Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Recent studies have implicated cytokines associated with CD4+ T lymphocytes of both T helper (Th)1 and Th2 subsets in resistance to experimental blood stage malaria. As the B7/CD28 costimulatory pathway has been shown to influence the differentiation of Th cell subsets, we investigated the contribution of the B7 molecules CD80 and CD86 to Th1/Th2 cytokine and immunoglobulin isotype profiles and to the development of a protective immune response to malaria in NIH mice infected with Plasmodium chabaudi. Effective blockade of CD86/CD28 interaction was demonstrated by elimination of interleukin (IL)-4 and up-regulation of interferon (IFN)-gamma responses by P. chabaudi-specific T cells and by reduction of P. chabaudi-specific immunoglobulin G1 (IgG1). The shift towards a Th1 cytokine pattern corresponded with efficient control of acute parasitaemia but an inability to resolve chronic infection. Moreover, combined CD80/CD86 blockade by using anti-CD80 and anti-CD86 monoclonal antibodies raised IFN-gamma production over that seen with CD86 blockade alone, with augmentation of this Th1-associated cytokine reducing levels of peak primary parasitaemia. These results demonstrate that IL-4 production by T cells in P. chabaudi-infected NIH mice is dependent upon CD86/CD28 interaction and that IL-4 and IFN-gamma contribute significantly, at different times of infection, to host resistance to blood stage malaria. In addition, combined CD80/CD86 blockade resulted in preferential expansion of IFN-gamma-producing T cells during P. chabaudi infection, suggesting that costimulatory pathways other than B7/CD28 may contribute to T-cell activation during continuous antigen stimulation. This study indicates a role for B7/CD28 costimulation in modulating the CD4+ T-cell response during malaria, and further suggests involvement of this pathway in other infectious and autoimmune diseases in which the Th cell immune response is also skewed.
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PMID:Modulation of experimental blood stage malaria through blockade of the B7/CD28 T-cell costimulatory pathway. 1023 33

Since the rhesus is often used as a "gatekeeper" model for the evaluation of malaria and simian immunodeficiency virus (SIV)/HIV vaccines, the identification of strategies to enhance the activation of rhesus T cells would potentially aid in the generation of more potent vaccines directed against these infectious agents. Several molecules normally found on the surface of professional human APCs are capable of providing the second signals critical for T cell activation: B7-1 (CD80), ICAM-1 (CD54), and LFA-3 (CD58). With the exception of B7, T cell costimulatory molecules in the rhesus have not been identified. We have recently designed and characterized both recombinant vaccinia and recombinant avipox vectors containing the transgenes for a triad of human T cell costimulatory molecules (B7-1, ICAM-1, LFA-3; designated TRICOM). Here, we demonstrate the enhanced activation of rhesus T cells stimulated with rhesus APCs infected with TRICOM vectors in the presence of signal 1. Infection with TRICOM vectors led to significant improvement of APC capabilities in terms of reduction of the amount of signal 1 needed to activate naive T cells, and reduction in the amount of APCs required to activate T cells using a constant amount of signal 1. Antibody blocking studies demonstrated that each of the three costimulatory molecule transgenes contributed to the enhanced proliferation of T cells. TRICOM-enhanced T cell activation was shown to correspond to increases in type 1 cytokines and a reduced level of apoptosis. TRICOM-infected autologous B cells from rhesus immunized with either an SIV vaccine or a malaria vaccine stimulated significantly greater levels of IFN-gamma in response to specific peptide than stimulation with uninfected autologous B cells or B cells infected with wild-type vector. The ability to augment immune responses using poxvirus-based vaccines containing multiple costimulatory molecule transgenes can now be addressed in the rhesus macaque model.
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PMID:Enhanced activation of rhesus T cells by vectors encoding a triad of costimulatory molecules (B7-1, ICAM-1, LFA-3). 1173 38

