Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:BIOD00017 (IFN-gamma)
 28,919 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A natural body protein is probably a major cause of the deadliest complication of malaria, a finding that could point toward new methods of treatment. Studies in an experimental model indicate that tumor necrosis factor (TNF), a protein also known as cachectin, is an essential element in highly fatal cerebral malaria. This contention is supported by the following observations. First, during the course of an infection by P. berghei ANKA strain, mice of a CM-susceptible strain express markedly elevated levels of TNF in their serum at the time that neurological signs are evident. Second, in contrast, either mice from nonsusceptible strains, susceptible strains depleted of CD4+ T lymphocytes, or susceptible mice inoculated with malaria organisms incapable of producing CM all fail to express high serum TNF activity. Third, passive immunization against mouse TNF significantly prolong the survival of P. berghei-infected CBA/Ca mice, and prevented the development of neurologic signs to an extent that was highly significant. Treatment with the anti-TNF antibody also prevents the histopathological lesions that are characteristic of CM, i.e. plugging of cerebral vessels by macrophages, lymphoid and parasitized erythrocytes. We have recently shown that this increased TNF release and macrophage accumulation are schematically made of two components, each mediated by different cytokines presumably released by stimulated CD4+ T lymphocytes: (a) a quantitative component: increased accumulation of macrophages results from the concomitant release of IL-3 and GM-CSF, and (b) a qualitative component: macrophage number has not only to be raised, but macrophages need to be activated by IFN-gamma. Thus, CM appears to be the result of a cytokine cascade mediated by the immune response. TNF might also be involved in the pathogenesis of human cerebral malaria. Indeed, we have recently shown that in african children with falciparum malaria, elevated serum concentrations of this molecule are associated with severe neurological involvement and fatal outcome. Clinical trials of treatment with monoclonal anti-TNF antibodies are presently underway in an attempt to reduce mortality and morbidity in african children with cerebral malaria.
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PMID:Essential role of tumor necrosis factor and other cytokines in the pathogenesis of cerebral malaria: experimental and clinical studies. 135 36

CD36 is an 88-kDa glycoprotein that has been identified on platelets, monocytes, and some endothelial cells. Experimental evidence suggests that CD36 mediates the binding of Plasmodium falciparum-infected RBC to a variety of cells, and therefore may play a role in the vascular complications associated with malaria. Additionally, CD36 may also bind the extracellular matrix proteins thrombospondin and collagen. Human umbilical vein endothelial cells have been used in in vitro models examining the binding of P. falciparum RBC to endothelial cells, but they do not consistently express cell surface CD36. Inasmuch as human dermal microvascular endothelial cells (HDMEC) differ in a variety of ways from large vessel endothelial cells, we have examined HDMEC for cell surface expression of CD36 in vivo and in vitro. Direct immunofluorescence of skin showed bright staining of HDMEC with antibody recognizing CD36 and flow cytometric analysis of cultured HDMEC revealed cell surface expression. In contrast, large vessel endothelial cells were not stained with antibody recognizing CD36 in vivo and cultured cells derived from umbilical vein failed to express cell surface CD36 in vitro. Western immunoblots of lysates of HDMEC but not human umbilical vein endothelial cells demonstrated an 88-kDa protein that comigrated with CD36 from platelets. Functional studies demonstrated that adherence of PRBC to HDMEC was inhibited up to 66% by mAb recognizing CD36. Furthermore, the expression of CD36 on HDMEC was increased in a dose- and time-dependent manner by IFN-gamma, and was decreased by protein kinase C agonists. These data demonstrate that HDMEC express functionally active CD36 and this expression can be positively and negatively regulated by soluble factors. This study demonstrates that HDMEC are useful in the study of CD36-mediated binding of PRBC to endothelial cells in vitro and provides further evidence of distinct phenotypic differences between HDMEC and large vessel endothelial cells.
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PMID:Human dermal microvascular endothelial but not human umbilical vein endothelial cells express CD36 in vivo and in vitro. 137 Jan 73

