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Thomas B. Nutman - One of the best experts on this subject based on the ideXlab platform.
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cytotoxic t lymphocyte associated Antigen 4 ctla 4 and programmed death 1 pd 1 mediated regulation of monofunctional and dual functional cd4 and cd8 t cell responses in a chronic helminth infection
Infection and Immunity, 2019Co-Authors: Anuradha Rajamanickam, Thomas B. Nutman, Subash Babu, Saravanan Munisankar, Chandrakumar DollaAbstract:Chronic helminth infections are known to be associated with the modulation of Antigen-specific T-cell responses. Strongyloides stercoralis infection is characterized by the downmodulation of Antigen-specific Th1 and Th17 responses and the upregulation of Th2 and Th9 responses. Immune homeostasis is partially maintained by negative regulators of T-cell activation, cytotoxic T-lymphocyte-associated Antigen 4 (CTLA-4) and programmed death 1 (PD-1), which dampen effector responses during chronic infections. However, their roles in S. stercoralis infection are yet to be defined. Therefore, we sought to determine the role of CTLA-4 and PD-1 in regulating CD4+ and CD8+ T-cell responses and examined the frequencies of monofunctional and dual functional Th1/T cytotoxic type 1 (Tc1), Th17/Tc17, Th2/Tc2, and Th9/Tc9 cells in S. stercoralis infection in 15 infected individuals stimulated with Parasite Antigen following CTLA-4 or PD-1 blockade. Our data reveal that CTLA-4 or PD-1 blockade results in significantly enhanced frequencies of monofunctional and dual functional Th1/Tc1 and Th17/Tc17 cells and, in contrast, diminishes the frequencies of monofunctional and dual functional Th2/Tc2 and Th9/Tc9 cells with Parasite Antigen stimulation in whole-blood cultures. Thus, we demonstrate that CTLA-4 and PD-1 limit the induction of particular T-cell subsets in S. stercoralis infection, which suggests the importance of CTLA-4 and PD-1 in immune modulation in a chronic helminth infection.
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elevated systemic and Parasite Antigen stimulated levels of type iii ifns in a chronic helminth infection and reversal following anthelmintic treatment
Frontiers in Immunology, 2018Co-Authors: Thomas B. Nutman, Subash Babu, Saravanan Munisankar, Chandrakumar Dolla, Anuradha Rajamanickam, Yukthi BhootraAbstract:Type III IFNs are important players in immunity to viral and bacterial infections. However, their association with helminth infections has not been examined. To explore the association of Type III IFNs with Strongyloides stercoralis (Ss) infection, we examined the systemic levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in Ss infected (INF, n = 44), helminth-uninfected (UN, n = 44) and in post-treatment INF individuals. We also examined the levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in whole blood culture supernatants stimulated with Ss somatic Antigens, or PPD or LPS. Finally, we performed correlations of systemic Type III IFN levels with absolute numbers of dendritic cell subsets. Ss infection is characterized by elevated systemic levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in comparison to UN individuals and a significant reduction following anthelmintic treatment. Ss infection is also characterized by elevated levels of unstimulated or Ss Antigen stimulated levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, CXCL10/IP-10 and a significant reduction following treatment. In addition, Ss infection is characterized by increased numbers of plasmacytoid and myeloid dendritic cells in comparison to UN individuals, with a significant reduction following anthelmintic treatment of INF individuals. Finally, Ss infection exhibits a significant positive correlation between the systemic levels of IFN lambda-2 and IFN lambda-3 and the numbers of plasmacytoid dendritic cells. Thus, Ss infection is characterized by elevations in systemic and Antigen-induced levels of Type III IFNs, which is positively associated with the numbers of plasmacytoid dendritic cells and reversed upon anthelmintic treatment.
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modulation of cd4 and cd8 t cell function and cytokine responses in strongyloides stercoralis infection by interleukin 27 il 27 and il 37
Infection and Immunity, 2017Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Paul Kumaran, Saravanan Munisankar, Chandrakumar Dolla, Yukthi Bhootra, Subash BabuAbstract:Strongyloides stercoralis infection is associated with diminished Antigen-specific Th1- and Th17-associated responses and enhanced Th2-associated responses. Interleukin-27 (IL-27) and IL-37 are two known anti-inflammatory cytokines that are highly expressed in S. stercoralis infection. We therefore wanted to examine the role of IL-27 and IL-37 in regulating CD4+ and CD8+ T cell responses in S. stercoralis infection. To this end, we examined the frequency of Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 cells in 15 S. stercoralis-infected individuals and 10 uninfected individuals stimulated with Parasite Antigen following IL-27 or IL-37 neutralization. We also examined the production of prototypical type 1, type 2, type 9, type 17, and type 22 cytokines in the whole-blood supernatants. Our data reveal that IL-27 or IL-37 neutralization resulted in significantly enhanced frequencies of Th1/Tc1, Th2/Tc2, Th17/Tc17, Th9, and Th22 cells with Parasite Antigen stimulation. There was no induction of any T cell response in uninfected individuals following Parasite Antigen stimulation and IL-27 or IL-37 neutralization. Moreover, we also observed increased production of gamma interferon (IFN-γ), IL-5, IL-9, IL-17, and IL-22 and decreased production of IL-10 following IL-27 and IL-37 neutralization and Parasite Antigen stimulation in whole-blood cultures. Thus, we demonstrate that IL-27 and IL-37 limit the induction of particular T cell subsets along with cytokine responses in S. stercoralis infections, which suggest the importance of IL-27 and IL-37 in immune modulation in a chronic helminth infection.
