Person: AKKOÇ, TUNÇ
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AKKOÇ
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TUNÇ
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Publication Metadata only Treatment with Mycobacterium vaccae ameliorates airway histopathology in a murine model of asthma(OCEAN SIDE PUBLICATIONS INC, 2008) AKKOÇ, TUNÇ; Yazi, Didem; Akkoc, Tunc; Yesil, Ozlem; Ozdernir, Cevdet; Aydogan, Metin; Koksalan, Kaya; Bahceciler, Nerin N.; Barlan, Isil B.The objective of this study was to evaluate the effect of intratracheal (i.t.) or subcutaneous (s.c.) Mycobacterium vaccae treatment on lung histopathology and cytokine responses in a murine model of asthma. BALB/c mice were divided into four groups. To establish an asthma model, Groups I, II and III received intraperitoneal (i.p.) ovalbumin (OVA) and were challenged with i.t. OVA three times (days 41-47). On the same days, mice in Groups I and II were treated with i.t. and s.c. Mycobacterium vaccae, respectively. Mice in Group IV served as controls. On day 49, lungs were taken out for histopathological evaluation. Cytokine levels were determined in splenocyte culture supernatants by ELISA. The thickness of basement membrane and hyperplasic goblet cells in small airways were found to be significantly more in Group III than Group I. Furthermore, smooth muscle and epithelial thickness in small and large airways and hyperplasic goblet cell numbers in all sized airways of this treatment group were not significantly different from controls. Epithelial thickness in medium and large airways, hyperplasic goblet cells in all sized airways, and basement membrane in small and large airways were not significantly different in Group II when compared to controls. OVA-stimulated IL-5 levels was significantly higher in Group I when compared to Group III. OVA-stimulated IL-5 and spontaneous IL-5 levels were significantly higher in Group 11 than Group III. We demonstrate that subcutaneous and intratracheal Mycobacterium vaccae administered along with allergen has an ameliorating effect in the modulation of airway histopathological changes in OVA sensitized mice.Publication Metadata only Transfer of T cells from intranasal ovalbumin-immunized mice ameliorates allergic response in ova-sensitized recipient mice(OCEAN SIDE PUBLICATIONS INC, 2008) AKKOÇ, TUNÇ; Akkoc, Tunc; Eifan, Aarif O.; Aydogan, Metin; Ozkara, Selvinaz; Bahceciler, Nerin N.; Barlan, Isil B.Mucosal immunotherapy is suggested as a treatment strategy for tolerance induction in allergic diseases. The purpose of this study was to determine the effect of transferred splenic T cells from intranasal ovalbumin (OVA)-immunized mice to naive mice before sensitization on its impact of cytokine production and airway histopathology. BALB/c mice in group I received intranasal immunotherapy (days1-6), carboxylfluorescein succinyl ester (CFSE)-labeled splenocytes or splenic T cells were i.v. transferred to naive recipients (group 11) before OVA sensitization. Acute murine asthma model was established by two i.p. OVA injections (days 21 and 28) and seven OVA nebulizations (days 42-48) in groups 1, 11 and III. Groups If[ and IV served as asthma model and control, respectively. CFSE-labeled cells in splenocytes and lymph node lymphocytes, lung histopathology, IL-4, IL-10, and interferon (IFN) gamma cytokines of recipients were analyzed 24 hours after OVA nebulization challenge. CFSE-labeled T cells from group I were detected in spleen and regional lymph nodes of the OVA-sensitized recipients (group 11). Smooth muscle and thickness of airways were less in intranasal OVA immunotherapy and OVA-sensitized recipients when compared with the asthma model (p < 0.05). Area of inflammation was significantly suppressed in OVA-sensitized recipients compared with the asthma model (p < 0.01). IL-10 and IFN-gamma levels in splenocyte supernatants were significantly increased in intranasal immunotherapy and OVA-sensitized recipients compared with asthma model and controls (P < 0.01). IL-4 levels were significantly less in intranasal immunotherapy group and the OVA-sensitized recipient group when compared with asthma the model group (p < 0.05). This study suggests that intranasal immunotherapy with allergens