It is now generally accepted that peripheral blood of humans not exposed previously to malaria contains T cells which proliferate vigorously in response to malaria parasites and antigens. Although it has been claimed that these cells express a memory phenotype, their origin is uncertain. We have examined the phenotype and immunological responses of such cells. We confirm that these cells do express the 'memory phenotype', CD45Ro, in that depletion of such cells, but not of CD45Ra (virgin) cells, abrogates the immune response to malaria parasites. In an effort to define the genesis of these responses, numerous malaria-specific T cell clones have been generated from non-exposed individuals. These were tested for reactivity to a large panel of common bacterial, viral, and fungal pathogenic and non-pathogenic organisms. Most clones proliferated vigorously in response to one or more such organisms, while many clones demonstrated smaller but significant degrees of proliferation in response to many different organisms. Our data offers insights into the maintenance of immunological memory. All clones examined were CD3+, CD4+, CD8-, TCR alpha beta+, and TCR delta-. The ratio of TCR alpha beta+ to TCR delta+ cells among peripheral blood lymphocytes increased during polyclonal culture in the presence of parasite. The high frequency of such cells in peripheral blood (1/800-1/9000), and their response to a wide range of geographically different Plasmodium falciparum isolates and clones by both proliferation and lymphokine secretion (predominantly IFN-gamma) with a high degree of sensitivity (less than 1 parasite/microliters blood in some cases) suggests that these cells must be quickly activated following malaria infection. Their contribution to the outcome of the disease (protection/immunopathology) may be significant.
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PMID:'Natural' T cells responsive to malaria: evidence implicating immunological cross-reactivity in the maintenance of TCR alpha beta+ malaria-specific responses from non-exposed donors. 139 Apr 41

Pf72/Hsp70-1, a heat-shock protein of m.w. 72 kDa from Plasmodium falciparum is one of the Ag of interest to be included in a polyvalent vaccine against malaria. It is one of the major immunogens present in a fraction of purified blood stage parasites that elicited protection against experimental infection of Saimiri monkeys with blood stages of P. falciparum. It is present at all blood stages and one of its B cell epitopes is also detected on the surface of the infected hepatocyte. Moreover, Pf72 appears to be well conserved among different isolates of P. falciparum. We have examined the immune response against Pf72/Hsp70-1 in individuals from different age groups living in a holoendemic area (West Africa). The immune response against the native Ag (purified from schizonts and called Pf/Hsp70) was analyzed both at the humoral level by ELISA and at the cellular level by assessing in vitro proliferation and IFN-gamma production of PBMC. Of the individuals studied 52% had a statistically significant level of anti-Pf/Hsp70 antibodies as compared with unexposed individuals. These positive individuals showed a heterogeneous distribution because significant levels of antibodies were found in 70% of the adults but in only 26% of the children. The presence of Pf/Hsp70-specific reactive T cells in the blood was detected in 32% of the individuals. The total anti-Pf/Hsp70 antibody level (IgG+IgM) appeared strongly age related and correlated positively with parasite exposure, whereas the T cell response failed to correlate either with the antibody level or with age. Moreover, PBMC of donors responded to the Pf/Hsp70 in a dissociated way, namely, by either T cell proliferation or IFN-gamma production. Ten synthetic peptides based on sequences found in the C-terminal part of Pf72/Hsp70-1 were further tested as potential T cell epitopes. The proliferative response of PBMC from individuals continuously exposed to the parasite showed that three peptides more frequently trigger significant T cell proliferation (in 21% to 27% of the individuals) and three others less frequently (10%). None of these peptides allowed detection of reactive T cells in PBMC of Europeans with no previous exposure to malaria. Some of the stimulating peptides are highly similar to human heat-shock Hsc and Hsp70 with large stretches of identical amino acids.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Antibodies and reactive T cells against the malaria heat-shock protein Pf72/Hsp70-1 and derived peptides in individuals continuously exposed to Plasmodium falciparum. 143 Nov 9

