopsy in three cases. All patients showed a marked increase in lymphocytes and a mild increase in neutrophils and eosinophils in BAL fluid. The number of T-lymphocytes expressing human leucocyte antigen-DR (HLA-DR) surface antigen was increased (p < 0.002). The majority of lymphocytes expressed the CD8 phenotype, so that the CD4/CD8 ratio was markedly decreased. Masson bodies were present in the lung specimens of all patients. Most of the epithelial cells surrounding the Masson bodies were immunoreactive with an anti-granulocyte/macrophage colony-stimulating factor (GM-CSF) monoclonal antibody. The great majority of mononuclear cells in the lung specimens showed immunoreactivity with anti-CD3, anti-CD8 and anti-CD45R0 monoclonal antibodies. In the Masson bodies, spindle cells were immunoreactive with anti-alpha smooth muscle (alpha-sm) actin monoclonal antibody. Glucocorticoid treatment (the therapy of choice in COP) downregulated GM-CSF messenger ribonucleic acid (mRNA) expression in lung epithelial cell lines. These findings indicate that the combination of bronchoalveolar lavage cell profile with histological evidence is a valuable means of corroborating a clinical diagnosis of cryptogenic organizing pneumonia, and that granulocyte/macrophage colony-stimulating factor may be one of the cytokines involved in the pathogenesis.

Biopsy↗

PubMed1995

Spontaneous and glucocorticoid-induced apoptosis in human mature T lymphocytes.

Glucocorticoid (GC)-induced apoptosis is a well-recognized physiologic regulator of murine T-cell number and function. We have analyzed its mechanisms in human mature T cells, which have been thought to be insensitive until recently. Peripheral blood T cells showed sensitivity to GC-induced apoptosis soon after the proliferative response to a mitogenic stimulation, and were also sensitive to spontaneous (ie, growth factor deprivation-dependent) apoptosis. CD8+ T cells were more sensitive to both forms than CD4+ T cells. Acquisition of sensitivity to GC-induced apoptosis was not associated with any change in number or affinity of GC receptors. Both spontaneous and GC-induced apoptosis were increased by the macromolecular synthesis inhibitors, cycloheximide (CHX) and puromycin. A positive correlation between the degree of protein synthesis inhibition and the extent of apoptosis was observed. Interleukin-2 (IL-2) IL-4, and IL-10 protected (IL-2 > IL-10 > IL-4) T cells from both forms of apoptosis in a dose-dependent manner. Our data suggest that spontaneous and GC-induced apoptosis regulate the human mature T-cell repertoire by acting early after the immune response and differentially affecting T-cell subsets.

Apoptosis↗

PubMed1995

Role of cytokines in distribution and differentiation of dendritic cell/Langerhans' cell lineage in human primary carcinomas of the lung.

The possibility that production of some cytokines in the carcinoma microenvironment is associated with the presence and differentiation of cells belonging to the dendritic cell (DC)/Langerhans' cell (LC) lineage was investigated. Immunohistochemical examination showed the presence of intraepithelial LCs (CD1a- and S100-positive cells) in 6 of 10 squamous cell carcinomas and in 8 of 10 adenocarcinomas. Langerhans' cells were mainly located close to lymphoid aggregates. In situ hybridization performed in four cases (three LC positive and one LC negative) of squamous cell carcinoma and in five cases (four LC positive and one LC negative) of adenocarcinoma showed that some mononuclear cells in the interstitium displayed hybridization with granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF alpha), and interleukin 1-beta (IL1 beta) cDNA probes. Only in LC-positive carcinomas did epithelial cells close to lymphoid aggregates display small amounts of GM-CSF and TNF alpha mRNA expression. Immunohistochemical analysis performed in the 20 cases of lung carcinoma showed that epithelial cells in tumors with lymphoid aggregates and LCs were immunoreactive with antihuman GM-CSF monoclonal antibody. Specimens negative for GM-CSF contained very few LCs. Northern blot analysis was used to investigate GM-CSF, TNF alpha, IL1 alpha, and IL1 beta mRNA expression in six human lung carcinoma cell lines. A constitutive expression of TNF alpha mRNA was found in all of them, whereas only three showed a low constitutive expression of GM-CSF mRNA. In the latter three cell lines treatment with phytohemagglutinin (PHA)-stimulated peripheral blood lymphocyte (PBL) supernatant (PHA-SUP) upregulated GM-CSF mRNA expression and induced that of IL1 alpha mRNA. Carcinomatous epithelial cells producing small amounts of cytokines could promote the recruitment of cells of DC/LC lineage. Subcellular factors produced by reactive lymphocytes and/or macrophages may influence the production of GM-CSF and IL1 alpha by various epithelia. Up-regulation of this production could favor the arrival and differentiation of DCs and activate LC functions.