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Parasite Antigen specific regulation of th1 th2 and th17 responses in strongyloides stercoralis infection
Journal of Immunology, 2015Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Paul Kumaran, Saravanan Munisankar, Chandrakumar Dolla, Subash BabuAbstract:Chronic helminth infections are known to be associated with modulation of Ag-specific CD4 + T responses. However, the role of CD4 + T cell responses in human infection with Strongyloides stercoralis is not well defined. To examine the role of CD4 + T cells expressing Th1, Th2, and Th17 cytokines in strongyloidiasis, we compared the frequency (F o ) of these subsets in infected (INF) individuals with F o in S. stercoralis –uninfected (UN) individuals. INF individuals exhibited a significant decrease in the spontaneous and Ag-specific F o of both monofunctional and dual-functional Th1 cells compared with UN. Similarly, INF individuals also exhibited significantly decreased F o of monofunctional and dual-functional Th17 cells upon Ag stimulation compared with UN. In contrast, both the spontaneous and the Ag-induced F o of monofunctional and dual-functional Th2 cells was significantly increased in INF compared with UN individuals. This differential T cell response was predominantly Ag specific because it was abrogated upon control Ag or mitogen stimulation. The regulation of Th1, Th2, and Th17 cells was predominantly dependent on IL-10, whereas the regulation of Th2, but not Th1 or Th17, cells was also dependent on TGF-β. In addition, treatment of S. stercoralis infection significantly increased the Ag-specific F o of Th1 and Th17 cells and decreased the F o of Th2 cells in INF individuals. Thus, S. stercoralis infection is characterized by a Parasite Ag-dependent regulation of monofunctional and dual-functional Th1, Th2, and Th17 cells, a regulation also reversible by antihelminthic treatment.
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Parasite Antigen driven expansion of il 5 and il 5 th2 human subpopulations in lymphatic filariasis and their differential dependence on il 10 and tgfβ
PLOS Neglected Tropical Diseases, 2014Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Parakkal Jovvian George, Luke E. Hanna, Vedachalam Chandrasekaran, Paul Kumaran, Subash BabuAbstract:BACKGROUND Two different Th2 subsets have been defined recently on the basis of IL-5 expression - an IL-5(+)Th2 subset and an IL-5(-)Th2 subset in the setting of allergy. However, the role of these newly described CD4(+) T cells subpopulations has not been explored in other contexts. METHODS To study the role of the Th2 subpopulation in a chronic, tissue invasive parasitic infection (lymphatic filariasis), we examined the frequency of IL-5(+)IL-4(+)IL-13(+) CD4(+) T cells and IL-5(-)IL-4 IL-13(+) CD4(+) T cells in asymptomatic, infected individuals (INF) and compared them to frequencies (Fo) in filarial-uninfected (UN) individuals and to those with filarial lymphedema (CP). RESULTS INF individuals exhibited a significant increase in the spontaneously expressed and Antigen-induced Fo of both Th2 subpopulations compared to the UN and CP. Interestingly, there was a positive correlation between the Fo of IL-5(+)Th2 cells and the absolute eosinophil and neutrophil counts; in addition there was a positive correlation between the frequency of the CD4(+)IL-5(-)Th2 subpopulation and the levels of Parasite Antigen - specific IgE and IgG4 in INF individuals. Moreover, blockade of IL-10 and/or TGFβ demonstrated that each of these 2 regulatory cytokines exert opposite effects on the different Th2 subsets. Finally, in those INF individuals cured of infection by anti-filarial therapy, there was a significantly decreased Fo of both Th2 subsets. CONCLUSIONS Our findings suggest that both IL-5(+) and IL-5(-)Th2 cells play an important role in the regulation of immune responses in filarial infection and that these two Th2 subpopulations may be regulated by different cytokine-receptor mediated processes.
Subash Babu - One of the best experts on this subject based on the ideXlab platform.