Antigen-presenting cells (APC) play a key role in orchestrating immune responses. T-cell proliferative responses are inhibited during the erythrocyte stages of malaria infection, and a number of studies have suggested that APC are responsible for this phenomenon. In the present studies we examine individual components of the T-cell-activating function of APC: expression of costimulatory and major histocompatibility complex (MHC) class II proteins, the ability to process and present antigen to T cells, and the ability to support cytokine production. We find that during the acute phases of Plasmodium yoelii erythrocyte stage infection, APC upregulate the expression of class II MHC and CD80, maintain expression of CD86, process and present antigen, and support gamma interferon production. However the CD11b(+) subpopulation produces a soluble factor or factors that specifically inhibit interleukin-2 (IL-2) production by responding CD4 T cells. This factor is distinct from prostaglandin E(2), NO, or transforming growth factor beta. The data suggest that IL-2 suppression observed during malaria infection is not due to functional defects of APC but is triggered by production of a factor(s) that actively suppresses production of IL-2 by T cells.
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PMID:Antigen-presenting cell function during Plasmodium yoelii infection. 1201 Sep 83

Plasmodium yoelli sporozoite surface protein 2 (pySSP2) is considered as an important antigen for protection studies in malaria vaccine development. For the liver stage protection, anti-pySSP2 cytotoxic T lymphocyte (CTL) activity in BALB/c mice was investigated by immunization of genetically engineered bone marrow-derived dendritic cells (DCs) expressing pySSP2 peptides. Retrovirus-transfected bone marrow cells cultured with GMCSF and IL-4 for 7 days demonstrated 70-80% of DCs with high CD11c, CD80, CD86, and MHC class I (I-Kd) expression. Dividing bone marrow cells were infected with retrovirus expressing SSP2 on fifth, sixth, and seventh days of culture by prolonged centrifugation for 1 h at 32 degrees C. Transfection efficacy of DCs was assessed using retrovirus-shuttled green fluorescence vector (pMSCV-EGFP neo). A total of 64% of CD11c positive transfected DCs showed green fluorescence. The degree of SSP2 expression in transfected DCs was assessed by immunoprecipitation with SSP2 antibody. Both SSP2 and EGFP transfected DCs had prolonged expression of the engineered gene until day 6 since the transfection. Antigen presentation to nai;ve CTLs was assessed by immunization of retrovirus-infected DCs into BALB/c mice. Kd restricted, antigen-specific two new MHC class I (I-Kd) binding motifs were identified (A and C) in pySSP2 protein. Both A and C induced peptide-specific, IFN-gamma-secreting cytolytic CTLs upon antigen recognition on target cells. Taken together, these data indicate that genetically modified DCs by prolonged centrifugation is effective in enhanced antigen presentation. Immunization of DCs encoding SSP2 gene resulted in identification of two K(d) restricted CTL epitopes and induction of IFN-gamma-secreting cytolytic CD8+ T cells.
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PMID:Immunization of retrovirus-transfected dendritic cells induces specific cytotoxic T lymphocytes for two distinct malarial peptides presented by Kd molecule. 1294 36

Soluble or sub-unit protein vaccines alone are incapable of generating antigen-specific cellular immune responses. This failure can be attributed to the manner in which the immune system processes antigen; endogenous antigens are cycled through the MHC class I pathway to stimulate CD8+ restricted responses and exogenous antigens are processed through the MHC class II pathway to generate humoral immunity. Traditionally sub-unit vaccines have been formulated with adjuvants to enhance immunogenicity, however in the last decade a number of adjuvants have been developed that effectively stimulate the generation of both humoral and cellular immune responses, although the manner in which they exert their effects has not been investigated. Here we describe Tomatine, a glycoalkaloid based adjuvant, capable of stimulating potent antigen-specific humoral and cellular immune responses that contribute to protection against malaria, Francisella tularensis and regression of experimental tumors. Using in vivo models we investigated the manner in which cellular immune responses were generated by Tomatine. We established that Tomatine did not require either lymph node or splenic macrophages to generate cytotoxic T lymphocytes (CTL) and delivered soluble protein into a pathway not dependant on the machinery of the classical MHC class I pathway. We also observed that at the molecular level Tomatine required both CD80 and CD86 costimulation to engender antigen-specific cellular immunity.
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PMID:Immunobiology of the Tomatine adjuvant. 1519 98

