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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the immunogenicity of defined sequences of the circumsporozoite (CS) protein of the murine malaria parasite, Plasmodium yoelii. A 21-ner synthetic peptide from the nonrepetitive region of the CS protein (position 59-79, referred to as Py1) induced T cell proliferative responses in H-2d and, to a lesser extent, in H-2b mice. Conversely, a synthetic peptide (referred to as Py4) consisting of four (QGPGAP) repeats of the P. yoelii CS protein, induced an antibody response only in H-2b mice. No antibody response was observed when the Py3 peptide, consisting of three (QGPGAP) repeats, was used as an immunogen. When cross-linked to the Py4 repetitive peptide, the Py1 sequence behaved as a T helper epitope allowing the production of anti-Py4 antibodies in H-2d mice. Several long-term T cell lines and clones specific for the nonrepetitive Py1 peptide were originated in vitro from both H-2d and H-2b mice. These lines and clones were CD4+ and proliferated in a major histocompatibility complex-restricted fashion. Furthermore, Py1-specific T cell lines and clones did not proliferate in the presence of synthetic peptides from an analogous region of another rodent malaria parasite, P. berghei, despite the high degree of homology existing in this sequence of the two CS proteins. Finally, supernatants from 7 out of 13 clones (from BALB/c mice) produced detectable amounts of interleukin 2 and interferon-gamma; whereas supernatants from the 4 clones from C57BL/6 and 2 from BALB/c mice contained detectable amounts of interleukin 5. These results show that functionally heterogenous CD4+ T cell populations, belonging to either TH1 or TH2 subset, are activated upon immunization of mice with the P. yoelii Py1 synthetic peptide. It is not yet known what differential role these CD4+ subsets play during the malaria infection or after immunization with different malaria T cell epitopes. This knowledge may have a particular impact in the design of effective subunit vaccines against malaria.
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PMID:Immune responses to defined epitopes of the circumsporozoite protein of the murine malaria parasite, Plasmodium yoelii. 169 52

We have mapped a T cell epitope in the circumsporozoite (CS) protein of the murine malaria parasite, Plasmodium yoelii. A 21-mer synthetic peptide corresponding to the amino acid positions 59-79 (referred to as Py1), induced specific proliferation in BALB/c and C57BL/6 mice, and provided help for the production of antibodies to peptides from the repetitive region, (QGPGAP)n, of the same CS protein, when mice were immunized with the Py1 peptide conjugated to the repetitive peptide. Long-term CD3+CD4+CD8-TCR alpha beta+ T cell lines and clones were derived from both strains of mice. These lines and clones, that proliferated in an MHC-restricted fashion, did not recognize peptides from the homologous region of another murine malaria parasite, P. berghei. About 50% of these clones produced detectable amounts of IFN-gamma and IL-2, whereas the remaining produced IL-4, IL-5, and IL-6. In preliminary experiments, some of these clones specifically inhibited P. yoelii sporozoite development in vitro and conferred protection in vivo in passive transfer experiments. These findings show that heterogenous T cell populations are activated in mice upon immunization with a short peptide from the P. yoelii CS protein and that some of these cells could be active in the effector arm of the immune response against malaria sporozoites.
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PMID:Peptide-primed CD4+ cells and malaria sporozoites. 170 50

V gamma 9+ T cells from malaria non-exposed donors make proliferative responses to Plasmodium falciparum on in vitro stimulation. V gamma 9+ cells are strongly activated by components of the schizont stage of the parasite and by antigens released into the culture upon schizogony, while CD4+V gamma 9- cells are stimulated by the earlier stages of the parasite. Using reverse transcriptase-polymerase chain reaction (RT-PCR) we determined mRNA expression for 14 cytokines in highly purified V gamma 9+ cells enriched by positive selection after in vitro stimulation with P. falciparum schizont antigens. Interferon-gamma (IFN-gamma) and Tumor Necrosis Factor-alpha (TNF-alpha) were detected in all samples tested. The majority of samples also expressed TNF-beta, transforming growth factor-beta (TGF-beta) and Interleukin-8 (IL-8). Only occasional samples expressed IL-2, IL-5 and IL-10. Using the ELISPOT assay we found that a large fraction of the reactive V gamma 9+ cells produced IFN-gamma and that gamma delta T cells are the major producers of IFN-gamma in cultures stimulated with schizont antigens. The majority of V gamma 9+ cells in these cultures also express the membrane-bound form of TNF-alpha. Expression of these cytokines speaks for a cytolytic and/or inflammatory role of gamma delta cells in the response to malaria in non-exposed individuals.
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PMID:Cytokine profiles for human V gamma 9+ T cells stimulated by Plasmodium falciparum. 750 22