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cytotoxic t lymphocyte associated Antigen 4 ctla 4 and programmed death 1 pd 1 mediated regulation of monofunctional and dual functional cd4 and cd8 t cell responses in a chronic helminth infection
Infection and Immunity, 2019Co-Authors: Anuradha Rajamanickam, Thomas B. Nutman, Subash Babu, Saravanan Munisankar, Chandrakumar DollaAbstract:Chronic helminth infections are known to be associated with the modulation of Antigen-specific T-cell responses. Strongyloides stercoralis infection is characterized by the downmodulation of Antigen-specific Th1 and Th17 responses and the upregulation of Th2 and Th9 responses. Immune homeostasis is partially maintained by negative regulators of T-cell activation, cytotoxic T-lymphocyte-associated Antigen 4 (CTLA-4) and programmed death 1 (PD-1), which dampen effector responses during chronic infections. However, their roles in S. stercoralis infection are yet to be defined. Therefore, we sought to determine the role of CTLA-4 and PD-1 in regulating CD4+ and CD8+ T-cell responses and examined the frequencies of monofunctional and dual functional Th1/T cytotoxic type 1 (Tc1), Th17/Tc17, Th2/Tc2, and Th9/Tc9 cells in S. stercoralis infection in 15 infected individuals stimulated with Parasite Antigen following CTLA-4 or PD-1 blockade. Our data reveal that CTLA-4 or PD-1 blockade results in significantly enhanced frequencies of monofunctional and dual functional Th1/Tc1 and Th17/Tc17 cells and, in contrast, diminishes the frequencies of monofunctional and dual functional Th2/Tc2 and Th9/Tc9 cells with Parasite Antigen stimulation in whole-blood cultures. Thus, we demonstrate that CTLA-4 and PD-1 limit the induction of particular T-cell subsets in S. stercoralis infection, which suggests the importance of CTLA-4 and PD-1 in immune modulation in a chronic helminth infection.
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elevated systemic and Parasite Antigen stimulated levels of type iii ifns in a chronic helminth infection and reversal following anthelmintic treatment
Frontiers in Immunology, 2018Co-Authors: Thomas B. Nutman, Subash Babu, Saravanan Munisankar, Chandrakumar Dolla, Anuradha Rajamanickam, Yukthi BhootraAbstract:Type III IFNs are important players in immunity to viral and bacterial infections. However, their association with helminth infections has not been examined. To explore the association of Type III IFNs with Strongyloides stercoralis (Ss) infection, we examined the systemic levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in Ss infected (INF, n = 44), helminth-uninfected (UN, n = 44) and in post-treatment INF individuals. We also examined the levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in whole blood culture supernatants stimulated with Ss somatic Antigens, or PPD or LPS. Finally, we performed correlations of systemic Type III IFN levels with absolute numbers of dendritic cell subsets. Ss infection is characterized by elevated systemic levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, IL-10, and CXCL10/IP-10 in comparison to UN individuals and a significant reduction following anthelmintic treatment. Ss infection is also characterized by elevated levels of unstimulated or Ss Antigen stimulated levels of IFN lambda-1, IFN lambda-2 and IFN lambda-3, CXCL10/IP-10 and a significant reduction following treatment. In addition, Ss infection is characterized by increased numbers of plasmacytoid and myeloid dendritic cells in comparison to UN individuals, with a significant reduction following anthelmintic treatment of INF individuals. Finally, Ss infection exhibits a significant positive correlation between the systemic levels of IFN lambda-2 and IFN lambda-3 and the numbers of plasmacytoid dendritic cells. Thus, Ss infection is characterized by elevations in systemic and Antigen-induced levels of Type III IFNs, which is positively associated with the numbers of plasmacytoid dendritic cells and reversed upon anthelmintic treatment.
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modulation of cd4 and cd8 t cell function and cytokine responses in strongyloides stercoralis infection by interleukin 27 il 27 and il 37
Infection and Immunity, 2017Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Paul Kumaran, Saravanan Munisankar, Chandrakumar Dolla, Yukthi Bhootra, Subash BabuAbstract:Strongyloides stercoralis infection is associated with diminished Antigen-specific Th1- and Th17-associated responses and enhanced Th2-associated responses. Interleukin-27 (IL-27) and IL-37 are two known anti-inflammatory cytokines that are highly expressed in S. stercoralis infection. We therefore wanted to examine the role of IL-27 and IL-37 in regulating CD4+ and CD8+ T cell responses in S. stercoralis infection. To this end, we examined the frequency of Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 cells in 15 S. stercoralis-infected individuals and 10 uninfected individuals stimulated with Parasite Antigen following IL-27 or IL-37 neutralization. We also examined the production of prototypical type 1, type 2, type 9, type 17, and type 22 cytokines in the whole-blood supernatants. Our data reveal that IL-27 or IL-37 neutralization resulted in significantly enhanced frequencies of Th1/Tc1, Th2/Tc2, Th17/Tc17, Th9, and Th22 cells with Parasite Antigen stimulation. There was no induction of any T cell response in uninfected individuals following Parasite Antigen stimulation and IL-27 or IL-37 neutralization. Moreover, we also observed increased production of gamma interferon (IFN-γ), IL-5, IL-9, IL-17, and IL-22 and decreased production of IL-10 following IL-27 and IL-37 neutralization and Parasite Antigen stimulation in whole-blood cultures. Thus, we demonstrate that IL-27 and IL-37 limit the induction of particular T cell subsets along with cytokine responses in S. stercoralis infections, which suggest the importance of IL-27 and IL-37 in immune modulation in a chronic helminth infection.
