Clinical and Experimental Immunology
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Comparison of the T lymphocyte-dependent induction of angiotensin-converting enzyme and leucine aminopeptidase in cultured human monocytes SUMMARY
The T lymphocyte-mediated induction of angiotensin-converting enzyme (ACE) in cultured autologous peripheral blood monocytes has been proposed as a model system for the investigation of the in vivo induction of ACE in the monocyte-derived granuloma epithelioid cells of some granulomatous diseases such as sarcoidosis. The studies described here were designed to evaluate the specificity of the model system by comparing the parameters for induction of ACE with those for the induction of another monocyte metallo-ecto-peptidase, leucine aminopeptidase (LAP). The concentration of LAP in freshly isolated monocytes was 009 mU/106 monocytes (s.e.m. 0.04) and increased to a maximal value of 019 mU/106 monocytes (s.e.m. 0.32) after 3 days when monocytes were cultured alone. ACE was not detectable in freshly isolated monocytes. However, after 6 days of culture, monocytes contained 0.22 m U ACE/106 monocytes (s.e.m. 0.04). Comparison of the levels of ACE and LAP induced during culture of monocytes alone indicated that the induction of these two enzymes was correlated. The induction of both enzymes was further enhanced by the presence of T lymphocytes in a dose-dependent manner. At 4 × 106 T lymphocytes per culture, ACE levels increased to 1.81 mU/106 monocytes (s.e.m. 0.24) and LAP levels to 1.03 mU/106 monocytes (s.e.m. 0.35). The enhancement of ACE activity required autologous lymphocytes, while heterologous T lymphocytes were equally effective in inducing LAP. Comparison of the levels of ACE and LAP induced during co-culture of autologous T lymphocytes and monocytes from 21 independent donors, demonstrated no correlation between the induction of ACE and LAP. These data indicate that, although T lymphocytes also enhance the induction of LAP, the underlying mechanism must differ from that of ACE induction.
Clinical and Experimental Immunology - Tập 83 Số 3 - Trang 510-515 - 2008
Correlation of virulence, lung pathology, bacterial load and delayed type hypersensitivity responses after infection with different <i>Mycobacterium tuberculosis</i> genotypes in a BALB/c mouse model SUMMARY
One of the most intriguing aspects of tuberculosis is that the outcome of an infection with M. tuberculosis (TB) is highly variable between individuals. The possibility of differences in virulence between M. tuberculosis strains or genotypes has only recently been studied. There is evidence of multifactorial genetic predisposition in humans that influences the susceptibility to tuberculosis. A better understanding of differences in virulence between M. tuberculosis genotypes could be important with regard to the efforts at TB control and the development of improved antituberculosis vaccines. Survival, lung pathology, bacterial load and delayed type hypersensitivity (DTH) responses of BALB/c mice after intratracheal infection with any of 19 different M. tuberculosis complex strains of 11 major genotype families were studied. The results indicate that among genetically different M. tuberculosis strains a very broad response was present with respect to virulence, pathology, bacterial load and DTH. ‘Low’-responders were the H37Rv, Canetti, Beijing-1 strains, while Beijing-2,3, Africa-2 and Somalia-2 strains were ‘high’-responders. A severe pathological response correlates with a high mortality and a high CFU counts in lungs, but poorly with the degree of the DTH response.
Clinical and Experimental Immunology - Tập 137 Số 3 - Trang 460-468 - 2004
Enhancement of T cell recruitment and infiltration into tumours Summary Studies have documented that cancer patients with tumours which are highly infiltrated with cytotoxic T lymphocytes show enhanced survival rates. The ultimate goal of cancer immunotherapy is to elicit high-avidity tumour-specific T cells to migrate and kill malignant tumours. Novel antibody therapies such as ipilumimab (a cytotoxic T lymphocyte antigen-4 blocking antibody) show enhanced T cell infiltration into the tumour tissue and increased survival. More conventional therapies such as chemotherapy or anti-angiogenic therapy and recent therapies with oncolytic viruses have been shown to alter the tumour microenvironment and thereby lead to enhanced T cell infiltration. Understanding the mechanisms involved in the migration of high-avidity tumour-specific T cells into tumours will support and provide solutions for the optimization of therapeutic options in cancer immunotherapy.
Clinical and Experimental Immunology - Tập 178 Số 1 - Trang 1-8 - 2014
Protective effects of cyclophosphamide, cyclosporin A and FK506 against antigen-induced lung eosinophilia in guinea-pigs SUMMARY
A close association has been recognized between activated T cells and eosinophils in asthma, albeit circumstantial. The present study attempted to investigate this relationship in an animal model of lung eosinophilia using the new generation of T cell-selective immunosuppressants, cyclosporin A and FK506, compared with the myelotoxic immunosuppressive agent cyclophosphamide. Antigen challenge of ovalbumin-sensitized guinea-pigs resulted in a lung eosinophilia which was assessed by bronchoalveolar lavage. All three agents caused a marked suppression of lung eosinophilia at 24 h post-challenge when the compounds were administered at the time of sensitization but not when administered for 3 days before lavage. However, the lung eosinophilia at 72 h post-challenge was reduced significantly by FK506 and by cyclophosphamide, but not by cyclosporin A, when the drugs were administered for 3 days, before lavage. These results strongly suggest the involvement of T cells in antigen-induced late phase (72 h) eosinophilia in guinea-pigs but not at 24 h. The effects of cyclophosphamide were always associated with a reduction in circulating white cell counts, whereas cyclosporin A and FK506 showed no myelotoxic properties. These results suggest the potential therapeutic use of selective, non-cytotoxic immunosuppressive agents in asthma.