Acute Plasmodium yoelii murine malaria is associated with a marked depression of splenic T cell responses. The present study was undertaken to address the question if a defect in T cell proliferation results from a relative increase of a non-T cell population in the spleen or real biological changes occurring in T cells of the spleen after infection. When animals were acutely infected, the splenic cells responded poorly to cross-linked anti-CD3 mAb, Con A, and PWM stimulation. At this stage, a very limited array of cytokine was expressed. We failed to detect the transcripts for IL-2R p55, IL-2, IL-6, IL-10, and IFN-gamma in mice with acute P. yoelii malaria irrespective of the number of splenocytes subjected to RT-PCR. In contrast, late in the infection when mice cleared the parasites and became resistant to reinfection, mRNAs for the above cytokines as well as for IL-4, IL-5, GM-CSF, and TNF-alpha were detectable. During this late phase of infection, lymphocytes proliferated vigorously in response to TCR- and T cell mitogen-mediated stimulation. Surprisingly, during an early phase (as early as 3 days postinfection) with low parasitemia, before the establishment of T cell unresponsiveness, a broad array of cytokine expression including IL-2 and IFN-gamma expression as well as marked lymphoproliferative response upon T cell mitogen- and TCR-mediated stimulation was observed. When the expression of cytokine gene in freshly isolated (ex vivo) splenocytes from P. yoelii-infected animals was investigated, a similar pattern of cytokine profile was detected. We devised a methodology in which RNA from an increasing number of splenocytes (ranging from 1 to 16 million) was used to compensate for any difference in the frequency of splenic T cells between immune and acutely infected mice and to augment target molecules which could be measured simultaneously by PCR. The data presented in this study led us to speculate that "anergy" or relative increase of a non-T cell population cannot account solely for the T cell unresponsiveness in the acute phase of infection. We suggest that inactivation or/and ablation of reactive T cells may explain T cell hyporesponsiveness during acute malaria.
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PMID:Plasmodium yoelii in mice: differential induction of cytokine gene expression during hyporesponsiveness induction and restimulation. 784 88

The induction of T helper cell subsets during the course of non-lethal or lethal blood-stage Plasmodium chabaudi AS infection was investigated using inbred strains of mice which differ in the level of resistance to this intraerythrocytic parasite. Resistant C57Bl/6 mice experience a non-lethal course of infection characterized by moderate levels of both parasitaemia and anaemia and resolution of primary acute infection by 4 weeks, while susceptible A/J mice experience lethal infection with fulminant parasitaemia and severe anaemia. T helper subset function was assessed during infection by determining the kinetics of spleen cell production in vitro of the Th1-derived cytokine, interferon-gamma (IFN-gamma), and of the Th2-derived cytokine, IL-5, using sandwich ELISAs. Spleen cells from resistant C57Bl/6 mice were found to produce high levels of IFN-gamma within 1 week of infection in response to both the mitogen concanavalin A (Con A) and malaria antigen. Furthermore, CD4+ T cells were found to be the source of IFN-gamma while both CD4+ and CD8+ T cells were found to produce IL-5. Decreased IFN-gamma production after day 10 was concomitant with significant production of IL-5 between 2 and 3 weeks post infection. In contrast, spleen cells from susceptible A/J mice produced high levels of IL-5 within the first week of infection. In addition, these animals were found to have high serum levels of IL-5. These results, thus, confirm previous observations that resolution of primary blood-stage P. chabaudi infection occurs by sequential activation of Th1 CD4+ T cells followed by activation of the Th2 subset, and in addition, suggest that induction of a strong Th2 response early in infection may lead to a severe and lethal course of malaria.
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PMID:Differential induction of helper T cell subsets during blood-stage Plasmodium chabaudi AS infection in resistant and susceptible mice. 809 4

In recent years, cell-mediated immunity against malaria has been the subject of intensive investigation either in humans from malaria endemic areas, or experimental models. Cellular immune mechanisms have been regarded as secondary to humoral immunity but, there is increasing evidence that shows its critical role in protection against blood stage plasmodium parasites. In the context of a large humoral-cellular interaction, T helper lymphocytes and monocytes/macrophages may play a key role in the elimination of plasmodial blood stages, particularly P. falciparum. IL-2, IL-4, IL-5, IFN-gamma cytokines secreted principally by CD4+ T lymphocytes and oxygen and nitrogen radicals produced by activated macrophages, are involved in the control of plasmodial infection. The spleen also plays a very important function in the anti-malarial protection by its increased capacity for filtration/destruction of parasitized red blood cells and by induction of B and T memory lymphocytes. Successful vaccination against malaria needs a choice of plasmodial antigens or B and T immunodominants epitopes able to stimulate plasmodium-specific lymphocytes and functional modification in the spleen.
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PMID:[Cell-mediated immunity and protection against blood stages of Plasmodium falciparum]. 812 17

The design of vaccine strategies in general, and those for malaria in particular, need to take into account the balance of T helper subsets (TH) they induce. The TH1 cells, which secrete interferon-gamma and interleukin-2 (IL-2), are associated with cell-mediated immunity (CMI), rather than humoral responses, and afford protection against intracellular infections, including those caused by parasites. In contrast, the TH2 cells secrete IL-4, IL-5, and IL-10, elicit high titer antibody responses, provide poor CMI, and are often correlated with susceptibility to infection. Depending on the type of TH cell bias required, it is possible to manipulate the immune response to a protein/peptide by 1) using different adjuvants, 2) conjugating the protein to various carriers, 3) immunizing in the presence of cytokines, or 4) using alternative routes of administration. To apply these approaches to malarial vaccines, it is necessary to identify which stage(s) of the parasite to target and what type of TH cell bias is protective against that particular stage. We favor using carriers such as Brucella abortus, which focus the antigen on a specific particle and which can trigger a TH1 cell response.
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PMID:The potential for recruiting immune responses toward type 1 or type 2 T cell help. 817 30