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Parasite Antigen specific regulation of th1 th2 and th17 responses in strongyloides stercoralis infection
Journal of Immunology, 2015Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Paul Kumaran, Saravanan Munisankar, Chandrakumar Dolla, Subash BabuAbstract:Chronic helminth infections are known to be associated with modulation of Ag-specific CD4 + T responses. However, the role of CD4 + T cell responses in human infection with Strongyloides stercoralis is not well defined. To examine the role of CD4 + T cells expressing Th1, Th2, and Th17 cytokines in strongyloidiasis, we compared the frequency (F o ) of these subsets in infected (INF) individuals with F o in S. stercoralis –uninfected (UN) individuals. INF individuals exhibited a significant decrease in the spontaneous and Ag-specific F o of both monofunctional and dual-functional Th1 cells compared with UN. Similarly, INF individuals also exhibited significantly decreased F o of monofunctional and dual-functional Th17 cells upon Ag stimulation compared with UN. In contrast, both the spontaneous and the Ag-induced F o of monofunctional and dual-functional Th2 cells was significantly increased in INF compared with UN individuals. This differential T cell response was predominantly Ag specific because it was abrogated upon control Ag or mitogen stimulation. The regulation of Th1, Th2, and Th17 cells was predominantly dependent on IL-10, whereas the regulation of Th2, but not Th1 or Th17, cells was also dependent on TGF-β. In addition, treatment of S. stercoralis infection significantly increased the Ag-specific F o of Th1 and Th17 cells and decreased the F o of Th2 cells in INF individuals. Thus, S. stercoralis infection is characterized by a Parasite Ag-dependent regulation of monofunctional and dual-functional Th1, Th2, and Th17 cells, a regulation also reversible by antihelminthic treatment.
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Parasite Antigen driven expansion of il 5 and il 5 th2 human subpopulations in lymphatic filariasis and their differential dependence on il 10 and tgfβ
PLOS Neglected Tropical Diseases, 2014Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Parakkal Jovvian George, Luke E. Hanna, Vedachalam Chandrasekaran, Paul Kumaran, Subash BabuAbstract:BACKGROUND Two different Th2 subsets have been defined recently on the basis of IL-5 expression - an IL-5(+)Th2 subset and an IL-5(-)Th2 subset in the setting of allergy. However, the role of these newly described CD4(+) T cells subpopulations has not been explored in other contexts. METHODS To study the role of the Th2 subpopulation in a chronic, tissue invasive parasitic infection (lymphatic filariasis), we examined the frequency of IL-5(+)IL-4(+)IL-13(+) CD4(+) T cells and IL-5(-)IL-4 IL-13(+) CD4(+) T cells in asymptomatic, infected individuals (INF) and compared them to frequencies (Fo) in filarial-uninfected (UN) individuals and to those with filarial lymphedema (CP). RESULTS INF individuals exhibited a significant increase in the spontaneously expressed and Antigen-induced Fo of both Th2 subpopulations compared to the UN and CP. Interestingly, there was a positive correlation between the Fo of IL-5(+)Th2 cells and the absolute eosinophil and neutrophil counts; in addition there was a positive correlation between the frequency of the CD4(+)IL-5(-)Th2 subpopulation and the levels of Parasite Antigen - specific IgE and IgG4 in INF individuals. Moreover, blockade of IL-10 and/or TGFβ demonstrated that each of these 2 regulatory cytokines exert opposite effects on the different Th2 subsets. Finally, in those INF individuals cured of infection by anti-filarial therapy, there was a significantly decreased Fo of both Th2 subsets. CONCLUSIONS Our findings suggest that both IL-5(+) and IL-5(-)Th2 cells play an important role in the regulation of immune responses in filarial infection and that these two Th2 subpopulations may be regulated by different cytokine-receptor mediated processes.
Rajamanickam Anuradha - One of the best experts on this subject based on the ideXlab platform.
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modulation of cd4 and cd8 t cell function and cytokine responses in strongyloides stercoralis infection by interleukin 27 il 27 and il 37
Infection and Immunity, 2017Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Paul Kumaran, Saravanan Munisankar, Chandrakumar Dolla, Yukthi Bhootra, Subash BabuAbstract:Strongyloides stercoralis infection is associated with diminished Antigen-specific Th1- and Th17-associated responses and enhanced Th2-associated responses. Interleukin-27 (IL-27) and IL-37 are two known anti-inflammatory cytokines that are highly expressed in S. stercoralis infection. We therefore wanted to examine the role of IL-27 and IL-37 in regulating CD4+ and CD8+ T cell responses in S. stercoralis infection. To this end, we examined the frequency of Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 cells in 15 S. stercoralis-infected individuals and 10 uninfected individuals stimulated with Parasite Antigen following IL-27 or IL-37 neutralization. We also examined the production of prototypical type 1, type 2, type 9, type 17, and type 22 cytokines in the whole-blood supernatants. Our data reveal that IL-27 or IL-37 neutralization resulted in significantly enhanced frequencies of Th1/Tc1, Th2/Tc2, Th17/Tc17, Th9, and Th22 cells with Parasite Antigen stimulation. There was no induction of any T cell response in uninfected individuals following Parasite Antigen stimulation and IL-27 or IL-37 neutralization. Moreover, we also observed increased production of gamma interferon (IFN-γ), IL-5, IL-9, IL-17, and IL-22 and decreased production of IL-10 following IL-27 and IL-37 neutralization and Parasite Antigen stimulation in whole-blood cultures. Thus, we demonstrate that IL-27 and IL-37 limit the induction of particular T cell subsets along with cytokine responses in S. stercoralis infections, which suggest the importance of IL-27 and IL-37 in immune modulation in a chronic helminth infection.
