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G A DosReis

Publications and source records attributed to G A DosReis.

At least 19 recordsLinked to original sources
PubMed2001

Fas ligand triggers pulmonary silicosis.

We investigated the role of Fas ligand in murine silicosis. Wild-type mice instilled with silica developed severe pulmonary inflammation, with local production of tumor necrosis factor (TNF)-alpha, and interstitial neutrophil and macrophage infiltration in the lungs. Strikingly, Fas ligand-deficient generalized lymphoproliferative disease mutant (gld) mice did not develop silicosis. The gld mice had markedly reduced neutrophil extravasation into bronchoalveolar space, and did not show increased TNF-alpha production, nor pulmonary inflammation. Bone marrow chimeras and local adoptive transfer demonstrated that wild-type, but not Fas ligand-deficient lung macrophages recruit neutrophils and initiate silicosis. Silica induced Fas ligand expression in lung macrophages in vitro and in vivo, and promoted Fas ligand-dependent macrophage apoptosis. Administration of neutralizing anti-Fas ligand antibody in vivo blocked induction of silicosis. Thus, Fas ligand plays a central role in induction of pulmonary silicosis.

Adoptive Transfer↗
PubMed2001

Apoptosis and parasitism: from the parasite to the host immune response.

Apoptosis, a form of programmed cell death (PCD), plays a central role in normal tissue development as well as in the pathogenesis of different diseases. PCD is responsible for the non-inflammatory physiological elimination of potentially harmful or unnecessary cells during embryogenesis, and for the proper functioning of continuous cell renewal systems in adult organisms. Maturation of the immune system and the specific immune response are examples of situations where PCD plays important roles. This review discusses the importance of apoptosis in two fundamental elements of a host-parasite interaction: the parasite (Section 1), and the host's immune response (Section 2). Section 1 discusses questions raised by the description of apoptosis in unicellular eukaryotes, such as the evolutionary origin of the molecular components of PCD, its role in the emergence and maintenance of parasitism, and the constraints of a multicellular organization for the proper operation of a cell death programme. The proposal is that PCD can occur in any situation where living cells display features of an organized network which operates through interactions within themselves and/or with elements of their environment. The possibility is also discussed that evolutionary relics of a complete cell death system may operate in unicellular parasites with functions other than inducing cell death. Section 2 reviews data on the mechanisms of host-cell PCD and the consequences of this phenomenon in host defence and pathogenesis. Infectious agents, from viruses to parasites, can either delay or induce apoptosis of different types of host cells. Apoptosis following lymphocyte polyclonal activation and stimulation of peripheral T lymphocytes, as a result of the engagement of specific counter-receptor systems, is of special interest for defining host immunocompetence and mechanisms of immunopathology.

Animals↗
PubMed2001

The dual role of CTLA-4 in Leishmania infection.

The role of CTLA-4 in inducing the production of transforming growth factor beta (TGF-beta) from T cells during a Leishmania infection has only recently been recognized. However, CTLA-4 and TGF-beta affect T helper cells differently, depending on the maturation. This review discusses the data obtained from different experimental models and demonstrates that CTLA-4 is a target molecule for vaccination and therapy against leishmaniasis.

Abatacept↗
PubMed2000

TGF-beta mediates CTLA-4 suppression of cellular immunity in murine kalaazar.

Recent studies indicate important roles for CTLA-4 engagement in T cells, and for TGF-beta production in the immunopathogenesis of murine kalaazar or visceral leishmaniasis, but a functional link between these two pathways in helping intracellular parasite growth is unknown. Here we report that Ag or anti-CD3 activation of splenic CD4+ T cells from visceral leishmaniasis leads to intense CTLA-4-mediated TGF-beta1 production, as assessed either by CTLA-4 blockade or by direct CTLA-4 cross-linkage. Production of TGF-beta1 accounted for the reciprocal regulation of IFN-gamma production by CTLA-4 engagement. Following CD4+ T cell activation, intracellular growth of Leishmania chagasi in cocultured splenic macrophages required both CTLA-4 function and TGF-beta1 secretion. Cross-linkage of CTLA-4 markedly increased L. chagasi replication in cocultures of infected macrophages and activated CD4+ T cells, and parasite growth could be completely blocked with neutralizing anti-TGF-beta1 Ab. Exogenous addition of rTGF-beta1 restored parasite growth in cultures protected from parasitism by CTLA-4 blockade. These results indicate that the negative costimulatory receptor CTLA-4 is critically involved in TGF-beta production and in intracellular parasite replication seen in murine kalaazar.

