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P Vassalli

Publications and source records attributed to P Vassalli.

At least 91 records · Page 5Linked to original sources
PubMed1988

Recombinant murine IL-3 fails to stimulate T or B lymphopoiesis in vivo, but enhances immune responses to T cell-dependent antigens.

We have explored the in vivo effect of IL-3 on the lymphopoiesis and humoral responses of mice bearing osmotic minipumps loaded with murine rIL-3 for 1 to 4 wk. A marked splenomegaly due to the accumulation of hemopoietic precursors was seen, but no increase was found in the lymphoid organs in the total number of cells belonging to the T or B lymphocyte lineage, i.e., of L3T4+ or Lyt-2+, or of allospecific cytotoxic T lymphocyte precursor for the T lineage, or of sIg+ or B220+ cells, or of B colony-forming cells for the B lineage; total activity of natural killer and lymphokine-activated killer cells was decreased. In contrast to the splenomegaly, a marked diminution in the number of thymocytes was observed, suggesting that rIL-3 in large amounts does suppress the T lymphopoiesis, perhaps as the result of the selective stimulation of early progenitor cells toward the hemopoietic pathway. rIL-3 perfusion during immunization increased the IgM and IgG responses to a T cell-dependent antigen, human IgG, and prevented tolerance induction by the deaggregated human IgG, although in the same conditions it did not modify the response to a T cell-independent antigen. Our results suggest that in vivo IL-3 does not act directly on lymphocytes or their precursors, but may potentiate the humoral immune response to T cell-dependent antigens, presumably by acting on accessory cells.

Animals↗
PubMed1988

Aggravation of experimental cutaneous leishmaniasis in mice by administration of interleukin 3.

Previous studies from our laboratory have shown that some in vitro maintained Leishmania major-specific L3T4+ T cells were capable of exacerbating cutaneous leishmaniasis after adoptive transfer to normal syngeneic mice. Results presented in this report show that these cells released substantial amounts of interleukin 3 (IL 3) and granulocyte-macrophage colony-stimulating factors after specific stimulation in vitro. In order to assess the involvement of such lymphokines in the exacerbation of cutaneous leishmaniasis by these L3T4+ T cells, the effect of the administration of important doses of IL 3 on the course of infection with L. major was investigated. The treatment of genetically susceptible BALB/c mice with IL 3 resulted in an enhancement of the size of lesions and favored the multiplication of parasites at anatomical sites distant from the primary lesion. Although IL 3 did not modify the development of lesions in genetically resistant CBA mice, this lymphokine promoted the growth of Leishmania in lymph node draining the lesion. Finally, the addition of IL 3 to macrophages parasitized in vitro enhanced the survival of intracellular Leishmania major.

Animals↗
PubMed1988

Selective production of interleukin 3 (IL3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in vitro by murine L3T4+ T cells: lack of spontaneous IL3 and GM-CSF production by Ly-2-/L3T4- lpr subset.

Murine spleen and lymph node L3T4+ T cells were found to spontaneously produce high levels of interleukin 3 (IL3) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in cultures containing 10% fetal calf serum (FCS) in the absence of other stimulation. The IL3 and GM-CSF activities in culture supernatants peake between the fifth and seventh day of culture. The specificity of the bioassays was attested by the use of rabbit anti-IL3 and anti-GM-CSF antibodies, as well as by the detection of a maximal accumulation of IL3 and GM-CSF mRNA on the fourth day. In contrast, no significant activities of IL2, IL4 or interferon-gamma were detected in these culture supernatants. The markedly limited production of IL3 and GM-CSF in cultures performed in 1% autologous normal mouse serum and the inhibitory effect of anti-Ia or anti-L3T4 monoclonal antibody strongly suggest that the selective production of most, if not all IL3 and GM-CSF by L3T4+ T cells is a result of activation of L3T4+ T cells by fetal calf serum. All the strains of mice tested except athymic nude mice produced substantial amounts of IL3 and GM-CSF during the culture. This is in contrast to a previous report (Palacios, Eur. J. Immunol. 1984. 14: 599), indicating that only spleen cells of the MRL strain homozygous for the lpr gene spontaneously release IL3 in cultures. We found that spleen and lymph node cells from MRL/MpJ-lpr/lpr or C57BL/6J-lpr/lpr mice released, in fact, much less IL3 and GM-CSF in cultures. This was, however, due to the high proportion of the peculiar lpr Ly-2-/L3T4-T cells in spleen and lymph nodes, since after depletion of this lpr T cell subset, lymph node cells from C57BL/6J-lpr/lpr mice produced IL3 and GM-CSF at levels comparable to those in C57BL/6J-+/+ mice. These results further support the notion that the lpr Ly-2-/L3T4- T cell subset is immunologically nonfunctional and its accumulation dilutes functional L3T4+ T cells in mice bearing the lpr mutation.

