scholarly journals Antagonizing Deactivating Cytokines To Enhance Host Defense and Chemotherapy in Experimental Visceral Leishmaniasis

2005 ◽  
Vol 73 (7) ◽  
pp. 3903-3911 ◽  
Author(s):  
Henry W. Murray ◽  
Kathleen C. Flanders ◽  
Debra D. Donaldson ◽  
Joseph P. Sypek ◽  
Philip J. Gotwals ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Th1 Cell ◽  
Pentavalent Antimony ◽  
Ifn Γ ◽  
Liver Infection

ABSTRACT In experimental visceral leishmaniasis, inhibition of interleukin 10 (IL-10) signaling enhances Th1-cell-associated responses, promoting gamma interferon (IFN-γ) secretion, granuloma assembly, macrophage activation with substantial liver parasite killing, and synergy with pentavalent antimony (Sb) chemotherapy. To determine if inhibiting other suppressive cytokines has similar therapeutic potential, Leishmania donovani-infected BALB/c mice were injected with anti-IL-4 monoclonal antibody or receptor fusion antagonists of IL-13 or transforming growth factor β (TGF-β). Targeting IL-13 or TGF-β enabled inhibition of L. donovani replication but little parasite killing; anti-IL-4 had no effect. None of the three antagonists promoted IFN-γ production, granuloma maturation, or Sb efficacy. Excess IL-13 and TGF-β exacerbated liver infection; however, effects were transient. Among IL-10, IL-4, IL-13, and TGF-β, cytokines capable of disabling Th1-cell mechanisms (including those which support chemotherapy), IL-10 appears to be the appropriate target for therapeutic inhibition in visceral L. donovani infection.

scholarly journals Effects of Gamma Interferon, Interleukin-10, and Transforming Growth Factor β on the Survival of Mycobacterium avium subsp. paratuberculosis in Monocyte-Derived Macrophages from Naturally Infected Cattle

2004 ◽  
Vol 72 (4) ◽  
pp. 1974-1982 ◽  
Author(s):  
M. S. Khalifeh ◽  
J. R. Stabel
Keyword(s):  
Growth Factor ◽  
Cell Cultures ◽  
Mycobacterium Avium ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Ifn Γ ◽  
Culture Supernatants

ABSTRACT Gamma interferon (IFN-γ) plays a significant role in the control of mycobacterial infections, including Mycobacterium avium subsp. paratuberculosis. However, the contribution of other immunoregulatory cytokines, such as interleukin-10 (IL-10) and transforming growth factor β (TGF-β), in Johne's disease has not been investigated as yet. In this study, we examined the effects of in vivo and in vitro infection with M. avium subsp. paratuberculosis on the production of IFN-γ, IL-10, and TGF-β by peripheral blood mononuclear cells (PBMC). We also examined the effects of exogenous IFN-γ, IL-10, and TGF-β on M. avium subsp. paratuberculosis survival in the cell cultures. PBMC obtained from naturally infected cows, regardless of their disease status, specifically upregulated IL-10 and TGF-β in culture supernatants in response to stimulation with live M. avium subsp. paratuberculosis. Nonstimulated PBMC recovered from subclinically infected animals secreted the lowest levels of TGF-β, but after stimulation with live M. avium subsp. paratuberculosis, TGF-β levels in the culture supernatants increased to levels similar to that produced by PBMC from healthy animals. The numbers of viable M. avium subsp. paratuberculosis recovered from cultures from naturally infected animals were higher than those from healthy cows after in vitro infection with M. avium subsp. paratuberculosis. The addition of exogenous IL-10 and TGF-β to PBMC isolated from healthy cows inhibited the bactericidal activity of these cells as evidenced by the increased number of viable M. avium subsp. paratuberculosis recovered from these cultures compared to cell cultures containing medium alone. These data suggest important immune regulatory roles for IL-10 and TGF-β during infection with M. avium subsp. paratuberculosis that may be directly related to their effects on macrophage activation and killing of M. avium subsp. paratuberculosis.

scholarly journals Immunoenhancement Combined with Amphotericin B as Treatment for Experimental Visceral Leishmaniasis

