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G A DosReis

Publications and source records attributed to G A DosReis.

28 records · Page 2Linked to original sources
PubMed1996

Trypanosoma cruzi-induced immunosuppression: selective triggering of CD4+ T-cell death by the T-cell receptor-CD3 pathway and not by the CD69 or Ly-6 activation pathway.

In a model of experimental Chagas' disease induced with metacyclic forms of Trypanosoma cruzi, CD4+ but not CD8+ T cells undergo T-cell receptor (TCR)-CD3-mediated activation-induced cell death (AICD) in vitro. CD4+ T cells from T. cruzi-infected mice also developed unresponsiveness in proliferative responses to TCR-CD3-mediated stimulation. A linear correlation was found between extent of proliferative unresponsiveness and loss of CD4+ T-cell viability. CD4+ T-cell activation through the CD69 or Ly-6 A/E pathway, on the other hand, did not result in proliferative unresponsiveness compared with controls. Lack of suppression in proliferation assays correlated with lack of AICD by cells stimulated through the CD69 or Ly-6 A/E pathway. Concomitant stimulation through CD69, however, did not rescue CD4+ T cells from CD3-induced death. Flow cytometry study of cells stimulated in vitro showed no defect in interleukin-2 receptor expression by CD4+ T cells from infected donors, which escaped TCR-mediated AICD. In vivo injection of anti-CD3 into acutely infected mice, but not into control mice, led to splenocyte DNA fragmentation and failed to increase splenic CD4+ T-cell numbers. These results show that TCR-CD3-mediated AICD is involved in CD4+ T-cell unresponsiveness in vitro following infection with T. cruzi. In addition, successful activation of these cells through the CD69 and Ly-6 pathways is due to differences in the inability of these stimuli to trigger AICD. Since TCR-CD3-mediated AICD can be induced in vivo in infected mice, these findings may be relevant for the onset of immunological disturbances in the host.

Animals↗
PubMed1995

Activation-induced CD4+ T cell death by apoptosis in experimental Chagas' disease.

Infection of mice with Trypanosoma cruzi, the causative protozoan agent of human Chagas' disease, leads to immunosuppression of the T cell compartment and to chronic cardiac inflammation which resembles the human infection. Recently, reinduction of programmed cell death by apoptosis in mature T cells has been demonstrated. It has been suggested that mature T cell apoptosis could play a role in immunosuppression caused by virus infection. In this report, we have investigated the occurrence of mature T cell apoptosis in murine experimental Chagas' disease. Infection with T. cruzi metacyclic forms led to a relative accumulation of CD8 T cells over CD4 T cells in the spleens of infected mice. Splenic T cells from T. cruzi-infected donors, but not from control littermates, died in vitro upon stimulation with T cell mitogens Con A and anti-TCR-alpha beta mAb in a dose-dependent fashion. DNA fragmentation into nucleosome-sized bands was detected in the supernatants of CD4+ T cells from infected origin, after stimulation with the T cell mitogen Con A. Upon in vitro stimulation with either anti-TCR-alpha beta or Con A, CD4+ T cells were susceptible to elimination, whereas CD8+ T cells were not. Splenic T cells from infected donors were markedly unresponsive to anti-TCR mAb in proliferative assays and underwent apoptosis in vitro, as assessed by electron microscopy. Apoptosis also occurred in vivo in the course of acute infection, as seen by DNA fragmentation in freshly explanted splenic cells and purified T cell subsets. The data indicate that activation-induced CD4+ T cell death by apoptosis is a prominent feature of experimental infection with T. cruzi, and could play a role in immunosuppression and parasite persistence in infected hosts.

Animals↗
PubMed1995

Programmed T-cell death in experimental chagas disease.

In mature T cells, programmed cell death is thought to serve a regulatory function by limiting both the duration and amplitude of immune responses. Programmed cell death might also be involved in immuno-pathogenesis of certain infectious diseases: recent evidence suggests that programmed T-cell death plays an important role in immune suppression during viral infections. In this article, George DosReis, Maria Evangelina Fonseca and Marcela Lopes review their findings on programmed T-cell death in experimental infection induced by the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease. They also discuss the differential behavior of CD4(+) and CD8(+) T-cell subsets regarding programmed cell death, and same possible pathogenic aspects of host-parasite interaction, where abnormal or exaggerated programmed T-cell death could be involved.

Journal Article↗
PubMed1995

Apoptosis as a cause of T-cell unresponsiveness in experimental Chagas' disease.

