bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in cytokine production associated with acquired immunity toPlasmodium falciparummalaria
Authors: Rhee M S M , Akanmori B D , Waterfall M , Riley E M 
Published: March 2003

SummaryIndividuals living in malaria-endemic areas eventually develop clinical immunity to Plasmodium falciparum. That is, they are able to limit blood parasite densities to extremely low levels and fail to show symptoms of infection. As the clinical symptoms of malaria infection are mediated in part by pro-inflammatory cytokines it is not clear whether the acquisition of clinical immunity is due simply to the development of antiparasitic mechanisms or whether the ability to regulate inflammatory cytokine production is also involved. We hypothesize that there is a correlation between risk of developing clinical malaria and the tendency to produce high levels of proinflammatory cytokines in response to malaria infection. In order to test this hypothesis, we have compared the ability of peripheral blood mononuclear cells from malaria-naive and malaria-exposed adult donors to proliferate and to secrete IFN-γ in response to P. falciparum schizont extract (PfSE). In order to determine how PfSE-induced IFN-γ production is regulated, we have also measured production of IL-12p40 and IL-10 from PfSE-stimulated PBMC and investigated the role of neutralizing antibody to IL-12 in modulating IFN-γ production. We find that cells from naive donors produce moderate amounts of IFN-γ in response to PfSE and that IFN-γ production is strongly IL-12 dependent. Cells from malaria-exposed donors living in an area of low malaria endemicity produce much higher levels of IFN-γ and this response is also at least partially IL-12 dependent. In complete contrast, cells from donors living in an area of very high endemicity produce minimal amounts of IFN-γ. No significant differences were detected between the groups in IL-10 production, suggesting that this cytokine does not play a major role in regulating malaria-induced IFN-γ production. The data from this study thus strongly support the hypothesis that down-regulation of inflammatory cytokine production may be a component of acquired clinical immunity to malaria but the mechanism by which this is achieved remains to be elucidated.
The frequency of CLA+ CD8+ T cells in the blood of psoriasis patients correlates closely with the severity of their disease
Authors: Sigmundsdóttir H , Gudjónsson J E , Jónsdóttir I , Lúdvíksson B R , Valdimarsson H 
Published: March 2003

SummaryPsoriasis is thought to be a T cell-mediated skin disease and the cutaneous lymphocyte antigen (CLA) is an important skin homing epitope for T cells. We have studied the relationship between disease severity (PASI) and phenotypic analysis of T cells in the blood of 36 patients with psoriasis focusing on the expression of CLA, VLA-4 and CD25 on CD4+ and CD8+ T cells. The patients had a higher frequency of circulating CLA+ CD8+ cells than healthy controls. Furthermore, a much stronger correlation was observed between PASI and the frequency of CLA+ CD8+ than CLA+ CD4+ T cells. The frequency of CLA+D8+ T cells correlated more strongly with redness, thickness and scaling of the skin lesions than the total affected body surface area. In contrast to CLA the T cell expression of VLA-4 did not demonstrate any such correlation. Finally, the expression of the activation marker CD25 on CD8+ T cells showed a strong correlation with disease severity in patients with moderate to severe psoriasis (PASI &gt; 10) but such correlation was not observed for CD4+ T cells. These findings support the notion that circulating CLA+ CD8+ T cells may play an important role in the pathogenesis of psoriasis.
Evidence of a role for CD200 in regulation of immune rejection of leukaemic tumour cells in C57BL/6 mice
Authors: Gorczynski R M , Chen Z , Hu J , Kai Y , Lei J 
Published: March 2003

SummaryIncreased expression of the molecule CD200 in mice receiving renal allografts is associated with immunosuppression leading to increased graft survival, and altered cytokine production in lymphocytes harvested from the transplanted animals. Preferential production of IL-4, IL-10 and TGFβ occurs on donor-specific restimulation in vitro, with decreased production of IL-2, IFNγ and TNFα. These effects are enhanced by simultaneous infusion of CD200 immunoadhesin (CD200Fc) and donor CD200 receptor (CD200r) bearing macrophages to transplanted mice. C57BL/6 mice do not normally resist growth of EL4 or C1498 leukaemia tumour cells. Following transplantation of cyclophosphamide-treated C57BL/6 with T-depleted C3H bone marrow cells, or for the EL4 tumour, immunization of C57BL/6 mice with tumour cells transfected with a vector encoding the co-stimulatory molecule CD80 (EL4-CD80), mice resist growth of tumour challenge. Immunization of C57BL/6 mice with EL4 cells overexpressing CD86 (EL4-CD86) is ineffective. Protection from tumour growth in either model is suppressed by infusion of CD200Fc, an effect enhanced by co-infusion of CD200r+ macrophages. CD200Fc acts on both CD4+ and CD8+ cells to produce this suppression. These data are consistent with the hypothesis that immunosuppression following CD200–CD200r interaction can regulate a functionally important tumour growth inhibition response in mice.
Involvement of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in the pathogenesis of granulomatous colitis in rats
Authors: Hokari R , Kato S , Matsuzaki K , Iwai A , Kawaguchi A , Nagao S , Miyahara T , Itoh K , Sekizuka E , Nagata H , Ishii H , Iizuka T , Miyasaka M , Miura S 
Published: March 2003