Clinical and Experimental Immunology - Tập 89 Số 3 - Trang 347-350 - 2008
Hepatic interleuklin 15 (IL-15) expression: implications for local NK/NKT cell homeostasis and development SUMMARY Interleukin 15 (IL-15) is critical for the development of human and murine natural killer (NK) cells and hepatic-derived NK T cells (NKT) in mice, and for the homeostatic maintenance of NK/NKT and CD8+ memory T cells. The lymphocyte repertoire of an adult human liver includes significant populations of NK and NKT-like cells, which may arise locally from hepatic haematopoietic stem cells (HSCs). We investigated hepatic IL-15 levels and the expression of IL-2/IL-15-receptor β-chain (IL-2/IL-15Rβ ; CD122) on mature hepatic lymphocytes and HSCs. Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect secreted/intracellular IL-15 transcripts. IL-15 protein was localized using immunohistochemistry; levels were measured by enzyme-linked immunosorbent assay IL-2/IL-15Rβ expression by flow-cytometry. Normal hepatic IL-15 protein was detected at 0.43 ng/100 mg total protein (n = 11, range 0.10 ng−0.9 ng). There was a significant increase in HCV-infected tissue (1.78 ng, P < 0.005, n = 11, range 0.18–2.43 ng). The staining pattern suggests that infiltrating monocytes and tissue resident Kupffer cells are the main producers. IL-15 protein was detected in supernatants from cultured liver biopsy specimens in the absence of stimulation (mean 175.8 pg/100 mg wet tissue, n = 3), which increased significantly upon stimulation (P < 0.05, mean 231.21 pg). On average, 61% of hepatic HSCs expressed IL-2/IL-15Rβ suggesting a local lymphopoietic role. Eighty per cent of NK and 45.8% of CD56+ T cells expressed IL-2/IL-15Rβ, suggesting involvement in local CD56+ cell activation and expansion. Constitutive expression of IL-15 protein and IL-2/IL-15Rβ on hepatic lymphocytes suggests a key role in the generation and maintenance of the unique hepatic lymphoid repertoire. The significant increase observed in HCV-infected liver suggests a role for IL-15 in host antiviral responses in the liver.
Clinical and Experimental Immunology - Tập 138 Số 1 - Trang 94-101 - 2004
Impairment of natural killer (NK) cytotoxic activity in hepatitis C virus (HCV) infection SUMMARY
In the present study, we evaluated the NK cell cytotoxic activity in a group of HCV-infected individuals. Although the number of NK cells present in the peripheral blood of the HCV-infected patients was comparable to non-infected individuals, spontaneous NK cytotoxicity was four-fold lower (P < 0.001) than in normal donors. This functional impairment was not overcome by depletion of adherent or B cells, and it was partially restored by short-term (18 h) stimulation with IL-2. However, long-term stimulation (72 h) with this lymphokine induced activated killer cell (LAK) activity comparable to normal controls. The reduction in NK cytotoxic response does not seem to be due to soluble suppressive factors, since incubation of normal peripheral blood mononuclear cells (PBMC) with infectious HCV serums for a 4-h period does not affect NK spontaneous cytotoxic activity. Successful in vitro infection of PBMC with HCV infectious serum also resulted in an impairment of NK cytotoxicity, suggesting that altered NK function is associated with HCV infection and may be responsible, at least in part, for the chronicity of the infection.
Clinical and Experimental Immunology - Tập 109 Số 3 - Trang 451-457 - 2003
Antigen presentation by macrophages is enhanced by the uptake of necrotic, but not apoptotic, cells Summary The aim of this study was to determine whether phagocytosis of necrotic or apoptotic cells affects antigen presentation by murine bone marrow-derived macrophages. After uptake of necrotic neutrophils, macrophages were able to stimulate significantly higher T cell proliferation in vitro against both the recall antigen albumin and the mitogen concanavalin A. No such effect was seen following phagocytosis of apoptotic neutrophils. Flow cytometry revealed that, within 4h of ingestion, macrophages that had taken up the necrotic cells expressed higher levels of CD40 than those that had phagocytosed apoptotic cells. Macrophage cultures pulsed with apoptotic, but not necrotic, neutrophils contained higher levels of transforming growth factor β1, but lower concentrations of tumour necrosis factor α, compared to untreated controls. Our interpretation of these results is that macrophages that have taken up necrotic neutrophils co-stimulate T cells with greater efficiency due to rapid CD40 up-regulation, whereas those that have ingested apoptotic cells are not only ineffective in co-stimulation, but also secrete inhibitory cytokine.