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Parasite Antigen specific regulation of th1 th2 and th17 responses in strongyloides stercoralis infection
Journal of Immunology, 2015Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Paul Kumaran, Saravanan Munisankar, Chandrakumar Dolla, Subash BabuAbstract:Chronic helminth infections are known to be associated with modulation of Ag-specific CD4 + T responses. However, the role of CD4 + T cell responses in human infection with Strongyloides stercoralis is not well defined. To examine the role of CD4 + T cells expressing Th1, Th2, and Th17 cytokines in strongyloidiasis, we compared the frequency (F o ) of these subsets in infected (INF) individuals with F o in S. stercoralis –uninfected (UN) individuals. INF individuals exhibited a significant decrease in the spontaneous and Ag-specific F o of both monofunctional and dual-functional Th1 cells compared with UN. Similarly, INF individuals also exhibited significantly decreased F o of monofunctional and dual-functional Th17 cells upon Ag stimulation compared with UN. In contrast, both the spontaneous and the Ag-induced F o of monofunctional and dual-functional Th2 cells was significantly increased in INF compared with UN individuals. This differential T cell response was predominantly Ag specific because it was abrogated upon control Ag or mitogen stimulation. The regulation of Th1, Th2, and Th17 cells was predominantly dependent on IL-10, whereas the regulation of Th2, but not Th1 or Th17, cells was also dependent on TGF-β. In addition, treatment of S. stercoralis infection significantly increased the Ag-specific F o of Th1 and Th17 cells and decreased the F o of Th2 cells in INF individuals. Thus, S. stercoralis infection is characterized by a Parasite Ag-dependent regulation of monofunctional and dual-functional Th1, Th2, and Th17 cells, a regulation also reversible by antihelminthic treatment.
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Parasite Antigen driven expansion of il 5 and il 5 th2 human subpopulations in lymphatic filariasis and their differential dependence on il 10 and tgfβ
PLOS Neglected Tropical Diseases, 2014Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Parakkal Jovvian George, Luke E. Hanna, Vedachalam Chandrasekaran, Paul Kumaran, Subash BabuAbstract:BACKGROUND Two different Th2 subsets have been defined recently on the basis of IL-5 expression - an IL-5(+)Th2 subset and an IL-5(-)Th2 subset in the setting of allergy. However, the role of these newly described CD4(+) T cells subpopulations has not been explored in other contexts. METHODS To study the role of the Th2 subpopulation in a chronic, tissue invasive parasitic infection (lymphatic filariasis), we examined the frequency of IL-5(+)IL-4(+)IL-13(+) CD4(+) T cells and IL-5(-)IL-4 IL-13(+) CD4(+) T cells in asymptomatic, infected individuals (INF) and compared them to frequencies (Fo) in filarial-uninfected (UN) individuals and to those with filarial lymphedema (CP). RESULTS INF individuals exhibited a significant increase in the spontaneously expressed and Antigen-induced Fo of both Th2 subpopulations compared to the UN and CP. Interestingly, there was a positive correlation between the Fo of IL-5(+)Th2 cells and the absolute eosinophil and neutrophil counts; in addition there was a positive correlation between the frequency of the CD4(+)IL-5(-)Th2 subpopulation and the levels of Parasite Antigen - specific IgE and IgG4 in INF individuals. Moreover, blockade of IL-10 and/or TGFβ demonstrated that each of these 2 regulatory cytokines exert opposite effects on the different Th2 subsets. Finally, in those INF individuals cured of infection by anti-filarial therapy, there was a significantly decreased Fo of both Th2 subsets. CONCLUSIONS Our findings suggest that both IL-5(+) and IL-5(-)Th2 cells play an important role in the regulation of immune responses in filarial infection and that these two Th2 subpopulations may be regulated by different cytokine-receptor mediated processes.
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il 4 tgf β and il 1 dependent expansion of Parasite Antigen specific th9 cells is associated with clinical pathology in human lymphatic filariasis
Journal of Immunology, 2013Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Parakkal Jovvian George, Vedachalam Chandrasekaran, Paul Kumaran, Luke Elizabeth Hanna, Subash BabuAbstract:Th9 cells are a subset of CD4 + T cells, shown to be important in allergy, autoimmunity, and antitumor responses; however, their role in human infectious diseases has not been explored in detail. We identified a population of IL-9 and IL-10 coexpressing cells (lacking IL-4 expression) in normal individuals. These cells respond to Antigenic and mitogenic stimulation, but are distinct from IL-9 + Th2 cells. We also demonstrate that these Th9 cells exhibit Ag-specific expansion in a chronic helminth infection (lymphatic filariasis). Comparison of Th9 responses reveals that individuals with pathology associated with filarial infection exhibit significantly expanded frequencies of filarial Ag-induced Th9 cells, but not of IL9 + Th2 cells in comparison with filarial-infected individuals without associated disease. Moreover, the per cell production of IL-9 is significantly higher in Th9 cells compared with IL9 + Th2 cells, indicating that the Th9 cells are the predominant CD4 + T cell subset producing IL-9 in the context of human infection. This expansion was reflected in elevated Ag-stimulated IL-9 cytokine levels in whole blood culture supernatants. Finally, the frequencies of Th9 cells correlated positively with the severity of lymphedema (and presumed inflammation) in filarial-diseased individuals. This expansion of Th9 cells was dependent on IL-4, TGF-β, and IL-1 in vitro. We have therefore identified an important human CD4 + T cell subpopulation coexpressing IL-9 and IL-10, but not IL-4, the expansion of which is associated with disease in chronic lymphatic filariasis and could potentially have an important role in the pathogenesis of other inflammatory disorders.