Animals↗
PubMed1988

Effect of helper and/or cytotoxic T-lymphocyte depletion on low-dose streptozocin-induced diabetes in C57BL/6J mice.

The low-dose streptozocin (STZ) model of diabetes has been reported to involve direct STZ beta-cytotoxicity and/or immunologically mediated beta-cell destruction. Because the T-lymphocyte dependency of such a model is controversial, we further assessed the role of T-lymphocytes by determining the occurrence and magnitude of hyperglycemia as well as the pancreatic insulin contents in both STZ-injected nude C57BL/6J male mice and STZ-injected euthymic C57BL/6J male mice selectively depleted in helper and/or cytotoxic T-lymphocytes with monoclonal antibodies (MoAbs). The effectiveness of MoAb treatment was assessed in lymph node cells by flow-microfluorometry analysis and in spleen cells by concanavalin A stimulation, allospecific cytotoxic T-lymphocyte activity, and T-lymphocyte lymphokine production. Sixteen days after the first STZ injection, hyperglycemia (plasma glucose greater than 200 mg/dl) occurred in significantly fewer helper T-lymphocyte-depleted mice (P less than .005) or helper and cytotoxic T-lymphocyte-depleted mice (P less than .001) than in non-MoAb-treated mice. However, a progressive increase in the number of mice with hyperglycemia ensued in all MoAb-treated groups, and 2 mo after STZ was administered, the prevalence of hyperglycemia, mean plasma glucose levels, and pancreatic insulin contents did not differ significantly from the values obtained in the non-MoAb-treated animals. Similarly, STZ-injected C57BL/6J male nude mice developed hyperglycemia that was associated with a marked decrease in pancreatic insulin contents on a time course comparable with that of STZ-injected euthymic C57BL/6J male mice depleted in helper or in helper and cytotoxic T-lymphocytes by MoAbs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Inhibition of hemopoiesis in murine marrow cell cultures by recombinant murine tumor necrosis factor alpha: evidence for long-term effects on stromal cells.

The addition of recombinant murine tumor necrosis factor alpha (rmTNF-alpha) to serum-free methylcellulose cultures inhibited macrophage colony formation stimulated by purified colony stimulating factor-1 (CSF-1), recombinant granulocyte-macrophage-CSF (rmGM-CSF), and recombinant interleukin 3 (rmIl-3). The concentration of rmTNF-alpha inhibiting colony formation by 50% (IC50) was between 2 and 20 ng/ml. Erythroid colony formation in cultures with erythropoietin (EPO) alone or EPO, rmIl-3, and rmGM-CSF in combination were reduced to a much lesser extent. In established long-term marrow cultures (LTMC), addition of 20 and 200 ng/ml of rmTNF-alpha resulted in release of cells from the adherent layer during the first week. Treatment of cultures with rmTNF-alpha for 4 consecutive weeks led to prolonged inhibition of cell production lasting up to 8 weeks after cessation of treatment. One day after addition of a low dose of TNF (2 ng/ml), "fat" cells were no longer observed in the adherent layer. Our results indicate that TNF inhibition of hemopoiesis occurs both at the progenitor cell and stromal cell levels.

Animals↗
PubMed1988

The roles of granulocyte-macrophage colony-stimulating factor and interleukin 3 in stromal cell-mediated hemopoiesis in vivo.

Adherent cells from murine long-term marrow cultures (LTMC) were examined for presence of mRNA for granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (Il-3). Six hours after medium replacement, GM-CSF mRNA was detected but was no longer detectable 24 h after feeding; Il-3 mRNA was not detected at any time. Neutralizing antibodies against these factors had no effect on hemopoiesis. Exogenous Il-3 increased cell production, notably mature erythroid progenitors, whereas GM-CSF had little long-term effect even at high concentrations. Furthermore, GM-CSF appeared to be specifically removed from the medium, whereas virtually all of the Il-3 could be recovered under identical incubation conditions. These results show that Il-3 is not required for maintaining long-term hemopoiesis in vitro, whereas the precise role of GM-CSF in this system remains unclear.

