Publications
72 results found
Kapp K, Pruefer S, Habermeier A, et al., 2013, GRANULOCYTE FUNCTION IS NOT IMPAIRED BY ARGININE DEFICIENCY, Publisher: FERRATA STORTI FOUNDATION, Pages: 423-423, ISSN: 0390-6078
Munder M, Engelhardt M, Knies D, et al., 2013, Cytotoxicity of tumor antigen specific human T cells is unimpaired by arginine depletion, PLOS One, Vol: 8, ISSN: 1932-6203
Tumor-growth is often associated with the expansion of myeloid derived suppressor cells that lead to local or systemic arginine depletion via the enzyme arginase. It is generally assumed that this arginine deficiency induces a global shut-down of T cell activation with ensuing tumor immune escape. While the impact of arginine depletion on polyclonal T cell proliferation and cytokine secretion is well documented, its influence on chemotaxis, cytotoxicity and antigen specific activation of human T cells has not been demonstrated so far. We show here that chemotaxis and early calcium signaling of human T cells are unimpaired in the absence of arginine. We then analyzed CD8+ T cell activation in a tumor peptide as well as a viral peptide antigen specific system: (i) CD8+ T cells with specificity against the MART-1aa26–35*A27L tumor antigen expanded with in vitro generated dendritic cells, and (ii) clonal CMV pp65aa495–503 specific T cells and T cells retrovirally transduced with a CMV pp65aa495–503 specific T cell receptor were analyzed. Our data demonstrate that human CD8+ T cell antigen specific cytotoxicity and perforin secretion are completely preserved in the absence of arginine, while antigen specific proliferation as well as IFN-γ and granzyme B secretion are severely compromised. These novel results highlight the complexity of antigen specific T cell activation and demonstrate that human T cells can preserve important activation-induced effector functions in the context of arginine deficiency.
Abebe T, Takele Y, Weldegebreal T, et al., 2013, Arginase activity - a marker of disease status in patients with visceral leishmaniasis in Ethiopia, PLOS Neglected Tropical Diseases, Vol: 7, ISSN: 1935-2735
The underlying mechanisms resulting in the profound immune suppression characteristic of human visceral leishmaniasis (VL) are not fully understood.Here, we tested the hypothesis that arginase, an enzyme associated with immunosuppression, is higher in patients with VL and contributes to impaired T cell responses. We recruited patients with VL before and after treatment and healthy controls and measured the arginase metabolism in the blood of these individuals. Our results show that arginase activity is significantly higher in the blood of patients with active VL as compared to controls. These high levels of arginase decline considerably once the patients are successfully treated. We identified the phenotype of arginase-expressing cells among PBMCs as neutrophils and show that their frequency was increased in PBMCs of patients before treatment; this coincides with reduced levels of L-arginine in the plasma and decreased expression levels of CD3ζ in T cells.
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
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.
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
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
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
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
Munder M, Choi B-S, Rogers M, et al., 2009, L-Arginine deprivation impairs <i>Leishmania major</i>-specific T-cell responses, EUROPEAN JOURNAL OF IMMUNOLOGY, Vol: 39, Pages: 2161-2172, ISSN: 0014-2980
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- Citations: 54
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, Kropf P, 2009, Evaluation of T cell responses in healing and nonhealing leishmaniasis reveals differences in T helper cell polarization <i>ex vivo</i> and <i>in vitro</i>, PARASITE IMMUNOLOGY, Vol: 31, Pages: 199-209, ISSN: 0141-9838
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- Citations: 10
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
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
Munder M, Choi B-S, Kropf P, 2008, Differential regulation of T cell effector functions by L-arginine availability during experimental leishmaniasis, Annual Congress of the British-Society-of-Immunology, Publisher: WILEY-BLACKWELL PUBLISHING, INC, Pages: 127-127, ISSN: 0019-2805
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
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
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
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- Citations: 289
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
Antoniazi S, Price HP, Kropf P, et al., 2004, Chemokine gene expression in toll-like receptor-competent and -deficient mice infected with <i>Leishmania major</i>, INFECTION AND IMMUNITY, Vol: 72, Pages: 5168-5174, ISSN: 0019-9567
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- Citations: 35
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