regulates T-cell responses and ameliorates airway histopathology in sensitized mice, hence, encouraging mucosal tolerance induction as a suitable treatment of allergic diseases.Publication Metadata only Association between previous enterobiasis and current wheezing: Evaluation of 1018 children(OCEAN SIDE PUBLICATIONS INC, 2007) AKKOÇ, TUNÇ; Bahceciler, Nerin N.; Ozdemir, Cevdet; Kucukosmanoglu, Ercan; Arikan, Cigdem; Over, Ufuk; Karavelioglu, Salim; Akkoc, Tunc; Yazi, Didem; Yesil, Ozlem; Soysal, Ahmet; Bakir, Mustafa; Barlan, Isil B.The aim of this study was to investigate the association between parasitosis and allergy. We surveyed all children aged 4-12 years living in poor hygienic conditions in a shantytown of Istanbul. After obtaining data from the International Study of Asthma and Allergies in Childhood (ISAAC) and an additional questionnaire, performing a skin-prick test (SPT), and determining total IgE, stool and perianal tape specimens were obtained from 1018 participating children. The prevalence of past episodes of wheezing, current wheezing, asthma, and rhinitis was 31, 14.6, 10.7, and 26.2%, respectively. Parasitosis was present in 49.1%, Enterobius vermicularis (23.3%), being the most common. A history of treatment for enterobiasis was present in 37%. Comparison of children with and without current enterobiasis revealed no significant difference in allergic manifestations and SPT results, except for serum total IgE level (p = 0.018), whereas children with previous enterobiasis were more likely to have current wheezing (p = 0.012). Current wheezers were more likely to have previous enterobiasis (p = 0.01) and a higher maternal employment level (p = 0.036) when compared with those without. According to logistic regression analysis, covariables significantly positively related with current wheezing were previous enterobiasis (p = 0.003) and being : 5 years of age (p = 0.043), whereas being the first child of the family (p = 0.043) was negatively related. A previous infection with E. vermicularis was found to potentiate current wheezing in a population living in a shantytown in Istanbul.Publication Metadata only Adoptive transfer of splenocytes from immunotherapy, group ameliorating the histopathological changes and increased IL-10 and IFN-g levels in the recipient mice(MOSBY-ELSEVIER, 2007) AKKOÇ, TUNÇ; Akkoc, T.Publication Metadata only Predictors for the severity of bronchial hyperreactivity in childhood asthma(AMER THORACIC SOC, 2001) AKKOÇ, TUNÇ; Bahceciler, NN; Arikan, C; Akkoc, T; Barlan, IBBronchial hyperreactivity (BHR) is a common characteristic of asthma and is shown to be a risk factor in the development and outcome of asthma. In this study, we aimed to assess the risk factors at referral for the severity of BHR, which was determined at the end of a mean of 3 yr of follow-up in 98 children with asthma (mean (+/- SD) age, 11.0 (+/- 3.4) yr, male/female = 50/48]. We also evaluated the cross-sectional risk factors for the severity of BHR in the observed children. Information on risk factors at referral was collected from the computer records of the patients followed by an end-of-study visit. Lung function, skin-prick, and bronchial provocation tests were done and total serum IgE level was measured on this visit. The relationship between BHR and risk factors was investigated by multiple linear regression analysis. A lower level of FEV1% at referral was found to be an important predictor of more severe BHR at the end of the follow-up. None of the other risk factors evaluated predicted the severity of current BHR. We concluded that decreased lung function at referral is associated with a more severe BHR determined at the end of a 3-yr follow-up in children with asthma.Publication Metadata only Increased activation-induced cell death of high IFN-gamma-producing T(H)1 cells as a mechanism of T(H)2 predominance in atopic diseases(MOSBY-ELSEVIER, 2008) AKKOÇ, TUNÇ; Akkoc, Tunc; de Koning, Pieter J. A.; Ruckert, Beate; Barlan, Isil; Akdis, Mubeccel; Akdis, Cezmi A.Background: A dysregulated and T(H)2-biased immune response appears to be a key pathogenetic factor in atopic diseases. Increased activation and massive infiltration of T cells in the dermis without any evidence for the