Animals↗
PubMed1987

Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease.

Lethally irradiated mice were injected with semiallogeneic, T-depleted bone marrow cells and an amount of peripheral T lymphocytes sufficient to induce graft-vs.-host disease (GVHD) becoming apparent on the second week after the graft and leading to an increasing mortality rate within the following weeks (greater than 90% mortality within 80 d). Mice receiving bone marrow cells alone had no GVHD and were used as controls. Beginning on day 8, mice with GVHD were injected weekly with 2 mg of either rabbit anti-mouse recombinant tumor necrosis factor/cachectin (TNF-alpha) IgG, or normal rabbit IgG. On the 16-18th d, mice were killed to examine the skin and intestinal lesions of the acute phase of GVHD. The anti-TNF treatment resulted in an almost complete prevention of the severe lesions seen in the mice treated with normal rabbit IgG, i.e., the skin epidermal cell necrosis, foci of lichenoid hyperplastic reactions, and loss of the hypodermic fat; in the gut dilatation with marked flattening of the villi and elevation of the crypts, with increased numbers of mitoses and isolated crypt cell necrosis. In addition to preventing these acute lesions, anti-TNF treatment resulted in a significantly decreased mortality (approximately 70% survival at 80 d). These results suggest that during acute GVHD, the activation of grafted lymphocytes leads to a local release of TNF in the cutaneous and intestinal mucosae, which induces epithelial cell alterations and increases the inflammatory reaction.

Animals↗
PubMed1987

Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria.

Tumor necrosis factor, or cachectin (TNF-alpha), a protein with a wide range of biological activities, is produced mainly by macrophages and may be important in inflammatory processes. The role of TNF-alpha in the pathogenesis of cerebral malaria was investigated in a murine model. Most CBA mice infected with Plasmodium berghei anka die between days 6 and 14 with acute neurological manifestations unrelated to the level of parasitemia, whereas mice of some other strains have malaria of the same severity that ends in death after 3 to 4 weeks without neurological manifestations. The activity of serum TNF-alpha was considerably increased in CBA/Ca mice with cerebral malaria but not in Plasmodium berghei-infected mice that did not develop this complication. One injection of rabbit antibody to TNF-alpha on day 4 or 7 fully protected infected mice from cerebral malaria without modifying the parasitemia, whereas immunoglobulins from normal rabbit had no effect. In mice with cerebral malaria, the cerebral vessels showed focal accumulations of packed macrophages often containing infected erythrocytes; this lesion was not seen in mice treated with antibody to TNF-alpha or in untreated mice without cerebral malaria. These findings indicate that TNF-alpha has an important role in the pathogenesis of cerebral malaria in this murine model and suggest that local accumulation and activation of macrophages may lead to the predominance of lesions in the central nervous system.

Animals↗
PubMed1987

Autoimmune syndrome after induction of neonatal tolerance to alloantigens: effects of in vivo treatment with anti-T cell subset monoclonal antibodies.

BALB/c (H-2d) mice rendered tolerant to h-2b alloantigens by neonatal injection of semiallogeneic (C57BL/6 X BALB/c)F1 spleen cells develop autoimmune features due to an abnormal activation of persisting F1 donor B cells. The role of T cells in this autoimmune syndrome was studied by in vivo treatment of tolerant mice with anti-L3T4(GK-1.5) or anti-Ly-2 (H-35-17.2) monoclonal antibodies. The treatment of tolerant mice from day 2 to day 21 of life with anti-L3T4 MAb completely prevented the occurrence of circulating immune complexes of anti-ssDNA anti-Sm and anti-hapten (FITC) IgG antibodies as well as the glomerular deposition of Ig that were usually seen in untreated tolerant mice. This effect persisted for at least 6 wk after stopping this treatment. When the injections of anti-L3T4 MAb were delayed until day 15 of life, a very significant decrease of the autoimmune manifestations was still observed. Treatment of tolerant mice with anti-Ly-2 MAb during the same period had no effects on the autoimmune disease as compared with untreated tolerant mice. No effects on the maintenance of tolerance vs H-2b alloantigens were observed after treatment with anti-L3T4 MAb, as followed by the decrease of CTL and CTL-p alloreactivity and by the persistence of F1 donor B cells, indicated by the presence of Ig bearing the Ighb donor allotype. These results suggest the existence of interactions between L3T4+ T cells and persisting autoreactive B cells from F1 donor origin in the development of the autoimmune syndrome after neonatal induction of transplantation tolerance.