A murine model of Chagas' disease induced by metacyclic forms of T. cruzi was used to evaluate T-cell function during infection. T-cell unresponsiveness to TcR;CD3 stimulation in vitro and lymphocyte activation in vivo occurred simultaneously. These paradoxical findings are discussed in the light of recent evidence that mature activated T cells become susceptible to TcR-mediated apoptosis. Activation-induced death in T cells from T. cruzi-infected mice has recently been demonstrated in this model. Evidence that TcR-induced death of activated T cells could be a cause for T-cell unresponsiveness in vitro and in vivo, as well as the possible molecular mechanisms involved, are discussed.

Animals↗
PubMed1990

Naturally activated and resting T cells differ in their activation requirements for growth and secretory activities.

"Naturally activated" (NA) and "small resting" (SR) T lymphocytes were stimulated with anti-CD3 or anti-thy 1 monoclonal antibodies (mAbs). Both proliferation and secreted IL-2, IL-3/GM-CSF activities were found in NA T cell, but not in SR T cell cultures. SR T cells could be fully activated by anti-CD3 only if PMA or IL-2 was added to the cultures. NA T cell proliferation induced with anti-CD3 was blocked with anti-IL-2 or anti-IL-2R mAbs. The combination of anti-CD3 and rec IL-4 was not effective in promoting SR T cell proliferation. IL-4 plays a minor role in NA T cell activation with anti-CD3, as assayed with neutralizing anti IL-4 mAbs. No differences in the proliferative and secretory activities were found when NA or SR T cells were stimulated with Con A. Both NA and SR T cells responded when stimulated with the calcium ionophone A23187 plus PMA. Only NA T cells responded to A23187 alone. The mechanisms and the possible physiologic relevance of this differential responsiveness behavior are discussed.

Animals↗
PubMed1990

Comparative analysis of splenic cell proliferation induced by interleukin 3 and by syngeneic accessory cells (syngeneic mixed leukocyte reaction): evidence that autoreactive T-cell functioning instructs hematopoietic phenomena.

Murine syngeneic mixed leukocyte reaction (SMLR) was studied under totally autologous culture conditions using syngeneic normal mouse serum in the culture. SMLR was detected in splenic, but not in lymph node, nonadherent responding cell populations (NWNAC). In the absence of stimulator, accessory cells (AC), IL3-containing fluids also induced splenic, but not lymph node, NWNAC growth. SMLR-derived supernatants contained IL3, but not IL2, activity, and production of this IL3 activity could be prevented by adding anti-CD4 mAbs to SMLR cultures. Precursor frequencies of both SMLR and IL3 splenic responses were very low and similar, and there was a synergism between IL3 and AC in induction of NWNAC growth. Growth of responding NWNAC was further enhanced by T-cell depletion with anti-Thy1 mAb and complement. Lack of T-cell proliferation in the SMLR was confirmed by BUdR and light protection experiments. Autoradiographs indicated that the same cell type grew in both SMLR and IL3-induced NWNAC cultures. Besides blast cells, cells with the appearance of immature monocytes with 3H-labeled nuclei were found in both kinds of culture. No labeled lymphocytes could be found. Both SMLR and IL3-induced NWNAC cultures contained expanded numbers of M-CSF-responsive monocyte precursors. On the other hand, SMLR- but not IL3-induced cultures contained expanded numbers of IL3-responsive, immature precursors capable of giving rise to large colonies of monocytic-like cells. Although IL2 could not be detected in SMLR supernatants, both cell growth and IL3 production could be blocked with anti-IL2 receptor and anti-IL2 mAbs. Exogenous IL2, on the other hand, enhanced both cell growth and IL3 production in the SMLR. These results indicate that, under totally autologous conditions, CD4+ autoreactive T-cells do not proliferate in the SMLR, but rather instruct the growth of splenic hematopoietic precursors capable of differentiating along the monocytic lineage. Autoreactive T-cell activation in the SMLR seems to involve minimal IL2 production, which is critically necessary for triggering IL3 production in a markedly amplified manner. These results suggest a link between normal regulation of hematopoiesis and MHC-restricted, autoreactive T-cell activation.

Animals↗
PubMed1986

Purinergic modulation of T-lymphocyte activation: differential susceptibility of distinct activation steps and correlation with intracellular 3',5'-cyclic adenosine monophosphate accumulation.