Adenocarcinoma↗

PubMed1993

Inducible accessory function of a macrophage cell line.

Costimulatory molecules in addition to occupancy of the T-cell antigen receptor, are required to induce T-cell proliferation. Previous work suggested that membrane molecules responsible for costimulatory activity were not constitutively expressed on the antigen presenting cell (APC) surface. In the present study, we have identified a cloned macrophage cell line (FLJ2) with inducible APC function. The unactivated FLJ2 line could not induce T-cell proliferation. FLJ2 could present alloantigen, and stimulate proliferation of either a T-cell clone or normal resting T cells following activation with IFN gamma or unexpectedly with lipopolysaccharide (LPS)-Activated FLJ2 cells could be fixed and APC function was preserved. The relevant inducible molecules required for APC function appeared distinct from Ia and IL1. The expression of ICAM-1 and LFA-1 was increased during activation and anti-LFA-1 antibody blocked APC function. This suggests that one important feature of the activation process may be improvement of cellular adhesion.

Animals↗

PubMed1992

Distribution and phenotype of immune cells in normal human gingiva: active immune response versus unresponsiveness.

The oral cavity, and particularly the gingival mucosa, is continuously exposed to numerous food and bacterial plaque antigens, though evident immunologic reactions are uncommon. It is therefore possible that the mucosal associated lymphoid tissue (MALT) of this region is preferentially biased towards unresponsiveness, rather than immune cell activation. The distribution and phenotype of immune cells in normal human gingiva were examined. Their distribution varied, and high and low cellularity areas could be distinguished in the same specimen. The number of CD3 positive (CD3+) T lymphocytes was more than thrice higher in a high cellularity area. In both types of area, intraepithelial T lymphocytes were not activated. Moreover, they showed chromatin condensation and cell shrinkage characteristic of apoptosis. In the stroma of high cellularity areas, foci of cell activation and numerous B cells were present, suggesting a localized active immune response. The vast majority of intraepithelial and stromal T lymphocytes expressed the "memory" CD45RO+ phenotype. The absence of an immune response within the epithelium and the localized response in the stroma (probably due to the binding of memory T cells to antigens in a low affinity, cross-reactive fashion) may be a part of a protective mechanism against indiscriminate stimulation by a multitude of external antigens.

Adult↗

PubMed1990

A role for cytokines in antigen presentation: IL-1 and IL-4 induce accessory functions of antigen-presenting cells.

Fixation of APC with 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide (ECDI) eliminates their ability to stimulate proliferation of alloreactive T cells or the D10 T cell clone, although a partial response, IL-4 production, was measured. However, if APC were activated before fixation, they could be ECDI-fixed and retain the ability to induce T cell proliferation. IL-1, IL-4 or LPS were capable of activating APC in this way, whereas IFN-gamma was not. This activation step occurred in 6 h, required protein synthesis, and was distinct from increases in Ia or IL-1. This suggests resting APC lack structures that are essential for inducing T cell proliferation.

Animals↗

PubMed1990

A raf/myc virus immortalized macrophage cell line which supports the growth of B-cell and B-cell hybridomas.