Infection with Plasmodium berghei ANKA (PbA) leads, in susceptible strains of mice, to the development of cerebral malaria (CM), a lethal syndrome that reproduces some features of human CM. To study a possible relationship between genetic susceptibility to CM and the cytokine expression pattern, we quantitatively evaluated gene expression on RNA extracted from various organs of malaria-infected mice, using strains that are susceptible and resistant to CM. Northern blot analysis and semi-quantitative PCR showed that CM is associated with an increased TNF-alpha mRNA accumulation in the brain of mice developing the neurologic complications of CM. An increased IFN-gamma mRNA accumulation and a decreased expression of IL-4 and TGF-beta genes were also observed in mice susceptible to CM. In vitro restimulation studies using crude malarial Ag showed that lymphoid cell proliferation was higher in CM-susceptible than in CM-resistant infected mice. Moreover, susceptible mice produced large amounts of IFN-gamma, in a dose-dependent manner, in response to PbA Ag, whereas cells from resistant mice failed to produce significant amounts of this cytokine. Conversely, IL-2 and IL-4 production was significantly higher in infected CM-resistant mouse cells. No difference was seen in the production of IL-3 and IL-5 between resistant and susceptible PbA-infected mice. Upon stimulation with various malarial Ag, comparable amounts of TNF-alpha were produced by macrophages of either strain of mice. Taken together, these findings indicate that susceptibility to CM resides at the level of T cells rather than macrophages. Furthermore, the cytokine production profile is consistent with a predominant Th1-like response in mice developing cerebral complications of malaria.
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PMID:Profiles of cytokine production in relation with susceptibility to cerebral malaria. 840 39

The development of parasite-specific T-cell lines represents one approach to the potential identification of relevant immunogens in erythrocytic malarial infection. However, the use of parasitized-erythrocyte lysates as antigens inhibits the proliferation of T cells. To circumvent this problem, we preincubated antigen-presenting cells (APCs) from spleens of malaria-naive, BALB/c mice with a Plasmodium vinckei vinckei (hereafter referred to as P. vinckei)-parasitized erythrocyte lysate. APCs were subsequently irradiated and washed prior to being incubated with T lymphocytes from P. vinckei-immune, histocompatible mice. After 8 to 10 cycles of antigenic stimulation and rest, two T-cell lines were analyzed. Both lines were predominantly CD4+. Proliferation assays demonstrated marked lymphocyte blastogenesis to syngeneic but not allogeneic APCs that had preprocessed malarial antigen. Antigen incubated directly with T cells and nonpulsed APCs in vitro did not result in T-cell proliferation. Assays of interleukin-2 (IL-2), IL-4, IL-5, and gamma interferon were compatible with one cell line being predominantly TH1 and the other being TH2. Thus, APCs that have preprocessed malarial antigen and are free of extraneous parasite material induce highly reactive, antigen-specific, major histocompatibility complex-restricted T-cell lines that functionally appear capable of inducing humoral and/or cell-mediated immunity.
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PMID:An approach to development of specific T-lymphocyte lines by use of preprocessed antigens in Plasmodium vinckei vinckei murine malaria. 847 85

Spleen and lymph node cells from Plasmodium yoelii 17X-infected, C57BL/6 (B6), and DBA/2 (D2) mice were cultured in vitro with parasite antigens. The ability of these cells to proliferate was quantified by uptake of [3H]thymidine and ELISA was used to measure secretion of IFN-gamma and IL-5. B6 mice are relatively susceptible to P. yoelii 17X infection compared to D2 mice. Susceptible mouse strains develop higher levels of parasitemia, become more anemic, and take longer to resolve their infections than do resistant strains. Following splenectomy, D2 mice resisted P. yoelii 17X infections as well as did sham-operated controls, but splenectomized B6 mice failed to resolve their infections and all died. Spleen cells from infected mice of either strain were activated in vitro as evidenced by their proliferation in the absence of exogenous antigen. When malaria antigen was added to these cultures, cells from resistant D2 mice responded strongly with increased proliferation, whereas cells from susceptible B6 mice responded weakly, and on Day 14 postinfection, responses were actually suppressed. Mesenteric lymph node cells from infected B6 and D2 mice did not proliferate in the presence or absence of P. yoelii 17X antigen unless the spleen was removed. Following splenectomy, mesenteric lymph node cells from D2 mice, but not B6 mice, proliferated strongly compared to cells from sham-operated controls. IFN-gamma and IL-5 production from spleen and lymph node cells was measured following in vitro stimulation with P. yoelii 17X antigen. Spleen cells from D2 mice produced levels of IFN-gamma increased over those of cells from B6 mice.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasmodium yoelii: cellular immune responses in splenectomized and normal mice. 851 76


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