Clone B is a cytotoxic T cell clone induced by immunization with Plasmodium yoelii sporozoites which recognizes an epitope on both the P. yoelii and Plasmodium berghei circumsporozoite proteins. It is CD8, uses the V beta 8.1 TCR, and is Kd restricted. When adoptively transferred, it protects mice against infection by both species of malaria sporozoites, and this protection is dependent on IFN-gamma. Clone B cells are more broadly reactive and protective than previously described murine T cell clones against malaria. Clone B may be an important model for immune protection against the spectrum of variant parasites in nature.
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PMID:A T cell clone directed at the circumsporozoite protein which protects mice against both Plasmodium yoelii and Plasmodium berghei. 151 74

Comprehension of the involvement of cytokines in the host response against invading parasites, to the detriment of the parasite and (in larger doses) to the host, is expanding rapidly. Most of these studies, largely for historic reasons and availability, have been done with TNF rather than the other mediators. As is emerging in other fields, study of interleukin-1 alone, and synergistically with TNF and IFN-gamma, warrants further exploration in parasitic diseases. There may well be a similar story for TNF-beta, waiting to unfold. It is appropriate here to show deference to earlier malariologists, back to the nineteenth century, whose observations and reasoning were evidently accurate when they attributed malarial illness and pathology (including cerebral malaria) to a malarial toxin (reviewed by Clark and Tomlinson, 1949). The only additional insight required of present-day workers has been to see the malaria parasite not as a source of a direct toxin, but of molecules, harmless in themselves, that can act as a trigger for toxic products of host origin. As a final twist, low concentrations of these host-derived "toxins" are not only harmless, but necessary for normal biological functions. They are deleterious only when overproduced.
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PMID:Roles of TNF in malaria and other parasitic infections. 155 Aug 69

Plasma and peripheral blood mononuclear cells (PBMC) were obtained from P. falciparum-infected individuals with and without the sickle cell trait at diagnosis and 7 days after treatment. HbAA and HbAS patients were compared for levels of plasma soluble IL-2 receptors (IL-2R) and the in vitro cellular reactivity to affinity-purified soluble P. falciparum antigens (SPAg), PPD and phytohaemagglutinin (PHA). At diagnosis, HbAS patients with clinical disease had lower plasma-soluble IL-2R levels and parasite counts than the corresponding HbAA patients, whereas HbAS and HbAA patients with asymptomatic infections had comparable soluble IL-2R levels and parasite counts. PBMC from HbAS patients had higher proliferation and IFN-gamma production in response to SPAg than PBMC from HbAA patients. The difference in the lymphoproliferative responses to SPAg between the two groups was evident in patients with asymptomatic infections. In all patients, the clinical severity, the soluble IL-2R levels and the parasite counts were directly related. The former two were inversely related to the proliferative responses to SPAg. After treatment, all the studied parameters were comparable in the two groups. The study indicates that during P. falciparum infection, HbAS compared with HbAA patients had lower in vivo cellular activation and higher in vitro cellular reactivity in response to soluble malaria antigens.
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PMID:Modulation of the cellular immune response during Plasmodium falciparum infections in sickle cell trait individuals. 156 96

Serum cytokine profiles were evaluated in immunized and nonimmunized human volunteers after challenge with infectious Plasmodium falciparum sporozoites. Three volunteers had been immunized with x-irradiated sporozoites and were fully protected from infection. Four nonimmune volunteers all developed symptomatic infection at which time they were treated. Sera from all volunteers were collected at approximately 20 time points during the 28-d challenge period; levels of IL-1 alpha, IL-1 beta, IL-2, IFN-gamma, tumor necrosis factor-alpha, IL-4, IL-6, granulocyte macrophage-colony-stimulating factor, and soluble CD4, CD8, and IL-2 receptor (sCD4, sCD8, and sIL-2R, respectively) were determined by ELISA. C-reactive protein (CRP) was assayed by radial immunodiffusion. Parasitemic subjects developed increases in CRP and IFN-gamma, with less marked increases in sIL-2R and sCD8; the other cytokines tested did not change. CRP increases were abrupt and occurred at the onset of fever (day 14 after challenge). IFN-gamma increases were also abrupt, preceding those of fever and CRP by one day. Increases in sIL-2R and sCD8 were more gradual. Increases in fever, CRP, IFN-gamma, and sCD8 were concordant in each volunteer. Early IL-6 increases were noted in the protected vaccinees. Thus, after challenge with virulent P. falciparum, unique systemic cytokine profiles were detectable both in immunized, nonparasitemic volunteers and in unvaccinated, parasitemic subjects. The contrasting cytokine profiles in the two groups may relate to mechanisms of protection and immunopathology in experimental human malaria.
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PMID:Serum cytokine profiles in experimental human malaria. Relationship to protection and disease course after challenge. 164 22