Acute and chronic Plasmodium falciparum malaria are accompanied by severe immunodepression possibly related to subversion of dendritic cells (DC) functionality. Phagocytosed hemozoin (malarial pigment) was shown to inhibit monocyte functions related to immunity. Hemozoin-loaded monocytes, frequently found in circulation and adherent to endothelia in malaria, may interfere with DC development and play a role in immunodepression. Hemozoin-loaded and unloaded human monocytes were differentiated in vitro to immature DC (iDC) by treatment with GM-CSF and IL-4, and to mature DC (mDC) by LPS challenge. In a second setting, hemozoin was fed to iDC further cultured to give mDC. In both settings, cells ingested large amounts of hemozoin undegraded during DC maturation. Hemozoin-fed monocytes did not apoptose but their differentiation and maturation to DC was severely impaired as shown by blunted expression of MHC class II and costimulatory molecules CD83, CD80, CD54, CD40, CD1a, and lower levels of CD83-specific mRNA in hemozoin-loaded iDC and mDC compared with unfed or latex-loaded DC. Further studies indicated activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) in hemozoin-loaded iDC and mDC, associated with increased expression of PPAR-gamma mRNA, without apparent involvement of NF-kappaB. Moreover, expression of PPAR-gamma was induced and up-regulation of CD83 was inhibited by supplementing iDC and mDC with plausible concentrations of 15(S)-hydroxyeicosatetraenoic acid, a PPAR-gamma ligand abundantly produced by hemozoin via heme-catalyzed lipoperoxidation.
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PMID:Hemozoin (malarial pigment) inhibits differentiation and maturation of human monocyte-derived dendritic cells: a peroxisome proliferator-activated receptor-gamma-mediated effect. 1535 56

Helminthiases, which are highly prevalent in areas where malaria is endemic, have been shown to modulate or suppress the immune response to unrelated antigens or pathogens. In this study, we established a murine model of coinfection with a gastrointestinal nematode parasite, Heligmosomoides polygyrus, and the blood-stage malaria parasite Plasmodium chabaudi AS in order to investigate the modulation of antimalarial immunity by concurrent nematode infection. Chronic infection with the nematode for 2, 3, or 5 weeks before P. chabaudi AS infection severely impaired the ability of C57BL/6 mice to control malaria, as demonstrated by severe mortality and significantly increased malaria peak parasitemia levels. Coinfected mice produced significantly lower levels of gamma interferon (IFN-gamma) during P. chabaudi AS infection than mice infected with malaria alone. Concurrent nematode infection also suppressed production of type 1-associated, malaria-specific immunoglobulin G2a. Mice either infected with the nematode alone or coinfected with the nematode and malaria had high transforming growth factor beta1 (TGF-beta1) levels, and concurrent nematode and malaria infections resulted in high levels of interleukin-10 in vivo. Splenic CD11c(+) dendritic cells (DC) from mice infected with malaria alone and coinfected mice showed similarly increased expression of CD40, CD80, and CD86, but DC from coinfected mice were unable to induce CD4(+) T-cell proliferation and optimal IFN-gamma production in response to the malaria antigen in vitro. Importantly, treatment of nematode-infected mice with an anthelmintic drug prior to malaria infection fully restored protective antimalarial immunity and reduced TGF-beta1 levels. These results demonstrate that concurrent nematode infection strongly modulates multiple aspects of immunity to blood-stage malaria and consequently impairs the development of protective antimalarial immunity.
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PMID:Impairment of protective immunity to blood-stage malaria by concurrent nematode infection. 1590 82