Abatacept↗
PubMed2000

Uptake of apoptotic cells drives the growth of a pathogenic trypanosome in macrophages.

After apoptosis, phagocytes prevent inflammation and tissue damage by the uptake and removal of dead cells. In addition, apoptotic cells evoke an anti-inflammatory response through macrophages. We have previously shown that there is intense lymphocyte apoptosis in an experimental model of Chagas' disease, a debilitating cardiac illness caused by the protozoan Trypanosoma cruzi. Here we show that the interaction of apoptotic, but not necrotic T lymphocytes with macrophages infected with T. cruzi fuels parasite growth in a manner dependent on prostaglandins, transforming growth factor-beta (TGF-beta) and polyamine biosynthesis. We show that the vitronectin receptor is critical, in both apoptotic-cell cytoadherence and the induction of prostaglandin E2/TGF-beta release and ornithine decarboxylase activity in macrophages. A single injection of apoptotic cells in infected mice increases parasitaemia, whereas treatment with cyclooxygenase inhibitors almost completely ablates it in vivo. These results suggest that continual lymphocyte apoptosis and phagocytosis of apoptotic cells by macrophages have a role in parasite persistence in the host, and that cyclooxygenase inhibitors have potential therapeutic application in the control of parasite replication and spread in Chagas' disease.

Amino Acid Chloromethyl Ketones↗
PubMed2000

Early in vitro priming of distinct T(h) cell subsets determines polarized growth of visceralizing Leishmania in macrophages.

An in vitro priming system of murine naive splenocytes was established to investigate early immune responses to Leishmania chagasi, the agent of visceral leishmaniasis in the New World. Priming of splenocytes from resistant C3H and CBA or susceptible BALB and B10 mice with L. chagasi resulted in blast transformation and in proliferating parasite-specific CD4(+) T cells secreting a differential complement of cytokines (IFN-gamma and low IL-10 levels for resistant T cells; IFN-gamma, IL-4 and high IL-10 levels for susceptible T cells). After priming, intracellular parasite load was much higher in susceptible than in resistant-type splenocyte cultures. On the other hand, infection of purified splenic macrophages from either resistant or susceptible mice with live L. chagasi promastigotes, resulted in comparable parasite loads. Moreover, when early CD4(+) T cell priming in splenocyte cultures was disrupted with anti-CD4 mAb, polarized parasite growth was abolished, becoming comparable in resistant and susceptible cultures. Neutralizing IL-4 activity during splenocyte priming did not affect the final parasite load in susceptible cultures. However, neutralizing IL-10 activity markedly decreased parasite load in susceptible, but not in resistant splenic macrophages. These results suggest that IL-10 plays an important role in L. chagasi infection in susceptible hosts. The results also indicate that innate control of growth of a visceralizing Leishmania in splenic macrophages results from the ability to activate different CD4(+) T cell subsets.

Animals↗
PubMed2000

Susceptible hosts: a resort for parasites right in the eye of the immune response.

Trypanosomatid protozoan parasites express an aggressive strategy of parasitism by infecting host macrophages and inducing extensive T-lymphocyte activation. One goal of such strategy is to drive the immune response of genetically susceptible hosts to a state of unresponsiveness regarding parasite killing. Unresponsiveness is achieved through different mechanisms, depending on the parasite species. In this brief review, recent findings on the molecular and cellular bases of the parasites' exploitation of host immune responses are discussed.

Animals↗
PubMed1999

Increased susceptibility of Fas ligand-deficient gld mice to Trypanosoma cruzi infection due to a Th2-biased host immune response.

Infection of BALB/c mice with Trypanosoma cruzi resulted in up-regulated expression of Fas and Fas ligand (FasL) mRNA by splenic CD4+ T cells, activation-induced CD4+ T cell death (AICD), and in Fas: FasL-mediated cytotoxicity. When CD4+ T cells from infected mice were co-cultured with T. cruzi-infected macrophages, onset of AICD exacerbated parasite replication. CD4+ T cells from T. cruzi-infected FasL-deficient BALB gld/gld mice had no detectable AICD in vitro and their activation with anti-TCR did not exacerbate T. cruzi replication in macrophages. However, infection of BALB gld/gld mice with T. cruzi resulted in higher and more prolonged parasitemia, compared to wild-type mice. Secretion of Th2 cytokines IL-10 and IL-4 by CD4+ T cells from infected gld mice was markedly increased, compared to controls. In addition, in vivo injection of anti-IL-4 mAb, but not of an isotype control mAb, reduced parasitemia in both gld and wild-type mice. These results indicate that, besides controlling CD4+ T cell AICD and parasite replication in vitro, an intact Fas: FasL pathway also controls the host cytokine response to T. cruzi infection in vivo, being required to prevent an exacerbated Th2-type immune response to the parasite.

