Publications
126 results found
Takele Y, Abebe T, Weldegebreal T, et al., 2013, Arginase activity in the blood of patients with visceral leishmaniasis and HIV infection, PLOS Neglected Tropical Diseases, Vol: 7, ISSN: 1935-2735
BackgroundVisceral leishmaniasis is a parasitic disease associated with high mortality. The most important foci of visceral leishmaniasis in Ethiopia are in the Northwest and are predominantly associated with high rates of HIV co-infection. Co-infection of visceral leishmaniasis patients with HIV results in higher mortality, treatment failure and relapse. We have previously shown that arginase, an enzyme associated with immunosuppression, was increased in patients with visceral leishmaniasis and in HIV seropositive patients; further our results showed that high arginase activity is a marker of disease severity. Here, we tested the hypothesis that increased arginase activities associated with visceral leishmaniasis and HIV infections synergize in patients co-infected with both pathogens.Methodology/Principal FindingsWe recruited a cohort of patients with visceral leishmaniasis and a cohort of patients with visceral leishmaniasis and HIV infection from Gondar, Northwest Ethiopia, and recorded and compared their clinical data. Further, we measured the levels of arginase activity in the blood of these patients and identified the phenotype of arginase-expressing cells. Our results show that CD4+ T cell counts were significantly lower and the parasite load in the spleen was significantly higher in co-infected patients. Moreover, our results demonstrate that arginase activity was significantly higher in peripheral blood mononuclear cells and plasma of co-infected patients. Finally, we identified the cells-expressing arginase in the PBMCs as low-density granulocytes.ConclusionOur results suggest that increased arginase might contribute to the poor disease outcome characteristic of patients with visceral leishmaniasis and HIV co-infection.
Cloke T, Munder M, Taylor G, et al., 2012, Characterization of a novel population of low-density granulocytes associated with disease severity in HIV-1 infection, PLOS One, Vol: 7, ISSN: 1932-6203
The mechanisms resulting in progressive immune dysfunction during the chronic phase of HIV infection are not fully understood. We have previously shown that arginase, an enzyme with potent immunosuppressive properties, is increased in HIV seropositive (HIV+) patients with low CD4+ T cell counts. Here we show that the cells expressing arginase in peripheral blood mononuclear cells of HIV+ patients are low-density granulocytes (LDGs) and that whereas these cells have a similar morphology to normal-density granulocyte, they are phenotypically different. Importantly, our results reveal that increased frequencies of LDGs correlate with disease severity in HIV+ patients.
Baker BS, Harrington JE, Choi B-S, et al., 2012, A randomised controlled pilot feasibility study of the physical and psychological effects of an integrated support programme in breast cancer, Complementary Therapies in Clinical Practice, Vol: 18, Pages: 182-189, ISSN: 1744-3881
Lamour SD, Choi B, Keun HC, et al., 2012, Metabolic characterization of leishmania major infection in activated and nonactivated macrophages., Journal of Proteome Research, Vol: 11, Pages: 4211-4222, ISSN: 1535-3907
Infection with Leishmania spp. can lead to a range of symptoms in the affected individual, depending on underlying immune-metabolic processes. The macrophage activation state hereby plays a key role. Whereas the l-arginine pathway has been described in detail as the main biochemical process responsible for either nitric oxide mediated parasite killing (classical activation) or amplification of parasite replication (alternative activation), we were interested in a wider characterization of metabolic events in vitro. We therefore assessed cell growth medium, parasite extract, and intra- and extracellular metabolome of activated and nonactivated macrophages, in presence and absence of Leishmania major. A metabolic profiling approach was applied combining (1)H NMR spectroscopy with multi- and univariate data treatment. Metabolic changes were observed along both conditional axes, that is, infection state and macrophage activation, whereby significantly higher levels of potential parasite end products were found in parasite exposed samples including succinate, acetate, and alanine, compared to uninfected macrophages. The different macrophage activation states were mainly discriminated by varying glucose consumption. The presented profiling approach allowed us to obtain a metabolic snapshot of the individual biological compartments in the assessed macrophage culture experiments and represents a valuable read out system for further multiple compartment in vitro studies.
Abebe T, Hailu A, Woldeyes M, et al., 2012, Local increase of arginase activity in lesions of patients with cutaneous leishmaniasis in Ethiopia, PLOS Neglected Tropical Diseases, Vol: 6, ISSN: 1935-2735
BackgroundCutaneous leishmaniasis is a vector-borne disease that is in Ethiopia mainly caused by the parasite Leishmania aethiopica. This neglected tropical disease is common in rural areas and causes serious morbidity. Persistent nonhealing cutaneous leishmaniasis has been associated with poor T cell mediated responses; however, the underlying mechanisms are not well understood.Methodology/Principal FindingsWe have recently shown in an experimental model of cutaneous leishmaniasis that arginase-induced L-arginine metabolism suppresses antigen-specific T cell responses at the site of pathology, but not in the periphery. To test whether these results translate to human disease, we recruited patients presenting with localized lesions of cutaneous leishmaniasis and assessed the levels of arginase activity in cells isolated from peripheral blood and from skin biopsies. Arginase activity was similar in peripheral blood mononuclear cells (PBMCs) from patients and healthy controls. In sharp contrast, arginase activity was significantly increased in lesion biopsies of patients with localized cutaneous leishmaniasis as compared with controls. Furthermore, we found that the expression levels of CD3ζ, CD4 and CD8 molecules were considerably lower at the site of pathology as compared to those observed in paired PBMCs.ConclusionOur results suggest that increased arginase in lesions of patients with cutaneous leishmaniasis might play a role in the pathogenesis of the disease by impairing T cell effector functions.