expansion of their numbers in peripheral blood characterize atopic dermatitis. Objective: To investigate differences and mechanisms of T(H)1 and T(H)2 cell activation-induced cell death (AICD) in atopic disease. Methods: Naive (CD4(+)CD45(+)RA) and memory (CD4(+)CD45(+)RO) T cells were isolated from healthy and atopic individuals. T(H)1 and T(H)2 subsets were in vitro differentiated. High IFN-gamma-producing T cells and CXCR3(+) T cells were purified, and AICD of isolated cells was determined in addition to expression of apoptosis receptors and caspase activation. Results: T(H)1 cells, particularly their high IFN-gamma-producing fraction, and CXCR3(+) T cells showed significantly increased apoptosis in atopic individuals. During their in vitro differentiation, both T(H)1 and T(H)2 cells of atopic individuals showed increased apoptosis compared with the healthy control group, with a significantly high apoptosis in T(H)1 cells. Increased expression of Fas, Fas-ligand, tumor necrosis factor receptor-H, and caspase activation was detected on T(H)1 cells that underwent apoptosis. Neutralization experiments demonstrated a dominant role of IFN-gamma and Fas-Fas-ligand interaction-mediated suicide in T(H)1 cell AICD. Conclusion: Predominant T(H)2 profile in atopic diseases might be a result of the increased tendency to activation and apoptosis of high IFN-gamma-producing T(H)1 cells.Publication Metadata only Mycobacterium vaccae immunization to OVA sensitized pregnant BALB/c mice suppressed placental and postnatal IL-5 and inducing IFN-gamma secretion(TAYLOR & FRANCIS INC, 2008) AKKOÇ, TUNÇ; Akkoc, Tunc; Eifan, Aarif O.; Ozdemir, Cevdet; Yazi, Didem; Yesil, Ozlem; Bahceciler, Nerin N.; Barlan, Isil B.Although the development of atopy in the newborn is determined by a multitude of factors, an intense Th1 stimulus early in life could be protective by facilitating a switch away from Th2. Aimed to determine the effect of single Mycobacterium vaccae (M. vaccae) immunization to OVA-sensitized pregnant mice on IL-5 and IFN-gamma secretion from placental lymphocytes and splenocytes of offspring. Pregnant BALB/c mice were divided into 4 groups, OVA-sensitized + M. vaccae immunized, OVA-sensitized, M. vaccae immunized and controls. Sensitization with OVA was initiated before mating, and aerosol OVA challenge were performed during pregnancy. M. vaccae immunization was performed on the 12(th) day of pregnancy. IL-5 and IFN-gamma levels of placental lymphocytes were analyzed on the 18(th) day of pregnancy and splenocytes of offspring on the 2(nd) and 28(th) days during postnatal period. A single administration of M. vaccae to OVA-sensitized pregnant mice downregulated IL-5 secretion and induced IFN-gamma secretion from placental lymphocytes. On the other hand, after M. vaccae immunization downregulation of IL-5 levels and upregulation of IFN-gamma secretion persisted in offspring when determined on 2(nd) and 28(th) days of life. Vaccination with M. Vaccae to OVA-sensitized pregnant BALB/c mice prevented Th2 immune responses by enhancing secretion of IFN-gamma and lowering IL-5 levels during pregnancy and the effect persisted during the postnatal period in offspring.Publication Metadata only IL-10 suppresses CD2-mediated T cell activation via SHP-1(PERGAMON-ELSEVIER SCIENCE LTD, 2009) AKKOÇ, TUNÇ; Taylor, Alison; Verhagen, Johan; Akkoc, Tunc; Wenig, Renate; Flory, Egbert; Blaser, Kurt; Akdis, Muebeccel; Akdisa, Cezrni A.Interleukin (IL)-10 is an essential suppressive cytokine and plays a key role in peripheral T cell tolerance to allergens, autoantigens, transplantation antigens and tumor antigens. However, the molecular mechanisms of direct T cell suppression by IL-10 are not fully understood. Here, we demonstrate that IL-10 directly inhibits CD2 signaling in T cells. T cell stimulation via CD2 alone induces activation and proliferation, when endogenous IL-10 sources are eliminated from cultures. IL-10 utilizes the src-homology-2 domain containing tyrosine phosphatase (SHP-1) to directly suppress T cell activation. The role of SHP-1 in IL-10-mediated suppression of CD2 co-stimulation on T cells is demonstrated by using dominant-negative SHP-1 over-expressing T cells and silencing endogenous SHP-1 by small inhibitory