SummaryAlthough increased expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) has been demonstrated in inflammatory sites of various diseases, its role in colitis remains unknown. In this study, we examined whether MAdCAM-1 is involved in the pathogenesis of granulomatous colitis induced by peptidoglycan-polysaccharide (PG-PS). Experimental colitis was induced by intramural injection of PG-PS to rat colon. After 3 weeks the colon was removed and the mucosal inflammation was assessed. The area of MAdCAM-1-positive venules and the subsets of infiltrating cells were determined in colonic mucosa by immunohistochemistry. In another experiment, monoclonal antibody against MAdCAM-1 was administered intraperitoneally to examine its attenuating effect on colitis. The intramural injection of PG-PS induced significant colonic inflammation with granuloma formation. The submucosa was drastically thickened with the infiltration of CD4 positive lymphocytes and ED-1 positive macrophages. Intense MAdCAM-1 expression was observed on endothelium of the submucosal venules in inflamed mucosa. Administration of anti-MAdCAM-1 antibody significantly attenuated the PG-PS-induced colonic damage and cell infiltration. Enhanced expression of MAdCAM-1 was demonstrated in venular endothelium of the inflamed colon in PG-PS-induced colitis. The attenuating effect of anti-MAdCAM-1 suggests the importance of the MAdCAM-1-dependent process in the formation of chronic granulomatous colitis.
Differential roles of osteopontin/Eta-1 in early and late lpr disease
Authors: Weber G F , Cantor H 
Published: March 2003

SummaryThe cytokine osteopontin (Eta-1) leads to macrophage-dependent polyclonal B-cell activation and is induced early in autoimmune prone mice with the lpr mutation, suggesting a significant pathogenic role for this molecule. Indeed, C57BL/6-Faslpr/lpr mice crossed with osteopontin−/– mice display delayed onset of polyclonal B-cell activation, as judged by serum immunoglobulin levels. In contrast, they are subject to normal onset, but late exacerbation of lymphoproliferation and evidence of kidney disease. These observations define two stages of Faslpr/lpr disease with respect to osteopontin-dependent pathogenesis that should be taken into account in the design of therapeutic approaches to the clinical disease.
IL-1ra and IL-1 production in human oral mucosal epithelial cells in culture: differential modulation by TGF-β1 and IL-4
Authors: Perrier S , Kherratia B , Deschaumes C , Ughetto S , Kemeny J -L , Baudet-Pommel M , Sauvezie B 
Published: March 2003

SummaryRegulatory cytokines mediate the participation of oral mucosal epithelial cells (OMEC) in local immune responses. The aim of this study was to characterize the isoforms of IL-1 receptor antagonist (IL-1ra) in cultured human primary OMECs and to compare its production with that of IL-1 alpha (IL-1α) and IL-1 beta (IL-1β). Western blot analysis showed that IL-1ra was 22 kDa in size hence slightly smaller than monocyte IL-1ra (25 kDa). A minor form of 20 kDa was also found in unstimulated cell culture lysates. In culture supernatants, IL-1 bioactivity increased after IL-1ra neutralization, indicating that the baseline production of IL-1ra is biologically relevant. Immunohistochemistry showed a relation between IL-1ra and involucrin expressions, suggesting that intracytoplasmic IL-1ra may be involved in cell terminal differentiation. In unstimulated culture lysates, there was far more IL-1ra than IL-1α and IL-1β. TGF-β1 markedly increased the IL-1ra/IL-1β ratio from 93·6 : 1 to 300 : 1. IL-4, which is generally described as an anti-inflammatory cytokine, increased IL-1 but not IL-1ra production. TNF-α increased intracellular production of the three IL-1 members. IL-1ra levels were lower in supernatants than in lysates of cultured cells. Our results show that human OMECs constitutively produce significant amounts of a biologically active form of IL-1ra. TGF-β1 µp-regulation points to a positive amplification loop and IL-4 to a down-regulation loop, both including Th2 cells and OMECs. They may be important in oral tolerance and IgA production, respectively.
Cytokine production and apoptosis among T cells from patients under treatment forPlasmodium falciparummalaria
Authors: Kemp K , Akanmori B D , Adabayeri V , Goka B Q , Kurtzhals J A L , Behr C , Hviid L 
Published: March 2003