Animals↗
PubMed1987

Modulations of functional activity in differentiated macrophages are accompanied by early and transient increase or decrease in c-fos gene transcription.

Marked changes in c-fos proto-oncogene mRNA level and transcription rate were observed upon modulation of the functional activity of cultured mouse peritoneal macrophages. Cholera toxin (CT), dexamethasone (dex), interferon-gamma (IFN-gamma), concanavalin A (Con A), and endotoxin (LPS) induced changes in mRNA levels and transcription rates of both urokinase-type plasminogen activator and tumor necrosis factor/cachectin genes, the products of which are sensitive indices of macrophage activity. All of these agents also caused rapid and transient changes in c-fos gene expression, either enhancement (CT, dex, and LPS) or decrease (IFN-gamma and Con A). Moreover, inhibition of protein synthesis elicited a transient increase in the level of c-fos gene transcription, suggesting that the transcriptional activity of the c-fos gene is controlled by labile protein repressor(s). Taken together, these results suggest a possible role for the c-fos gene product, a nuclear protein, in the modulation of the functional activity of differentiated macrophages.

Animals↗
PubMed1987

Epidermal lesions of the GVHR: evaluation of the role of different MHC and non MHC loci and of the Ly-2+ and L3T4+ T lymphocytes.

Irradiated mice (750 rad) were injected with T-depleted bone marrow cells (BMC) and T lymphocytes in various combinations of T/host incompatibility. The epidermis was examined histologically and the incidence of two basic epidermal lesions of graft-vs-host disease (GVHD), the epidermal cell necrosis (ECN) and the lichenoid hyperplastic reaction (LR), were evaluated by a semi-quantitative evaluation. During the acute phase of GVH reaction (GVHR) (days 15 to 25), there was an obvious increase in ECN in reactions elicited by minor loci, whole major histocompatability complex (MHC) differences, or a MHC class I or II difference only. Allogeneic effect without T lymphocyte/epidermis incompatibility did not induce a significant incidence of ECN. Neither depletion of the Ly-2+ nor that of the L3T4+ T lymphocyte subset by treatment with monoclonal antibody (performed in vitro, before injection or also by treatment of the recipient) did prevent the occurrence of ECN, indicating that both T lymphocyte subsets are capable of initiating the epidermal cell damage. The LR was due mainly to the T lymphocytes of the L3T4+, Ly-2- helper phenotype. During chronic GVHR (after 35 days) elicited by either Ly-2+ or L3T4+ lymphocytes, ECN and LR were no longer evident, but the number of epidermal cells and especially the number of replicating cells among the epidermal cells were markedly reduced.

Animals↗
PubMed1987

Phagocytosis and inflammatory stimuli induce GM-CSF mRNA in macrophages through posttranscriptional regulation.

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) is a powerful growth and differentiation factor which acts on hematopoietic progenitor cells and also activates differentiated granulocytes and macrophages. This study shows that mouse peritoneal macrophages can be induced to accumulate GM-CSF mRNA and to release GM-CSF by inflammatory agents (lipopolysaccharide, fetal calf serum, thioglycolate broth); phagocytosis; and adherence in the presence of fibronectin. GM-CSF mRNA accumulation, which is totally prevented by the corticosteroid dexamethasone and by interferon-gamma, is not accompanied by changes in the gene's transcriptional level. No interleukin 3 (multi-CSF) mRNA is detectable in induced macrophages. These findings have implications in the understanding of hematopoiesis and of the inflammation and repair process.

Animals↗
PubMed1987

Involvement of specific Lyt-2+ T cells in the immunological control of experimentally induced murine cutaneous leishmaniasis.

The involvement of Lyt-2+ T cells in the immunological control of cutaneous leishmaniasis was assessed by studying the course of the disease in mice in which the number of these cells was reduced by treatment with anti-Lyt-2 monoclonal antibody (mAb). Administration of anti-Lyt-2 mAb exacerbated Leishmania major-induced cutaneous lesions in both genetically resistant and susceptible mice. This effect correlated with a drastic reduction in the number of specific Lyt-2+ T cells generated during infection. These results, together with the observation that resistant mice possess higher numbers of specific Lyt-2+ T cells in lymph nodes draining their lesions than susceptible mice, 3 weeks after infection, indicate that Lyt-2+ T cells also play a role in the immunological control of Leishmania major-induced lesions.