Siddhartha Mahanty - One of the best experts on this subject based on the ideXlab platform.
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in vitro analysis of albendazole sulfoxide enantiomers shows that r albendazole sulfoxide is the active enantiomer against taenia solium
Antimicrobial Agents and Chemotherapy, 2013Co-Authors: Adriana Paredes, Tiago C Lourenco, Miguel Marzal, Andrea Rivera, Siddhartha Mahanty, Cristina Guerragiraldez, Pierre Dorny, Hector H Garcia, Theodore E NashAbstract:ABSTRACT Albendazole is an anthelmintic drug widely used in the treatment of neurocysticercosis (NCC), an infection of the brain with Taenia solium cysts. However, drug levels of its active metabolite, albendazole sulfoxide (ABZSO), are erratic, likely resulting in decreased efficacy and suboptimal cure rates in NCC. Racemic albendazole sulfoxide is composed of ABZSO (+)-( R )- and (−)-( S ) enantiomers that have been shown to differ in pharmacokinetics and activity against other helminths. The antiparasitic activities of racemic ABZSO and its (+)-( R )- and (−)-( S ) enantiomers against T. solium cysts were evaluated in vitro . Parasites were collected from naturally infected pigs, cultured, and exposed to the racemic mixture or to each enantiomer (range, 10 to 500 ng/ml) or to praziquantel as a reference drug. The activity of each compound against cysts was assayed by measuring the ability to evaginate and inhibition of alkaline phosphatase (AP) and Parasite Antigen release. (+)-( R )-ABZSO was significantly more active than (−)-( S )-ABZSO in suppressing the release of AP and Antigen into the supernatant in a dose- and time-dependent manner, indicating that most of the activity of ABZSO resides in the (+)-( R ) enantiomer. Use of this enantiomer alone may lead to increased efficacy and/or less toxicity compared to albendazole.
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regulation of Parasite Antigen driven immune responses by interleukin 10 il 10 and il 12 in lymphatic filariasis
Infection and Immunity, 1997Co-Authors: Siddhartha Mahanty, V. Kumaraswami, Manickam Ravichandran, U Raman, K Jayaraman, Thomas B. NutmanAbstract:We investigated the mechanisms by which interleukin-10 (IL-10) regulates Antigen-specific hyporesponsiveness in asymptomatic microfilaremic (MF) individuals. Peripheral blood mononuclear cells from MF individuals (n = 11) were stimulated in vitro with Brugia malayi Antigen (BMA) or mycobacterial purified protein derivative (PPD) in the presence of neutralizing anti-IL-10 or isotype control monoclonal antibodies. As expected, BMA stimulated little or no gamma interferon (IFN-gamma) secretion in MF individuals, whereas PPD stimulated IFN-gamma in all but one. Neutralization of endogenous BMA-driven IL-10 secretion led to augmentation of IFN-gamma in seven of nine MF individuals (1.5- to 10-fold) and did so in a BMA-specific manner (PPD-driven IFN-gamma was augmented in only two of eight MF individuals and only 1.5- to 2-fold), indicating that IL-10 downregulates type 1 responses in these individuals. Type 2 responses (IL-5 secretion) were unaffected by the IL-10 blockade. To assess whether IL-12 could reverse the type 1 downregulation observed, the effect of recombinant human IL-12 (rhIL-12) on BMA-driven IL-5 and IFN-gamma production was also evaluated. rhIL-12 augmented both BMA- and PPD-driven IFN-gamma production 5- to 10-fold in six of nine MF individuals. These data demonstrate that IL-10 downregulates BMA-driven type 1 responses and that IL-12 can overcome downregulation of Th1 responses associated with MF but does so in a non-Antigen-specific manner.