SummaryAvailable evidence suggests that Plasmodium falciparum malaria causes activation and reallocation of T cells, and that these in vivo primed cells re-emerge into the periphery following drug therapy. Here we have examined the cytokine production capacity and susceptibility to programmed cell death of peripheral T cells during and after the period of antimalarial treatment. A high proportion of peripheral CD3+ cells had an activated phenotype at and shortly after time of admission (day 0) and initiation of therapy. This activation peaked around day 2, and at this time-point peripheral T cells from the patients could be induced to produce cytokines at conditions of limited cytokine response in cells from healthy control donors. Activated CD8hi and TCR-γδ+ cells were the primary IFN-γ producers, whereas CD4+ cells constituted an important source of TNF-α. The proportion of apoptotic T cells was elevated at admission and peaked 2 days later, while susceptibility to activation-induced cell death in vitro remained increased for at least 1 week after admission. Taken together, the data are consistent with the concept of malaria-induced reallocation of activated T cells to sites of inflammation, followed by their release back into the peripheral blood where they undergo apoptotic death to re-establish immunological homeostasis as inflammation subsides. However, the high proportion of pre-apoptotic cells from the time of admission suggests that apoptosis also contributes to the low frequency and number of T cells in the peripheral circulation during active disease.
Thymic re-entry of mature activated T cells and increased negative selection in vascularized allograft recipients
Authors: Chau L A , Rohekar S , Wang J-J , Lian D , Chakrabarti S , Zhang L , Zhong R , Madrenas J 
Published: March 2003

SummaryTransplantation tolerance is a dynamic state that involves several homeostatic mechanisms intrinsic to the host. One of these mechanisms is activation-induced T cell death (AICD). However, it is unclear where AICD takes place during alloreactive responses. Since activated T cells can re-enter the thymus, we hypothesized that mature T cells activated by an allograft could be deleted upon re-entry into the thymus. To test this hypothesis, we used wild-type or 2C TCR transgenic mice receiving syngeneic or allogeneic heterotopic, vascularized heart grafts. First, we demonstrated that ex vivo CFSE-labelled T cells re-entered the thymus when transferred into allograft recipients but not when transferred into isograft recipients. Next, we compared the changes in cell subset numbers and incidence of apoptosis in the thymi and spleens of allograft or isograft recipients. Seven days after transplantation, at a time in which all the allografts were undergoing rejection, cells expressing donor-MHC class II molecules had migrated to the thymus and to the spleen. In the thymus of allograft recipients, overall cellularity was significantly reduced by 40% and associated with an increase in the number of double negative (CD4−CD8−) thymocytes and a decrease in double positive (CD4+CD8+) thymocytes, consistent with increased negative selection of thymocytes. Additionally, thymi of allograft recipients showed an increase in the number of recently activated, mature T cells (TCRhi, CD25+, CD44+) and a significant increase in the number of apoptotic cells, especially in the thymic medulla, that involved mature T cells as indicated by the TCRhi, CD44+, CD4 or CD8 single positive phenotype. Spleens of allograft recipients were increased in size and cellularity but did not show any of the changes in cell subsets seen in the thymi. Our data show that after allografting there is an increase in apoptotic cell death that is associated with negative selection of developing thymocytes as well as of alloreactive mature T cells that have re-entered the thymus upon activation in the periphery. This may occur upon migration of graft-derived antigen-presenting cells to the thymus.
Anti-multiple nuclear dots (anti-MND) and anti-SP100 antibodies in hepatic and rheumatological disorders
Authors: Muratori P , Muratori L , Cassani F , Terlizzi P , Lenzi M , Rodrigo L , Bianchi F B 
Published: March 2003