Varela-M RE, Villa-Pulgarin JA, Yepes E, et al., 2012, <i>In Vitro</i> and <i>In Vivo</i> Efficacy of Ether Lipid Edelfosine against <i>Leishmania</i> <i>spp</i>. and SbV-Resistant Parasites, PLOS NEGLECTED TROPICAL DISEASES, Vol: 6, ISSN: 1935-2735
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- Citations: 43
Feldmeyer N, Wabnitz G, Leicht S, et al., 2012, Arginine deficiency leads to impaired cofilin dephosphorylation in activated human T lymphocytes, International Immunology, Vol: 24, Pages: 303-313, ISSN: 1460-2377
Corware K, Harris D, Teo I, et al., 2011, Accelerated healing of cutaneous leishmaniasis in non-healing BALB/c mice using water soluble amphotericin B-polymethacrylic acid, BIOMATERIALS, Vol: 32, Pages: 8029-8039, ISSN: 0142-9612
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- Citations: 27
Fu H, Khan A, Coe D, et al., 2011, Arginine depletion as a mechanism for the immune privilege of corneal allografts, European Journal of Immunology, Vol: 41, Pages: 2997-3005, ISSN: 1521-4141
The cornea is an immune privileged tissue. Since arginase has been found to modulate T-cell function by depleting arginine, we investigated the expression of arginase in the cornea and its possible role in immune privilege using a murine transplant model. We found that both the endothelium and epithelium of murine corneas express functional arginase I, capable of down-regulating T-cell proliferation in an in vitro culture system. The administration of the specific arginase inhibitor N-hydroxy-nor-l-Arg to recipient mice resulted in an accelerated rejection of allogeneic C57BL/6 (B6) corneal grafts. In contrast, in vivo blockade of arginase activity had no effect in altering the course of rejection of primary skin grafts that express little, if any, arginase. In addition, the inhibition of arginase did not alter systemic T-cell proliferation. These data show that arginase is functional in the cornea and contributes to the immune privilege of the eye, and that modulation of arginase contributes to graft survival.
Cloke TE, Abebe T, Hailu A, et al., 2010, Antiretroviral therapy abrogates association between arginase activity and HIV disease severity, TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE, Vol: 104, Pages: 746-748, ISSN: 0035-9203
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- Citations: 5
Corware KD, Rogers M, Teo I, et al., 2010, An amphotericin B-based drug for treating experimental Leishmania major infection, Transactions of the Royal Society of Tropical Medicine and Hygiene, Vol: 104, Pages: 749-750
There is an urgent need for a non-toxic and low-cost treatment for cutaneous leishmaniasis. We synthesised and tested in vivo an amphotericin B-poly(methacrylic acid) drug (AmB-PMA) that had previously shown in-vitro activity against Leishmania major and L. donovani parasites. Efficacy was determined using L. major footpad infection in 30 non-healing BALB/c mice. Three subcutaneous injections of AmB-PMA at days 7, 14 and 21 post-infection resulted in a reduction of ∼80% in lesion size by day 35 post-infection in 18 treated mice compared with six untreated controls, and complete healing of lesions by day 50 with no lesion relapse seen at day 80 post-infection in six treated mice. Healing was associated with decreased IL-10 (P=0.002) and increased IFN-γ (P=0.005) in the footpad.