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elevated il 10 mrna expression and downregulation of th1 type cytokines in microfilaraemic individuals with wuchereria bancrofti infection
Parasite Immunology, 1997Co-Authors: Manickam Ravichandran, Siddhartha Mahanty, Thomas B. Nutman, V. Kumaraswami, Kunthala JayaramanAbstract:: To understand the molecular basis of Parasite-specific anergy in human lymphatic filariasis caused by the nematode Wuchereria bancrofti, Parasite Antigen-dependent cellular proliferation and cytokine gene expression were investigated. By reverse transcriptase polymerase chain reaction (RT-PCR), the levels of cytokine mRNA were determined in the peripheral blood mononuclear cells (PBMCs) of different clinical groups of filariasis patients. This includes individuals with circulating microfilariae (MF), patients with chronic lymphatic obstruction (CP), and exposed but uninfected individuals (EN). Those with CP exhibited both a Th2 and a Th1 Parasite Antigen-driven response. In PBMCs from those with MF, there was a marked downregulation of cellular response to Parasite Antigens, with lowered expression of Th1-specific cytokines (IFN-gamma and IL-2) and this was paralleled by increased IL-10 expression. The EN individuals had a purely Th1-type pattern with absence of IL-4 and IL-5 expression. Further, the mRNA expression of the costimulatory surface marker, CD80 (B7-1), was not associated with either disease status or IL-10 expression. There was a significant negative correlation between IL-10 mRNA expression and PBMC proliferation in the MF individuals, thus indicating the possible role of IL-10 in Antigen-specific hyporesponsiveness.
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High Levels of Spontaneous and Parasite Antigen-Driven Interieukin-10 Production Are Associated with Antigen-Specific Hyporesponsiveness in Human Lymphatic Filariasis
Journal of Infectious Diseases, 1996Co-Authors: Siddhartha Mahanty, Eric A. Ottesen, V. Kumaraswami, Stacey N. Mollis, Manickam Ravichandran, John S. Abrams, Kunthala Jayaraman, Thomas B. NutmanAbstract:To determine whether counterregulation by interleukin (IL)-10 plays a role in the generation or maintenance of the Antigen-specific hyporesponsiveness seen in asymptomatic microfilaremic (MF) patients, Parasite Antigen (PAg)- and nonParasite Antigen (NPAg)-driven IL-10 production by peripheral blood mononuclear cells (PBMC) was studied in 10 MF patients and in ll patients with chronic lymphatic pathology (CP). PBMC from MF patients spontaneously secreted 10-fold more IL-10 than did PBMC from patients with CP. PAg also induced significantly more IL-10 production by PBMC from CP patients. There was a negative correlation between PAg driven IL-10 production by PBMC and PAg-specific T cell proliferation in the MF group. IL-10 secretion by plastic adherent cells from MF persons was higher in response to PAg than NPAg, whereas IL-6 and tumor necrosis factor-alpha secretion were equivalent for PAg and NPAg, suggesting that PAg preferentially induces IL-10 secretion in these cells. Thus, PAg-induced IL-10 likely plays an important role in down-regulating Antigen-specific proliferative responses in MF patients.
Paul Kumaran - One of the best experts on this subject based on the ideXlab platform.
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modulation of cd4 and cd8 t cell function and cytokine responses in strongyloides stercoralis infection by interleukin 27 il 27 and il 37
Infection and Immunity, 2017Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Paul Kumaran, Saravanan Munisankar, Chandrakumar Dolla, Yukthi Bhootra, Subash BabuAbstract:Strongyloides stercoralis infection is associated with diminished Antigen-specific Th1- and Th17-associated responses and enhanced Th2-associated responses. Interleukin-27 (IL-27) and IL-37 are two known anti-inflammatory cytokines that are highly expressed in S. stercoralis infection. We therefore wanted to examine the role of IL-27 and IL-37 in regulating CD4+ and CD8+ T cell responses in S. stercoralis infection. To this end, we examined the frequency of Th1/Tc1, Th2/Tc2, Th9/Tc9, Th17/Tc17, and Th22/Tc22 cells in 15 S. stercoralis-infected individuals and 10 uninfected individuals stimulated with Parasite Antigen following IL-27 or IL-37 neutralization. We also examined the production of prototypical type 1, type 2, type 9, type 17, and type 22 cytokines in the whole-blood supernatants. Our data reveal that IL-27 or IL-37 neutralization resulted in significantly enhanced frequencies of Th1/Tc1, Th2/Tc2, Th17/Tc17, Th9, and Th22 cells with Parasite Antigen stimulation. There was no induction of any T cell response in uninfected individuals following Parasite Antigen stimulation and IL-27 or IL-37 neutralization. Moreover, we also observed increased production of gamma interferon (IFN-γ), IL-5, IL-9, IL-17, and IL-22 and decreased production of IL-10 following IL-27 and IL-37 neutralization and Parasite Antigen stimulation in whole-blood cultures. Thus, we demonstrate that IL-27 and IL-37 limit the induction of particular T cell subsets along with cytokine responses in S. stercoralis infections, which suggest the importance of IL-27 and IL-37 in immune modulation in a chronic helminth infection.