The mechanism by which purinergic agonists modulate murine T-lymphocyte activation and proliferation was investigated. Adenosine and other compounds such as ATP and 2-chloroadenosine (ClAdo) were found to block T-cell mitogenesis induced by concanavalin A (Con A) in a dose-dependent fashion. The nonmetabolizable adenosine analog ClAdo was the most potent agent capable of inhibiting T-cell mitogenesis. Extracellular addition of the permeable cAMP analog dibutyryl cyclic AMP (dbcAMP) also led to a dose-dependent blockade of T-cell mitogenesis, although with less efficiency when compared to ClAdo. Addition of IL-2-enriched fluids failed to reverse blockade of T-cell mitogenesis by ClAdo or dbcAMP. ClAdo blocked T-cell enlargement induced after 20 hr of culture with Con A. We analyzed the effect of micromolar concentrations of ClAdo on interleukin-2 (IL-2) production, expression of IL-2 receptors (7D4 and 3C7 surface antigens), and induction of IL-2 responsiveness after in vitro cultivation with Con A. ClAdo inhibited both IL-2 secretion and induction of IL-2 responsiveness up to control levels in the same dose range it inhibited T-cell mitogenesis. However, cell surface expression of IL-2 receptors was not affected. Short incubations of resting splenic T cells with ClAdo led to a dose-dependent accumulation of cyclic AMP in responding cells. This effect was markedly reduced by the purinergic antagonist 3-isobutyl-1-methylxanthine (IBMX) but was not prevented by the adenosine uptake blocker dipyridamole. ClAdo elicited cAMP accumulation in the same dose range it inhibited T-cell activation events. Extracellular administration of dbcAMP to splenic T cells stimulated by Con A mimicked the effects of ClAdo on T-cell activation parameters, as revealed by a dose-dependent blockade of both IL-2 secretion and IL-2 responsiveness induction, without affecting IL-2 receptor expression. Short incubations of Con A-activated T-cell blasts with ClAdo also led to a dose-dependent accumulation of cAMP. We then analyzed the effect of purines and dbcAMP on IL-2-mediated activated T-cell growth. Purines caused a dose-dependent inhibition of IL-2-mediated T-cell proliferation and ClAdo was the most potent purinergic agonist tested. The effect of ClAdo on Con A-induced T blasts was shifted to the right, if compared to earlier T-cell activation steps.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗
PubMed1985

Analysis of autoreactive I region-restricted T cell colonies isolated from the guinea pig syngeneic mixed leukocyte reaction and from immune responses to conventional foreign antigens.

Guinea pig proliferating T cell colonies were isolated from T cell populations stimulated during the syngeneic mixed leukocyte reaction (SMLR) or following positive selection of immune T lymphocytes specific for pork insulin (PI) or the copolymer of L-glutamic acid, L-lysine (GL). SMLR-responding T cell colonies could be isolated in the absence of any extrinsic antigen and were strictly restricted to the recognition of Ia molecules on stimulator peritoneal exudate cells (PEC) and required both stimulator cells and interleukin 2-enriched fluids for optimal proliferative responses. Blocking of T cell colony proliferation with a panel of monoclonal anti-Ia antibodies showed that SMLR T cell colonies were restricted by discrete and distinct self-Ia epitopes. Analysis of individual T cell colonies generated against PI and GL revealed three types of colonies: (a) antigen specific, I region-restricted; (b) autoreactive, I region-restricted; and (c) antigen specific, but also autoreactive. These doubly reactive colonies were restricted to the same Ia epitope when stimulated with self-PEC alone or when stimulated with self-PEC in the presence of the relevant exogenous antigen. These results substantiate the hypothesis that both the SMLR and antigen-specific responses are mediated by a common set of precursor T lymphocytes and that the guinea pig SMLR is at least in part the result of the polyclonal proliferative responses of several distinct antigen-reactive T cell clones in the absence of exogenous antigen.

Animals↗
PubMed1983

Cyclosporin A-treated guinea pig responder cells secrete a genetically restricted factor that suppresses the mixed leukocyte reaction.

Cyclosporin A (CY A) is a hydrophobic, undecapeptide, fungal metabolite with potent immunosuppressive effects on T lymphocyte-mediated immune responses. Suppressor T lymphocytes generated during a mixed leukocyte reaction (MLR) performed in the presence of CY A, release a factor that suppresses a primary MLR of responder T cells, which is derived from the same strain as the factor producer but lacks specificity for the stimulator cell. These results suggest a finely regulated pathway by which CY A may induce and maintain a permanent state of transplantation tolerance in vivo.

Animals↗