Clinical and Experimental Immunology - Tập 127 Số 2 - Trang 220-225 - 2002
Role of cathepsin B in regulating migration and invasion of fibroblast-like synoviocytes into inflamed tissue from patients with rheumatoid arthritis Summary
Cathepsin B (CB), an important proteinase that participates in joint destruction in rheumatoid arthritis (RA), exhibits higher expression in fibroblast-like synoviocyte (FLS) of abnormal proliferative synovial tissues. Whether and how it affects the biological behaviours of RA-FLS, such as migration and invasion, are poorly understood. In the present study, CB expression in synovial tissues of patients with RA and ostearthritis (OA) were measured by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC), respectively. Stable depletion of endogenous CB was achieved by small interfering RNA (siRNA) transfection, and decrease of CB activity was acquired by using its specific inhibitor (CA074Me). The effects of CA074Me and RNA interference (RNAi) treatments on proliferation, migration, invasion, matrix metalloproteinase (MMP)-2/-9 expression, focal adhesion kinase (FAK) activation, and mitogen-activated protein kinases (MAPKs) phosphorylation of FLS were analysed. In RA synovial tissues, CB was expressed at elevated levels compared with OA synovial tissues. CA074Me could inhibit invasion of FLS obtained from RA patients in an ex-vivo invasion model. CA074Me and siRNA treatments suppressed the migration and invasion of FLS, reduced the activity, expression and mRNA level of MMP-2, restrained the activation of FAK and reduced the expression of F-actin. Moreover, CA074Me decreased the phosphorylation of P38 MAPK and c-Jun N-terminal kinase (JNK) in FLS, while siCB treatment reduced the phosphorylation of P38 but not JNK. CB substantially contributes to the invasive phenotype of FLS that leads to joint destruction in RA. This proteinase may show promise as a therapeutic target in inflammatory arthritis.
Clinical and Experimental Immunology - Tập 177 Số 3 - Trang 586-597 - 2014
The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease Summary Uncommitted (naive) murine CD4+ T helper cells (Thp) can be induced to differentiate towards T helper 1 (Th1), Th2, Th17 and regulatory (Treg) phenotypes according to the local cytokine milieu. This can be demonstrated most readily both in vitro and in vivo in murine CD4+ T cells. The presence of interleukin (IL)-12 [signalling through signal transduction and activator of transcription (STAT)-4] skews towards Th1, IL-4 (signalling through STAT-6) towards Th2, transforming growth factor (TGF)-β towards Treg and IL-6 and TGF-β towards Th17. The committed cells are characterized by expression of specific transcription factors, T-bet for Th1, GATA-3 for Th2, forkhead box P3 (FoxP3) for Tregs and RORγt for Th17 cells. Recently, it has been demonstrated that the skewing of murine Thp towards Th17 and Treg is mutually exclusive. Although human Thp can also be skewed towards Th1 and Th2 phenotypes there is as yet no direct evidence for the existence of discrete Th17 cells in humans nor of mutually antagonistic development of Th17 cells and Tregs. There is considerable evidence, however, both in humans and in mice for the importance of interferon (IFN)-γ and IL-17 in the development and progression of inflammatory and autoimmune diseases (AD). Unexpectedly, some models of autoimmunity thought traditionally to be solely Th1-dependent have been demonstrated subsequently to have a non-redundant requirement for Th17 cells, notably experimental allergic encephalomyelitis and collagen-induced arthritis. In contrast, Tregs have anti-inflammatory properties and can cause quiescence of autoimmune diseases and prolongation of transplant function. As a result, it can be proposed that skewing of responses towards Th17 or Th1 and away from Treg may be responsible for the development and/or progression of AD or acute transplant rejection in humans. Blocking critical cytokines in vivo, notably IL-6, may result in a shift from a Th17 towards a regulatory phenotype and induce quiescence of AD or prevent transplant rejection. In this paper we review Th17/IL-17 and Treg biology and expand on this hypothesis.
Clinical and Experimental Immunology - Tập 148 Số 1 - Trang 32-46 - 2007
Monoclonal antibodies to early pregnancy factor perturb tumour cell growth SUMMARY
The pregnancy-associated substance early pregnancy factor (EPF) has previously been reported as a product of tumours of germ cell origin. More recently EPF (or an EPF-related substance, tEPF) has also been detected in the serum of patients bearing tumours of non-germ cell origin. We report here the production of tEPF by a variety of cultured transformed and tumour cell lines, of both germ and non-germ cell origin. Antibodies specific for EPF remove all tEPF activity from tumour cell conditioned medium, tEPF production is found to be associated with cell division; tEPF is no longer detected after growth arrest or differentiation. Co-culture of tumour cells with increasing doses of anti-EPF monoclonal antibodies resulted in a significant, dose-dependent decrease in rate of cell growth and viability. Similar anti-EPF concentrations had no effect on the concanavalin A induced proliferation of mouse spleen cells. These studies suggest, therefore, that tEPF is a growth-regulated product of cultured tumour and transformed cells. These cells are also dependent upon tEPF for continued growth, i.e. tEPF is acting in the autocrine mode.
Clinical and Experimental Immunology - Tập 80 Số 1 - Trang 100-108 - 2008
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