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Parasite Antigen specific regulation of th1 th2 and th17 responses in strongyloides stercoralis infection
Journal of Immunology, 2015Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Paul Kumaran, Saravanan Munisankar, Chandrakumar Dolla, Subash BabuAbstract:Chronic helminth infections are known to be associated with modulation of Ag-specific CD4 + T responses. However, the role of CD4 + T cell responses in human infection with Strongyloides stercoralis is not well defined. To examine the role of CD4 + T cells expressing Th1, Th2, and Th17 cytokines in strongyloidiasis, we compared the frequency (F o ) of these subsets in infected (INF) individuals with F o in S. stercoralis –uninfected (UN) individuals. INF individuals exhibited a significant decrease in the spontaneous and Ag-specific F o of both monofunctional and dual-functional Th1 cells compared with UN. Similarly, INF individuals also exhibited significantly decreased F o of monofunctional and dual-functional Th17 cells upon Ag stimulation compared with UN. In contrast, both the spontaneous and the Ag-induced F o of monofunctional and dual-functional Th2 cells was significantly increased in INF compared with UN individuals. This differential T cell response was predominantly Ag specific because it was abrogated upon control Ag or mitogen stimulation. The regulation of Th1, Th2, and Th17 cells was predominantly dependent on IL-10, whereas the regulation of Th2, but not Th1 or Th17, cells was also dependent on TGF-β. In addition, treatment of S. stercoralis infection significantly increased the Ag-specific F o of Th1 and Th17 cells and decreased the F o of Th2 cells in INF individuals. Thus, S. stercoralis infection is characterized by a Parasite Ag-dependent regulation of monofunctional and dual-functional Th1, Th2, and Th17 cells, a regulation also reversible by antihelminthic treatment.
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Parasite Antigen driven expansion of il 5 and il 5 th2 human subpopulations in lymphatic filariasis and their differential dependence on il 10 and tgfβ
PLOS Neglected Tropical Diseases, 2014Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Parakkal Jovvian George, Luke E. Hanna, Vedachalam Chandrasekaran, Paul Kumaran, Subash BabuAbstract:BACKGROUND Two different Th2 subsets have been defined recently on the basis of IL-5 expression - an IL-5(+)Th2 subset and an IL-5(-)Th2 subset in the setting of allergy. However, the role of these newly described CD4(+) T cells subpopulations has not been explored in other contexts. METHODS To study the role of the Th2 subpopulation in a chronic, tissue invasive parasitic infection (lymphatic filariasis), we examined the frequency of IL-5(+)IL-4(+)IL-13(+) CD4(+) T cells and IL-5(-)IL-4 IL-13(+) CD4(+) T cells in asymptomatic, infected individuals (INF) and compared them to frequencies (Fo) in filarial-uninfected (UN) individuals and to those with filarial lymphedema (CP). RESULTS INF individuals exhibited a significant increase in the spontaneously expressed and Antigen-induced Fo of both Th2 subpopulations compared to the UN and CP. Interestingly, there was a positive correlation between the Fo of IL-5(+)Th2 cells and the absolute eosinophil and neutrophil counts; in addition there was a positive correlation between the frequency of the CD4(+)IL-5(-)Th2 subpopulation and the levels of Parasite Antigen - specific IgE and IgG4 in INF individuals. Moreover, blockade of IL-10 and/or TGFβ demonstrated that each of these 2 regulatory cytokines exert opposite effects on the different Th2 subsets. Finally, in those INF individuals cured of infection by anti-filarial therapy, there was a significantly decreased Fo of both Th2 subsets. CONCLUSIONS Our findings suggest that both IL-5(+) and IL-5(-)Th2 cells play an important role in the regulation of immune responses in filarial infection and that these two Th2 subpopulations may be regulated by different cytokine-receptor mediated processes.
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il 4 tgf β and il 1 dependent expansion of Parasite Antigen specific th9 cells is associated with clinical pathology in human lymphatic filariasis
Journal of Immunology, 2013Co-Authors: Rajamanickam Anuradha, Thomas B. Nutman, Parakkal Jovvian George, Vedachalam Chandrasekaran, Paul Kumaran, Luke Elizabeth Hanna, Subash BabuAbstract:Th9 cells are a subset of CD4 + T cells, shown to be important in allergy, autoimmunity, and antitumor responses; however, their role in human infectious diseases has not been explored in detail. We identified a population of IL-9 and IL-10 coexpressing cells (lacking IL-4 expression) in normal individuals. These cells respond to Antigenic and mitogenic stimulation, but are distinct from IL-9 + Th2 cells. We also demonstrate that these Th9 cells exhibit Ag-specific expansion in a chronic helminth infection (lymphatic filariasis). Comparison of Th9 responses reveals that individuals with pathology associated with filarial infection exhibit significantly expanded frequencies of filarial Ag-induced Th9 cells, but not of IL9 + Th2 cells in comparison with filarial-infected individuals without associated disease. Moreover, the per cell production of IL-9 is significantly higher in Th9 cells compared with IL9 + Th2 cells, indicating that the Th9 cells are the predominant CD4 + T cell subset producing IL-9 in the context of human infection. This expansion was reflected in elevated Ag-stimulated IL-9 cytokine levels in whole blood culture supernatants. Finally, the frequencies of Th9 cells correlated positively with the severity of lymphedema (and presumed inflammation) in filarial-diseased individuals. This expansion of Th9 cells was dependent on IL-4, TGF-β, and IL-1 in vitro. We have therefore identified an important human CD4 + T cell subpopulation coexpressing IL-9 and IL-10, but not IL-4, the expansion of which is associated with disease in chronic lymphatic filariasis and could potentially have an important role in the pathogenesis of other inflammatory disorders.