Using a combination of raf and myc oncogenes co-expressed by the recombinant retrovirus J-2 we have generated and characterized a cell line which very efficiently supports the growth of B-cells and B-cell hybridomas. Murine spleen cells were cultured under in vitro immunization conditions favoring the short term proliferation of splenic B lymphocytes and infected with J-2 virus. Screening of immortalized spleen cell pools for the capability to support long term B cell growth in vitro led to the selection of a clonal cell line termed alpha ChyJ2. The presence of macrophage specific features and surface markers suggest that alpha ChyJ2 belongs to the macrophage lineage. alpha ChyJ2 cells constitutively produce low levels of IL-1 like activity and high levels of IL-6. Expression of specific mRNAs as well as production of IL-1 alpha, IL-1 beta and IL-6 are inducible with LPS. Expression or production of other cytokines including IL-2, IL-3, IL-4, IL-5, TGF beta and GM-CSF could not be detected. As the biological effects of alpha ChyJ2 supernatant cannot be fully explained by the described pattern of cytokine production, participation of other, yet uncharacterized, factors is possible. Using alpha ChyJ2 as feeder cells for in vitro as well as in vivo immunizations increased the number of antibody secreting B-cell clones 2 to 15 fold, respectively.

B-Lymphocytes↗

PubMed1989

The role of arachidonic acid metabolite PGE2 on T cell proliferative response.

We have examined the role of cyclooxygenase and lipooxygenase-derived metabolites of arachidonic acid (AA) during T cell activation. One of the major products of cyclooxygenase activity is prostaglandin E2 (PGE2). As is known, macrophages (Mo) are the main PGE2 producer cells among the peripheral blood mononuclear cells (PBL) and can be induced to release PGE2 during T cell activation. On culturing PBL with T cell mitogens such as phytohemagglutinin (PHA) or monoclonal antibody OKT3, the levels of PGE2 produced by Mo were positively correlated with the entity of the T cell mitogenic signal. During T cell activation, subcellular factors able to provide positive or negative signals on the Mo PGE2 production are released in culture. We observed that recombinant IL2 strongly enhanced PGE2 synthesis in lipopolysaccharide (LPS) stimulated Mo culture, while recombinant interferon gamma (IFN-gamma) partially inhibited its production. Moreover, purified IL1 induced PGE2 synthesis in resting Mo and increased its production when Mo were activated by LPS. The PGE2 released during T cell activation seems to have no effect on T cell mitogenesis, since the addition of cyclooxygenase inhibitors did not influence the proliferative response of mitogen stimulated T cells. However, the addition of PGE2 to OKT3 stimulated PBL at the beginning of the culture period inhibited the proliferative response in a dose-dependent manner. Its addition had no effect on PHA-stimulated PBL cultures. The PGE2-dependent inhibition of OKT3-induced T cell proliferation declined progressively from about 50-10% as the addition of PGE2 was delayed from 0 to 24 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Factors↗

PubMed1987

Glucocorticoid receptors and corticosensitivity of human thymocytes at discrete stages of intrathymic differentiation.

Human thymus is composed of several discrete compartments. Stage III thymocytes, located mainly in the medulla, stain brightly with anti-T3 monoclonal antibody; stage II thymocytes, located in the cortex, are T3- but react with T6 antibodies. The earliest identifiable intrathymic cell (stage I) expresses the sheep erythrocyte glycoprotein T11 but not T6 or T3 antigens. Within the thymus a phenotypically heterogeneous pool of proliferating lymphoblasts is present. This capacity to proliferate without in vitro activation is mainly attributable to thymocytes unable to respond to mitogens and expressing the cortical T6 marker. Both T3+ and T3-T6- cells respond to mitogen. However, in order to exhibit maximal proliferative responses, T3+ but not T3-T6- thymocytes require the addition of exogenous IL 2. Thymocyte subsets at distinct stages of intrathymic differentiation were then analyzed for glucocorticoid (GC) receptor content by using a whole cell assay with 3H-triamcinolone acetonide as tracer. The least mature T3-T6- thymocyte subset contained the highest levels of GC receptors . T3+ thymocytes exhibited a receptor content higher than that found in T6+ cells and similar to that reported for peripheral blood lymphocytes. Apart from the number, the GC receptor sites in all thymocyte subsets were similar in their affinities, kinetic characteristics, specificity for steroids, and ability to undergo translocation from cytoplasm to nucleus, and they behave in all these respects like binding sites of GC receptors in lymphoid and other cells. Independently of both phenotype and GC receptor content, all in vivo activated thymocytes (i.e., spontaneously proliferating cells) were similarly sensitive to the steroid inhibitory action in vitro. Both in the presence and in the absence of exogenous IL 1 or IL 2, the PHA-induced mitogenesis of T3-T6- cells was less inhibited by GC than that of T3+ thymocytes. Exogenous IL 1 and IL 2 were equally effective in removing, although not completely, the GC inhibition on T3-T6- proliferative responses to PHA. Relative to T3+ cell mitogenesis, only exogenous IL 2 was able to antagonize the steroid inhibitory action. The capacity observed in vitro of GC to differentially affect the proliferative potential or the cell viability of thymocytes belonging to functionally distinct subsets suggests that these hormones could regulate the intrathymic maturative pathways. Finally, although at present the physiologic relevance of the highest expression of GC receptors in intrathymic precursor cells remains unclear, the receptor density may be considered a marker of differentiation for the T lymphoid lineage.