Multi-factorial immune mechanisms underlie protection induced with radiation-attenuated Plasmodia sporozoites (gamma-spz). Spz pass through Kupffer cells (KC) before invading hepatocytes but the involvement of KC in protection is poorly understood. In this study we investigated whether gamma-spz-immune KC respond to infectious spz in a manner that is distinct from the response of naive KC to infectious spz. KC were isolated from (1) naive, (2) spz-infected, (3) gamma-spz-immune, and (4) gamma-spz-immune-challenged C57BL/6 mice and examined for the expression of MHC class I and II, CD40 and CD80/CD86, IL-10 and IL-12 responses and antigen-presenting cell (APC) function. KC from gamma-spz-immune-challenged mice up-regulated class I and costimulatory molecules and produced elevated IL-12p40, relative to naive KC. In contrast, KC from naive mice exposed to infectious spz down-modulated class I and IL-12p40 was undetectable. Accordingly, KC from spz-infected mice had reduced APC function, while KC from gamma-spz-immune-challenged mice exhibited augmented APC activity. The nearly opposite responses are consistent with the fact that spz challenge of gamma-spz-immune mice results in long-lasting sterile protection, while infection of naive mice always results in malaria.
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PMID:The immune status of Kupffer cells profoundly influences their responses to infectious Plasmodium berghei sporozoites. 1599 65

There is a pressing need for adjuvants that will enhance the effectiveness of genetic vaccines. This is particularly important in cancer and infectious disease such as HIV and malaria for which successful vaccines are desperately needed. Here, we describe an approach to enhance immunogenicity that involves the activation of NF-kappaB by the transgenic expression of an intracellular signaling molecule, NF-kappaB-inducing kinase (NIK). In vitro, NIK increases dendritic cell antigen presentation in allogeneic and antigen-specific T cell proliferation assays by potently activating NF-kappaB and consequently up-regulating the expression of cytokines (TNF-alpha, IL-6, IL-12, IL-15, and IL-18), chemokines [IL-8, RANTES (regulated on activation, normal T cell expressed and secreted), macrophage inflammatory protein-1alpha, monocyte chemoattractant protein-1, and monocyte chemoattractant protein-3], MHC antigen-presenting molecules (class I and II), and costimulatory molecules (CD80 and CD86). In vivo, NIK enhances immune responses against a vector-encoded antigen and shifts them toward a T helper 1 immune response with increased IgG2a levels, T cell proliferation, IFN-gamma production, and cytotoxic T lymphocyte responses more potently than complete Freund's adjuvant, a very efficacious T helper 1-inducing adjuvant. These findings define NIK, and possibly other inducers of NF-kappaB activation, as a potent adjuvant strategy that offers great potential for genetic vaccine development.
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PMID:Activation of NF-kappaB by the intracellular expression of NF-kappaB-inducing kinase acts as a powerful vaccine adjuvant. 1697 87

Polyclonal B-cell activation is a feature of the early spleen cell response to blood-stage Plasmodium chabaudi malaria. Immunity to blood-stage malaria is guaranteed by the generation of B cells able to produce parasite-specific antibodies mainly from the immunoglobulin (Ig)G2a isotype. In the present study, we characterized the spleen B-cell compartment during blood-stage P. chabaudi infection. The numbers of B220(+) and B220(LOW) CD138(+) (plasma) cells increased sharply between days 4 and 7 post-infection (p.i.). At this time B220(+) cells expressed surface (s)IgM, but nearly all B220(LOW) CD138(+) cells showed concomitantly intracellular (i)IgM and IgG2a. Both follicular and marginal zone B cells were activated expressing high amounts of CD69. At day 40 p.i., B220(LOW) CD138(+) cell population was still increased but, differently from acute infection, 61.1% of these cells were positive for iIgG2a while only 14.2% expressed iIgM. Moreover, at days 20 and 40 p.i., 29.2% and 13.0% of B220(+) cells expressed sIgG2a, respectively. According to cell size and expression of CD80, CD86, CD11b, CD44 and CD38, B220(+) sIgG2a(+) cells had a phenotype characteristic of activated/memory B cells. Furthermore, 14.1% of B220(+) sIgG2a(+) cells at day 30 p.i. expressed a marginal zone B-cell phenotype. Importantly, B cells from 40-day-infected mice were very efficient in presenting parasite antigens leading to proliferation of both CD4(+) and CD8(+) cells. Our results contribute for understanding the dynamics of B cells during P. chabaudi infection, underlying the mechanisms of antigen presentation and antibody production, which are essential for the acquisition of protective immunity against malaria.
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PMID:Characterization of the spleen B-cell compartment at the early and late blood-stage Plasmodium chabaudi malaria. 1763 8


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