Animals↗
PubMed1999

Apoptosis in parasites and parasite-induced apoptosis in the host immune system: a new approach to parasitic diseases.

Apoptosis, a form of programmed cell death (PCD), has been described as essential for normal organogenesis and tissue development, as well as for the proper function of cell-renewal systems in adult organisms. Apoptosis is also pivotal in the pathogenesis of several different diseases. In this paper we discuss, from two different points of view, the role of apoptosis in parasitic diseases. The description of apoptotic death in three different species of heteroxenic trypanosomatids is reviewed, and considerations on the phylogenesis of apoptosis and on the eventual role of PCD on their mechanism of pathogenesis are made. From a different perspective, an increasing body of evidence is making clear that regulation of host cell apoptosis is an important factor on the definition of a host-pathogen interaction. As an example, the molecular mechanisms by which Trypanosoma cruzi is able to induce apoptosis in immunocompetent cells, in a murine model of Chagas' disease, and the consequences of this phenomenon on the outcome of the experimental disease are discussed.

Animals↗
PubMed1998

Proapoptotic activity of a Trypanosoma cruzi ceramide-containing glycolipid turned on in host macrophages by IFN-gamma.

The effects of glycoinositolphospholipid (GIPL), from the pathogenic protozoan Trypanosoma cruzi, and its isolated glycan and lipid (dihydroceramide) components, were investigated in J774 cells and primary macrophages. Isolated GIPL ceramide, but not intact GIPL or its glycan, induced intense fluid phase endocytosis when added exogenously. In the presence of the cytokine IFN-gamma, GIPL ceramide induced marked apoptosis in J774 cells and macrophages, independent of nitric oxide secretion. When cells were preincubated with the GIPL-derived glycan chain, addition of intact GIPL induced macrophage apoptosis in the presence of IFN-gamma. Synthetic C2-dihydroceramide also induced apoptosis in the presence of IFN-gamma. Induction of apoptosis in T. cruzi-infected macrophages by GIPL ceramide plus IFN-gamma led to increased parasite release compared with IFN-gamma treatment alone. Viable parasites released comprised both infective trypomastigote and spheromastigote forms. These results identify a novel pathway by which T. cruzi glycosylphosphatidylinositol family molecules affect host macrophages, with implications for the infectious process.

Animals↗
PubMed1998

Activation-induced T cell death exacerbates Trypanosoma cruzi replication in macrophages cocultured with CD4+ T lymphocytes from infected hosts.

Activation-induced cell death (AICD) of CD4+ T lymphocytes was described in infection with Trypanosoma cruzi, but a role for AICD in modulating parasite spread in host cells has not been investigated. In this study, replication of T. cruzi in vitro in murine macrophage (Mphi) monolayers was investigated. Long term (5 to 13 day) replication of infective (trypomastigote) T. cruzi forms was blocked by supernatants from activated (anti-TCR) CD4+ T cells of infected mice or by rIFN-gamma. However, when CD4+ T cells from infected mice were cocultured with Mphi and activated by anti-TCR, marked exacerbation of trypomastigote growth in Mphi ensued. The deleterious effect required contact between T cells and infected Mphi. Both anti-Fas and TCR activation killed a proportion of CD4+ T cells. Ly-6 activation did not induce AICD and did not exacerbate parasite growth. However, Fas-mediated killing of T cells before Ly-6 activation led to exacerbated parasite growth. Although a minor population, Fas-susceptible cells were the major source of IFN-gamma production by activated T cells. Addition of a neutralizing anti-Fas ligand antibody blocked 50 to 60% of CD4+ T cell AICD and reduced trypomastigote growth in T/Mphi cocultures stimulated by anti-TCR. The results demonstrate that in CD4+ T cells from infected mice, the onset of AICD selectively ablates IFN-gamma production and up-regulates parasite replication in Mphi in vitro. These findings suggest a deleterious role for AICD in T. cruzi infection.

Animals↗
PubMed1998

Unresponsive CD4+ T lymphocytes from Leishmania chagasi-infected mice increase cytokine production and mediate parasite killing after blockade of B7-1/CTLA-4 molecular pathway.