Animals↗
PubMed1987

In vivo effect of murine recombinant interleukin 3 on early hemopoietic progenitors.

Normal and irradiated mice were perfused with recombinant interleukin 3 (rIL3) and the number of early hemopoietic progenitors (CFU-S) was quantified in different organs. Normal mice perfused with rIL3 for 3 or 7 days showed a dramatic increase in the number of CFU-S in the spleen, liver and blood, while the bone marrow CFU-S number was slightly decreased. The total number of CFU-S per animal was only slightly increased; the major effect of rIL3 perfusion was thus on the distribution of CFU-S in the mice. Lethally irradiated mice injected with 5 X 10(4) syngeneic bone marrow cells and perfused with rIL3 were killed after 10 days. A significant increase in both the number and size of the splenic colonies was observed. The CFU-S content of these colonies, determined in a second set of irradiated mice, was increased by more than 25-fold, indicating that in conditions of hemopoietic depletion, rIL3 vastly increased the self-renewal capacity of early progenitors.

Animals↗
PubMed1987

Additive effects of interleukin 1 and tumour necrosis factor-alpha on the accumulation of the three granulocyte and macrophage colony-stimulating factor mRNAs in human endothelial cells.

The control of haematopoietic colony-stimulating factors (CSF) gene expression by interleukin 1 (IL-1) and tumour necrosis factor alpha (TNF-alpha) in cultured endothelial cells was studied by RNA hybridization and nuclear gene transcription. Both IL-1 and TNF-alpha induced, with somewhat different kinetics, a slow but marked accumulation of granulocyte-macrophage (GM)- and granulocyte (G)-CSF mRNAs in endothelial cells; macrophage (M)-CSF mRNA increased more rapidly but more moderately. Simultaneous treatment with maximally stimulating concentrations of both IL-1 and TNF-alpha had an additive effect on the accumulation of the three mRNAs, suggesting that both mediators act via independent pathways. The mechanism of CSF mRNA accumulation in endothelial cells was explored by nuclear run-on experiments, which showed that both IL-1 and TNF-alpha increase GM-CSF, G-CSF and M-CSF gene transcription to varying degrees.

Cells, Cultured↗
PubMed1987

Interstitial pneumonitis and hepatitis after transfer of bone marrow cells bearing the lpr gene to irradiated recipients: a disease due to large granular leucocytes?

Mice bearing the 'auto-immune' lpr gene develop a lympho-proliferative disease associated with the production of various antibodies. Lethally irradiated recipients were grafted with bone marrow cells (BMC) from syngeneic mice with or without the lpr gene. After 6 months, the survivors were 0/24 and 16/20 for the recipients of lpr and normal BMC respectively. The mortality rate was independent of the presence of T lymphocytes among the BMC. Histological evaluation showed that hepatitis, interstitial pneumonitis, and sclerosis of lymphohaemopoietic organs were the major causes of death for the recipients of lpr BMC. Hepatitis was associated with an increase in the number of liver interstitial cells (LIC) from about 2 X 10(6) up to about 10(7) cells per liver. The LIC associated with the hepatitis were composed of polymorphonuclear leucocytes and large mononuclear leucocytes, showing phenotypic (i.e. Thy.1+, asialo GM1, presence of cytoplasmic granules) and functional (i.e. non-phagocytic and cytolytic) properties of NK cells. The disease can be distinguished both from the spontaneous disease of the lpr mice (by the absence of 'lpr cells' and of anti-DNA antibodies) and from graft versus host disease by the absence of cutaneous and intestinal lesions. It may represent a model of tissue injury mediated by large granular leucocytes.

Animals↗
PubMed1986

Gamma interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors.

Exposure of mouse resident and thioglycollate-elicited peritoneal macrophages to IFN-gamma leads to a marked increase in the TNF-alpha (tumor necrosis factor/cachectin), IL-1 and u-PA (urokinase-type plasminogen activator) mRNA levels. Nuclear run-on experiments show that IFN-gamma acts by enhancing the transcription of these three genes. Transcription of these three genes is also rapidly and transiently induced by cycloheximide, an inhibitor of protein synthesis, indicating that they are under the control of short-lived repressors.

Animals↗