SummaryMultiple nuclear dots pattern has been described in primary biliary cirrhosis and, less often, in rheumatological disorders. Sp100 is the major antigen of multiple nuclear dots. We evaluated prevalence and diagnostic significance of multiple nuclear dots and anti-Sp100 reactivity both in hepatic and rheumatological diseases. A series of 283 consecutive liver patients (89 primary biliary cirrhosis, 12 primary sclerosing cholangitis, 85 autoimmune hepatitis, 97 hepatitis C virus-related chronic liver disease) and of 89 consecutive rheumatological cases were evaluated. Presence of multiple nuclear dots was assessed by indirect immunofluorescence on HEp-2 cells, anti-Sp100 reactivity by ELISA with recombinant protein. Multiple nuclear dots were detected in 20 patients (7%) with liver disease (of whom 15 with primary biliary cirrhosis), and in eight patients (9%) with rheumatological disorders. Anti-Sp100 was detected in 45 liver patients (16%), of whom 30 with primary biliary cirrhosis, but in only two with rheumatological disorders (2%) (P = 0·0004). The concordance between multiple nuclear dots and anti-Sp100 in liver and rheumatological patients was 90% and 25% (P = 0·0018), respectively. Among 89 consecutive patients with primary biliary cirrhosis, multiple nuclear dots and anti-Sp100 were present in 17% and 34%, respectively (P = 0·0152). Anti-Sp100 positivity was associated with older age and higher gamma-globulin levels. Multiple nuclear dots are similarly observed in liver and rheumatological patients. In contrast, anti-Sp100 is more frequent in liver patients and is significantly more often detected in primary biliary cirrhosis, of which it can be regarded as a highly specific serological marker. The antigenic target of multiple nuclear dots in most rheumatological patients is other than Sp100.
A hampered chemoattractant-induced cytoskeletal rearrangement in granulocytes of patients with unexplained severe chronic and relapsing infections of the upper and lower airways.In vitrorestoration by G-CSF exposure
Authors: Kalkman P M J , Fokkens W J , De Wit H J , Van De Merwe J P , Hooijkaas H , Van Haarst J M W , Hoogsteden H C , Drexhage H A 
Published: March 2003

SummaryGranulocytes play a major role in host defense against bacterial infections. Severe inborn defects in granulocyte function are associated with fulminant bacterial infections in early childhood. Subtle disturbances in granulocyte function might contribute to an enhanced susceptibility to bacterial infections in adulthood. We investigated chemoattractant (N-formyl-methionyl-leucyl-phenylalanine, fMLP and casein) induced cytoskeletal rearrangements (polarization) of blood granulocytes in 77 adults with chronic and recurrent therapy-resistant infections of the upper and lower airways. These infections could not be explained by B- and/or T-cell defects or local anatomic abnormalities. Besides polarization, chemotaxis of blood granulocytes was measured in 33 patients, as well as granulocyte superoxide production in eight patients.The chemoattractant-induced cytoskeletal rearrangement in patient blood granulocytes was significantly lower as compared to healthy control values with both fMLP and casein as stimuli. About two-thirds of the patients showed a defective polarization response to fMLP. Granulocyte colony-stimulating factor (G-CSF) when added in vitro corrected the defective polarization responses; responses in the normal range were not enhanced. The chemotactic motility of patient blood granulocytes was also slightly, but significantly lowered. However, it did not correlate to the lowered polarization. Granulocyte superoxide production was comparable in patients and in healthy controls.Our data thus show that subtle abnormalities in chemoattractant-induced cytoskeletal and motile function of blood granulocytes are frequent in patients with severe therapy-refractory bacterial infections of the upper and lower airways.
Increased levels of serum tissue inhibitor of metalloproteinase-1 but not metalloproteinase-3 in atopic dermatitis
Authors: KATOH N , HIRANO S , SUEHIRO M , IKENAGA K , YASUNO H 
Published: March 2003