Infection of BALB/c mice with Leishmania chagasi results in progressive increase of parasite burden in spleen, in spite of extensive T cell activation in situ. Explanted splenic CD4+ T cells showed decreased proliferation to anti-CD3, compared with controls, and no response to L. chagasi recombinant antigen Lcr1. Blockade of the negative costimulatory receptor CTLA-4 restored responses to anti-CD3 and induced vigorous responses to Lcr1. Blockade of B7-1, but not B7-2, also enhanced T cell responsiveness. CTLA-4 blockade completely restored activation-induced interleukin-2 secretion and increased interferon-gamma production. The effect, however, was not restricted to Th1 responses, since CTLA-4 blockade also enhanced antigen-induced interleukin-4 secretion. CTLA-4 blockade induced almost complete elimination of parasite burden in splenocyte cultures activated with anti-CD3 or Lcr1. These results indicate that CTLA-4 engagement by B7-1 plays an important role in maintaining unresponsiveness in CD4+ T cells in this model of chronic visceral leishmaniasis.

Abatacept↗
PubMed1997

Cell-mediated immunity in experimental Trypanosoma cruzi infection.

Infection of humans with the protozoan Trypanosoma cruzi leads to Chagas disease, or American trypanosomiasis, a disease that affects nearly 20 million people, and constitutes one of the largest socioeconomic burdens in Latin America. Much of the present knowledge on pathogenic mechanisms underlying T. cruzi infection comes from experimental murine models. Here, George A. DosReis reviews recent findings about the features of host cell-mediated immunity against the parasite and possible mechanisms leading to chronic infection.

Journal Article↗
PubMed1996

Ligation of CD4 concomitant to activation induces primary CD4+ T-cell adhesion and pseudopodia formation in vitro.

A regulatory function for CD4 molecules in lymphocyte adhesion and motility was investigated. Murine splenic CD4+ T cells, activated in the presence of phorbol ester and immobilized anti-CD4 mAb, adhered to the plastic surface and formed extended cytoplasmic projections (pseudopodia). Pseudopod formation was cell-density-dependent, peaked at Day 3, and disappeared by Day 5 in culture. This response could be inhibited by soluble anti-CD4 and by RGD-containing peptide. Ligation of CD4 was required at a late stage in cell activation, and stimulated cell motility in vitro. Addition of IL-4, but not IL-2, upregulated pseudopod formation induced by suboptimal stimuli. Anti-IL-4 mAb blocked pseudopod formation, and exogenous IL-4 restored the response. A combination of IL-4 plus phorbol ester, but not IL-2 plus phorbol ester, induced pseudopod formation in concert with CD4 ligation. Exogenous IL-2, on the other hand, blocked pseudopod formation. CD45RBlow CD4+ T cells were much more efficient than CD45RBhigh CD4+ T cells for pseudopod formation. These results indicate that CD4 ligation induces CD4+ T-cell adhesion and motility, mainly in the memory/activated subset, which might be relevant for immune responses in vivo.

Animals↗
PubMed1996

Down-regulation of T lymphocyte activation in vitro and in vivo induced by glycoinositolphospholipids from Trypanosoma cruzi. Assignment of the T cell-suppressive determinant to the ceramide domain.

The major surface glycoinositolphospholipid (GIPL) from Trypanosoma cruzi was purified and assessed in mouse T cell function assays. Purified GIPLs from T. cruzi strains Y and G, but not from a plant trypanosomatid (Phytomonas serpens), markedly blocked in vitro CD4+ and CD8+ T cell mitogenesis induced by bacterial superantigen and anti-TCR;CD3 Abs. Secretion of IL-2, but not of IL-4, bioactivity, was reduced by GIPLs. T. cruzi, but not P. serpens, GIPL also blocked recall cellular responses to T. cruiz. GIPLs from T. cruzi, but not from P. serpens, blocked in vivo regional lymph node T cell activation induced by anti-CD3 mAb. Blockage led to loss of IL-2 responsiveness, with inhibition of CD25 expression on both CD4+ and CD8+ subsets. Isolated phosphoinositol oligosaccharides from GIPLs had no effect on in vitro CD4+ T cell mitogenesis. Isolated ceramide from T. cruzi GIPLs contained mainly N-lignoceroyldihydrosphingosine and blocked CD4+ T cell activation in vitro with the same potency as the intact GIPL. Standard N-palmitoylsphingosine, but not N-palmitoyldihydrosphingosine, blocked CD4+ T cell mitogenesis. A longer fatty acid chain, such as in standard N-lignoceroyldihydrosphingosine, or in the natural trypanosomal GIPL-derived ceramide, however, conferred full inhibitory effects on CD4+ T cells. These results demonstrate that T. cruzi GIPL has T cell immunomodulatory activity in vitro and in vivo, and that this novel activity maps to the ceramide domain. These findings could have implications for immunologic disturbances induced in the host by the causative agent of Chagas' disease.

Animals↗