RNA. Findings are confirmed using both SHP-1-deficient mice and IL-10-deficient mice. CD2-induced proliferation is suppressed by exogenous IL-10 in IL-10-deficient, but not SHP-1-deficient murine T cells. In conclusion, SHP-1-mediated inhibition of CD2 signaling represents a novel mechanism for direct T cell suppression by IL-10. (C) 2008 Elsevier Ltd. All rights reserved.Publication Metadata only IL-10 inhibits CD28 and ICOS costimulations of T cells via src homology 2 domain-containing protein tyrosine phosphatase 1(MOSBY-ELSEVIER, 2007) AKKOÇ, TUNÇ; Taylor, Alison; Akdis, Muebeccel; Joss, Andrea; Akkoc, Tunc; Wenig, Renate; Colonna, Marco; Daigle, Isabelle; Flory, Egbert; Blaser, Kurt; Akdis, Cezmi A.Background: Specific T-cell activation requires T-cell receptor stimulation and the generation of costimulatory signals. Major costimulatory signals are delivered to T cells by the interaction of CD28 and inducible costimulator (ICOS). Objective: To investigate the molecular pathways involved in direct T-cell suppression by IL-10. Methods: T-cell proliferation analysis, immunoprecipitations, and Western blots were performed after T-cell receptor and CD28 and ICOS stimulations in the absence or presence of IL-10. Dominant-negative src homology 2 domain-containing protein tyrosine phosphatase I (SHP-1) overexpression, small inhibitory RNA, and SHP-1-deficient and IL-10-deficient mice were used. Results: IL-10 receptor-associated tyrosine kinase Tyk-2 acts as a constitutive reservoir for SHP-1 in resting T cells, and then tyrosine phosphorylates SHP-1 on IL-10 binding. SHP-1 rapidly binds to CD28 and ICOS costimulatory receptors and dephosphorylates them within minutes. In consequence, the binding of phosphatidylinositol 3-kinase to either costimulatory receptor no longer occurs, and downstream signaling is inhibited. Accordingly, spleen cells from SHP-1-deficient mice showed increased proliferation with CD28 and ICOS stimulation in comparison with wild-type mice, which was not suppressed by IL-10. Generation of dominant-negative SHP-1-overexpressing T cells or silencing of the SHP-1 gene by small inhibitory RNA both altered SHP-1 functions and abolished the T-cell suppressive effect of IL-10. Conclusion: The rapid inhibition of the CD28 or ICOS costimulatory pathways by SHP-1 represents a novel mechanism for direct T-cell suppression by IL-10. Clinical implications: Molecular mechanisms of direct T-cell suppression by IL-10 may provide a novel target for therapy of allergy/asthma and autoimmune disease.Publication Metadata only Impact of Mycobacterium vaccae immunization on lung histopathology in a murine model of chronic asthma(WILEY, 2003) AKKOÇ, TUNÇ; Ozdemir, C; Akkoc, T; Bahceciler, NN; Kucukercan, D; Barlan, IB; Basaran, MMBackground Therapeutic modalities of asthma have not been proved to be successful in reversing the already established chronic changes of airways. Objective We aimed to determine the impact of heat-killed Mycobacterium vaccae immunization, a potent Th1 stimulant, on chronic changes of asthma. Methods Newborn BALB/c mice were divided into three groups; mice in M. vaccae group received 10(7) colony-forming units (CFU)/50 muL of heat-killed M. vaccae subcutaneously on days 3, 14 and 42 before the development of chronic asthma model, whereas mice in control and chronic asthma groups received saline. Subsequently, mice in M. vaccae and chronic asthma groups were administered 10 mug/100 muL of ovalbumin (OVA) on days 43, 45, 47, 49, 51, 53 and 55 intraperitoneally, and 20 mug/10 muL of OVA on days 83, 86 and 89 intratracheally. Mice in control group received saline on the same days. Results Comparison of M. vaccae and chronic asthma groups showed statistically significant differences in goblet cell numbers, thickness of basement membrane and subepithelial smooth muscle of small, medium and large airways and epithelial thickness of medium airways. There was no significant difference between the control and M. vaccae groups except for goblet cell numbers of medium and large airways, and epithelial thickness of medium airways. Conclusion Results of our study suggested that immunization by M. vaccae of newborn mice would prevent some of the chronic changes of airways due to asthma.