Rogers ME, Corware K, Mueller I, et al., 2010, <i>Leishmania infantum</i> proteophosphoglycans regurgitated by the bite of its natural sand fly vector, <i>Lutzomyia longipalpis</i>, promote parasite establishment in mouse skin and skin-distant tissues, MICROBES AND INFECTION, Vol: 12, Pages: 875-879, ISSN: 1286-4579
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- Citations: 37
Cloke TE, Garvey L, Choi B-S, et al., 2010, Increased Level of Arginase Activity Correlates with Disease Severity in HIV-Seropositive Patients, JOURNAL OF INFECTIOUS DISEASES, Vol: 202, Pages: 374-385, ISSN: 0022-1899
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- Citations: 41
Luckner-Minden C, Fischer I, Langhans C-D, et al., 2010, Human eosinophil granulocytes do not express the enzyme arginase, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 87, Pages: 1125-1132, ISSN: 0741-5400
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- Citations: 11
Clements MF, Gidwani K, Kumar R, et al., 2010, Measurement of Recent Exposure to <i>Phlebotomus argentipes</i>, the Vector of Indian Visceral Leishmaniasis, by Using Human Antibody Responses to Sand Fly Saliva, AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE, Vol: 82, Pages: 801-807, ISSN: 0002-9637
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- Citations: 54
Kropf P, Kadolsky UD, Rogers M, et al., 2010, The Leishmaniasis Model, IMMUNOLOGY OF INFECTION, THIRD EDITION, Vol: 37, Pages: 307-328, ISSN: 0580-9517
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- Citations: 7
Mueller I, Munder M, Kropf P, et al., 2009, Polymorphonuclear neutrophils and T lymphocytes: strange bedfellows or brothers in arms?, TRENDS IN IMMUNOLOGY, Vol: 30, Pages: 522-530, ISSN: 1471-4906
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- Citations: 221
Rogers M, Kropf P, Choi B-S, et al., 2009, Proteophosophoglycans Regurgitated by <i>Leishmania</i>-Infected Sand Flies Target the L-Arginine Metabolism of Host Macrophages to Promote Parasite Survival, PLOS PATHOGENS, Vol: 5, ISSN: 1553-7366
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- Citations: 91
Modolell M, Choi B-S, Ryan RO, et al., 2009, Local Suppression of T Cell Responses by Arginase-Induced L-Arginine Depletion in Nonhealing Leishmaniasis, PLOS NEGLECTED TROPICAL DISEASES, Vol: 3, ISSN: 1935-2735
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- Citations: 79
Oberlies J, Watzl C, Giese T, et al., 2009, Regulation of NK Cell Function by Human Granulocyte Arginase, JOURNAL OF IMMUNOLOGY, Vol: 182, Pages: 5259-5267, ISSN: 0022-1767
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- Citations: 92
Choi B-S, Martinez-Falero IC, Corset C, et al., 2009, Differential impact of L-arginine deprivation on the activation and effector functions of T cells and macrophages, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 85, Pages: 268-277, ISSN: 0741-5400
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- Citations: 57
Choi B-S, Martinez-Falero IC, Corset C, et al., 2008, Differential impact of L-arginine deprivation on the activation and effector functions of T cells and macrophages, Annual Congress of the British-Society-of-Immunology, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 8-8, ISSN: 0019-2805
Cloke T, Garvey L, Choi B-S, et al., 2008, Arginase-induced L-arginine metabolism in HIV-infected patients, Annual Congress of the British-Society-of-Immunology, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 133-133, ISSN: 0019-2805
Hancock A, Choi B-S, Ryan RO, et al., 2008, Local suppression of T cell responses by arginase-induced L-arginine depletion in non-heating leishmaniasis, Annual Congress of the British-Society-of-Immunology, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 127-127, ISSN: 0019-2805
Muller I, Hailu A, Choi B-S, et al., 2008, Age-Related Alteration of Arginase Activity Impacts on Severity of Leishmaniasis, PLOS NEGLECTED TROPICAL DISEASES, Vol: 2, ISSN: 1935-2735
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- Citations: 34
Kropf P, Baud D, Marshall SE, et al., 2007, Arginase activity mediates reversible T cell hyporesponsiveness in human pregnancy, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 37, Pages: 935-945, ISSN: 0014-2980
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- Citations: 132
Rogers M, Ilg T, Sizova O, et al., 2007, Leishmania transmission from the sand fly vector: parasite secretory gel, Annual Congress of the British-Society-of-Immunology, Publisher: BLACKWELL PUBLISHING, Pages: 63-63, ISSN: 0019-2805
Choi B-S, Clara-Martinez-Fal I, Corset C, et al., 2007, Impact of L-arginine deprivation on macrophage effector functions, Annual Congress of the British-Society-of-Immunology, Publisher: BLACKWELL PUBLISHING, Pages: 83-83, ISSN: 0019-2805
Munder M, Schneider H, Luckner C, et al., 2006, Suppression of T-cell functions by human granulocyte arginase., Blood, Vol: 108, Pages: 1627-1634, ISSN: 0006-4971
Chronic inflammation is accompanied by impaired T-cell immunity. In the mouse, myeloid cell-associated arginase accounts for the suppression of immune reactivity in various models of tumor growth and chronic infections. Here we show that arginase I is liberated from human granulocytes, and very high activities accumulate extracellularly during purulent inflammatory reactions. Human granulocyte arginase induces a profound suppression of T-cell proliferation and cytokine synthesis. This T-cell phenotype is due to arginase-mediated depletion of arginine in the T-cell environment, which leads to CD3zeta chain down-regulation but does not alter T-cell viability. Our study therefore demonstrates that human granulocytes possess a previously unanticipated immunosuppressive effector function. Human granulocyte arginase is a promising pharmacologic target to reverse unwanted immunosuppression.
Kropf P, Fuentes JM, Fähnrich E, et al., 2005, Arginase and polyamine synthesis are key factors in the regulation of experimental leishmaniasis in vivo, FASEB JOURNAL, Vol: 19, Pages: 1000-+, ISSN: 0892-6638
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- Citations: 226
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