Antigens, Differentiation, T-Lymphocyte↗

PubMed1986

Proliferation of phenotypically immature human thymocytes with and without interleukin 2 receptors.

Previous studies have indicated that the human thymus is composed of several discrete compartments. Cortical thymocytes are reactive with the monoclonal antibody anti-T6, whereas most medullary cells, unreactive with anti-T6, stain brightly with anti-T3, which defines mature T cell populations. Only a minor thymocyte population lacks both T3 and T6 but expresses T11 antigens. Within the thymus, several proliferating lymphoblasts are present. In addition a distinct subset shows the capacity to proliferate in response to mitogens. By continuous Percoll density gradient centrifugation, we have obtained a cell fraction comprising the vast majority of cells able to proliferate spontaneously or after PHA stimulation. By a panning procedure performed with anti-T3 and anti-T6 antibodies, three phenotypically distinct thymocyte subsets were separated from this fraction, and their functional capabilities were tested. The spontaneous proliferating activity was found to be mainly attributable to thymocytes unable to respond to mitogen, expressing the cortical T6 marker and lacking receptors for IL 2. T3-positive cells are able to respond to mitogen. However, these thymocytes are incapable of producing the adequate amount of IL 2 required to fully saturate their intrinsic proliferative capability. Surprisingly, the phenotypically least mature intrathymic T lymphocytes (T3 and T6 negative) respond to phytomitogen, at least in part, in an interleukin-dependent manner. It is noteworthy that a large proportion of these T3- and T6-negative thymocytes express IL 2 receptors and class II MHC antigens without in vitro activation. These novel findings have potential implications in the context of current models of differentiation pathways within the human thymus.

Antibodies, Monoclonal↗

PubMed1986

Inhibitory effect of cyclosporin A on the OKT3-induced peripheral blood lymphocyte proliferation.

In this paper we studied the effect of cyclosporin A (CyA) on interleukin 1 (IL-1) and interleukin 2 (IL-2) production and on IL-2 receptor expression by human peripheral blood lymphocytes induced to proliferate following OKT3 monoclonal antibody stimulation. CyA inhibited T-cell proliferation in a dose-dependent manner and its effect was inversely correlated with the entity of the mitogenic signal. The drug reduced not only IL-2 synthesis but also IL-1 production. CyA was also found to be able to inhibit the expression of IL-2 receptors on T cells. By supplementing with IL-1 and/or IL-2 the cultures carried out in the presence of CyA, it became evident that the inhibition of IL-2 production mainly depended on the CyA-induced reduction of IL-1 synthesis. Thus the IL-2 production by "resting" T cells had to be considered as an IL-1-dependent event. In addition it was found that the presence of IL-1 constituted a crucial requirement for the induction and the positive modulation of IL-2 receptor expression. Although IL-2 could play a role in facilitating the expression of IL-2 receptors, its effectiveness to do so depended on the presence of IL-1. In conclusion, CyA is to be considered not only as a potent immunodepressive drug but also as a valuable tool for the study of T-cell activation and proliferation.

Antibodies, Monoclonal↗