A longitudinal study was conducted between October 1989 and February 1990 in a malaria holoendemic area of Gabon to determine the plasma concentration of various cytokines in individuals continuously exposed to infection with malaria parasites. No cases of severe malaria were seen and fever was the main presenting symptom of clinical malaria. Parasite rates were highest in children 6-9 years old but clinical malaria was seen essentially in children below 6 years of age. The incidence of clinical malaria was highest in November and February corresponding to the beginning and end of heavy rains respectively. Parasite rates did not show any seasonal variations. Overall, there was no seasonal variation in plasma cytokine levels but both IL-6 and IL-4 levels were highest in February. Plasma concentration of TNF-alpha and IFN-gamma were higher in parasitaemic than aparasitaemic individuals and donors who had clinical malaria had higher levels of TNF-alpha, IFN-gamma and IL-6 than asymptomatic parasitaemic donors. There was a negative correlation between age of the individual and the concentration of plasma TNF-alpha and IFN-gamma suggesting that the production of these cytokines could be modulated by repeated malarial infections. Asymptomatic parasitaemic children 5-7 years of age had higher levels of plasma TNF-alpha than clinically similar children below or above this age group suggesting that refractoriness to the clinical effects of TNF-alpha may be an important factor in the ability of these children to resist clinical malaria.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cytokines in the pathogenesis of malaria: levels of IL-I beta, IL-4, IL-6, TNF-alpha and IFN-gamma in plasma of healthy individuals and malaria patients in a holoendemic area. 166 45

Secretion of gamma interferon (IFN-gamma) in response to stimulation of Plasmodium falciparum-primed T cells by specific antigens may be a useful indicator of cellular immunity to malaria. An enzyme-linked immunospot (ELISPOT) assay designed to detect IFN-gamma at the single-cell level was used to study IFN-gamma-producing cells from P. falciparum-primed donors from The Gambia after in vitro stimulation with various malarial antigens. IFN-gamma secreted into the culture supernatant was measured by conventional enzyme-linked immunosorbent assay (ELISA). There was a good correlation in individual donors between the level of IFN-gamma secreted into the culture supernatant and the number of IFN-gamma-secreting cells. However, the ELISPOT assay was apparently more sensitive in demonstrating low levels of IFN-gamma production than the ELISA was. Thus after stimulation with crude P. falciparum antigen from infected erythrocytes, 72% of the primed donors responded positively in the ELISPOT assay but only 55% responded positively in the ELISA. When stimulated with synthetic peptides representing immunodominant epitopes of the malarial antigen Pf155/RESA, a vaccine candidate, 31 to 55% responded in the ELISPOT assay and 21 to 36% responded in the ELISA. Unprimed Europeans did not respond positively to these antigens in either of the assays, and background in antigen-free controls was generally low. These results indicate that measurement of IFN-gamma by the ELISPOT assay or ELISA should have wide applications in large-scale epidemiological studies of malaria immunity. In addition, the ELISPOT assay makes it possible to analyze the T cells responding to malarial antigens in terms of both numbers and functional heterogeneity.
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PMID:Number of cells from Plasmodium falciparum-immune donors that produce gamma interferon in vitro in response to Pf155/RESA, a malaria vaccine candidate antigen. 169 35


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