SummaryMatrix metalloproteinases and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs), contribute to inflammation-induced tissue destruction and subsequent remodeling for maintenance of tissue homeostasis. Since the production of these enzymes and their inhibitors is regulated by mediators such as proinflammatory cytokines and growth factors, elevated levels of serum TIMPs and/or MMPs have been documented in patients with several inflammatory disorders. In this study, we examined the role of TIMPs and MMPs in the pathogenesis of atopic dermatitis (AD) by evaluating the serum levels of TIMP-1 and MMP-3 in 40 patients with AD and 20 control subjects by ELISA. The serum TIMP-1 levels were significantly higher in AD patients in exacerbation status than in nonatopic subjects, whereas serum MMP-3 levels were not significantly different between them. As a result, AD patients revealed significantly elevated TIMP-1/MMP-3 ratios. The levels of serum TIMP-1 were significantly reduced in AD patients following conventional treatments. Significantly higher values of peripheral eosinophil counts, serum levels of IgE and lactate dehydrogenase, eruption score, and eruption area were noted in the AD patients with elevated TIMP-1 levels when compared with those with normal values. Moreover, the points of chronic eruptions such as lichenification and prurigo were significantly higher in the patients with elevated TIMP-1 levels than those with normal TIMP-1, while those of acute lesions such as oozy/microvesicles and oedema were not different between these groups. Serum TIMP-1 level may be a useful marker to estimate the long-term disease activity of AD.
Trypanosoma cruzimitochondrial malate dehydrogenase triggers polyclonal B-cell activation
Authors: Montes C L , Zuñiga E I , Vazquez J , Arce C , Gruppi A 
Published: March 2003

SummaryIt has been proposed that Trypanosoma cruzi, the aetiologic agent of Chagas’ disease, produces mitogenic substances responsible for the polyclonal B-cell activation observed during the acute phase of the infection. Isolation and characterization of the molecules involved in the induction of polyclonal activation observed during infectious diseases have posed a great challenge for the immunologist over the last decade. In this work we report that a 33 kD protein obtained from an alkaline fraction of T. cruzi epimastigotes (FI) stimulates proliferation and promotes differentiation into antibody-secreting cells of normal murine B cells in a T-cell independent manner. By flow cytometry we also found that the 33 kDa protein induces an increase in the expression of MHC class II and B7.2 but not B7.1 molecules on the B-cell surface. Sequencing by mass spectrometry identified the T. cruzi 33 kD protein as hypothetical oxidoreductase, a member of the aldo/ketoreductase family. In this report we demonstrate that this protein is also present in the infective bloodstream trypomastigote form of the parasite and was identified as T. cruzi mitochondrial malate dehydrogenase (mMDH) by enzyme activity and by Western blotting using a specific mMDH polyclonal antiserum. The biologic relevance of mMDH-induced polyclonal activation concerning T. cruzi infection is discussed.
Monocyte intracellular cytokine production during human endotoxaemia with or without a secondin vitroLPS challenge: effect of RWJ-67657, a p38 MAP-kinase inhibitor, on LPS-hyporesponsiveness
Authors: FAAS M M , MOES H , FIJEN J W , KOBOLD A C MULLER , TULLEKEN J E , ZIJLSTRA J G 
Published: March 2003

SummaryIn the present study, we investigated the effect of RWJ-67657, a p38 MAP kinase inhibitor, upon in vivo LPS-induced monocyte cytokine production and upon monocyte LPS-hyporesponsiveness. Thirty minutes before a single injection of LPS (4 ng/kg BW), healthy male volunteers received a single oral dose of RWJ-67657 at increasing dosages (0–1400 mg). Blood samples (pre-medication, 3, 6 and 24 h after LPS) were immediately incubated with LPS (reflecting LPS-hyporesponsiveness) or without LPS (reflecting in vivo monocyte stimulation) for 4 h at 37°C. Following red blood cells lysis and white blood cell permeabilization, cells were labelled with α-CD14-FITC and α-IL-1β, α-IL-12 or α-TNFα (PE-labelled), fixed, and analysed using flow cytometry. In vivo LPS injection resulted in an increased percentage of circulating monocytes producing IL-1β, TNFα and IL-12 only at 3 h after the LPS injection. This was dose-dependently inhibited by RWJ-67657 treatment. LPS-hyporesponsiveness to in vitro LPS treatment was most prominent at 3 and 6 h after the in vivo LPS injection; compared with pre-medication monocytes, at these intervals a reduced percentage of monocytes produced IL-1β, TNFα or IL-12 after the in vitro LPS stimulus. At t = 6 h, this LPS-hyporesponsiveness could dose-dependently be inhibited by RWJ-67657 treatment of the volunteers. We therefore conclude that p38 MAP kinase inhibition with RWJ-67657 inhibited monocyte production of cytokines following in vivo LPS injection. Treatment with RWJ-67657 also reversed the LPS-hyporesponsiveness. Whether this result can be extended to the clinical situation remains to be elucidated. Patients with sepsis or an otherwise high risk for multi-organ failure are potential study groups.