2003 ◽  
Vol 47 (8) ◽  
pp. 2513-2517 ◽  
Author(s):  
Henry W. Murray ◽  
Elaine B. Brooks ◽  
Jennifer L. DeVecchio ◽  
Frederick P. Heinzel
Keyword(s):  
Visceral Leishmaniasis ◽  
Total Dose ◽  
Amphotericin B ◽  
Leishmania Donovani ◽  
Low Dose ◽  
Interleukin 12 ◽  
Th1 Cell ◽  
Killing Effect ◽  
Ifn Γ ◽  
Visceral Infection

ABSTRACT To determine if stimulation of Th1-cell-associated immune responses, mediated by interleukin 12 (IL-12) and gamma interferon (IFN-γ), enhance the antileishmanial effect of amphotericin B (AMB), Leishmania donovani-infected BALB/c mice were first treated with (i) exogenous IL-12 to induce IFN-γ, (ii) agonist anti-CD40 monoclonal antibody (MAb) to maintain IL-12 and induce IFN-γ, or (iii) anti-IL-10 receptor (IL-10R) MAb to blockade suppression of IL-12 and IFN-γ. In animals with established visceral infection, low-dose AMB alone (two injections of 1 mg/kg of body weight; total dose, 2 mg/kg) killed 15 to 29% of liver parasites; by themselves, the immunointerventions induced 16 to 33% killing. When the interventions were combined, the leishmanicidal activities increased 3.4-fold (anti-CD40), 6.3-fold (anti-IL-10R), and 9-fold (IL-12) compared with the activities of AMB plus the control preparations; and overall killing (76 to 84%) approximated the 84 to 92% killing effect of 7.5-fold more AMB alone (three injections of 5 mg/kg; total dose, 15 mg/kg). These results suggest that strengthening the host Th1-cell response may be a strategy for the development of AMB-sparing regimens in visceral leishmaniasis.

scholarly journals Transforming Growth Factor β and Immunosuppression in Experimental Visceral Leishmaniasis

1998 ◽  
Vol 66 (3) ◽  
pp. 1233-1236 ◽  
Author(s):  
Virmondes Rodrigues ◽  
João Santana da Silva ◽  
Antonio Campos-Neto
Keyword(s):  
T Cells ◽  
Growth Factor ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Spleen Cells ◽  
Immunohistochemical Studies

ABSTRACT Hamsters infected with Leishmania donovani develop a disease similar to human kala-azar. They present hypergammaglobulinemia, and their T cells do not respond to parasite antigens. This unresponsiveness has been primarily ascribed to defects in antigen-presenting cells (APCs), because these cells are unable to stimulate proliferation of parasite-specific T cells from immunized animals. In this study, we show that APCs (adherent spleen cells) fromL. donovani-infected hamsters produce high levels of the inhibitory cytokine transforming growth factor β (TGF-β). Immunohistochemical studies with an anti-TGF-β monoclonal antibody (MAb) showed that this cytokine is abundantly produced in vivo by the spleen cells of infected animals. In addition, high levels of TGF-β are produced in vitro by infected hamster cells, either spontaneously or after stimulation with parasite antigen or lipopolysaccharide. Furthermore, in vivo-infected adherent cells obtained from spleens ofL. donovani-infected hamsters caused profound inhibition of the in vitro antigen-induced proliferative response of lymph node cells from hamsters immunized with leishmanial antigens. Moreover, this inhibition was totally abrogated by the anti-TGF-β MAb. These results suggest that the immunosuppression observed in visceral leishmaniasis is, at least in part, due to the abundant production of TGF-β during the course of the infection.

scholarly journals Interleukin-10 (IL-10) in Experimental Visceral Leishmaniasis and IL-10 Receptor Blockade as Immunotherapy

2002 ◽  
Vol 70 (11) ◽  
pp. 6284-6293 ◽  
Author(s):  
Henry W. Murray ◽  
Christina M. Lu ◽  
Smita Mauze ◽  
Sherry Freeman ◽  
Andre L. Moreira ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Transgenic Mice ◽  
Leishmania Donovani ◽  
Interleukin 10 ◽  
Th1 Cell ◽  
Th1 Cytokine ◽  
Parasite Replication ◽  
High Level ◽  
Oxide Synthase ◽  
Established Infection

ABSTRACT Interleukin-10 (IL-10) is thought to promote intracellular infection, including human visceral leishmaniasis, by disabling Th1 cell-type responses and/or deactivating parasitized tissue macrophages. To develop a rationale for IL-10 inhibition as treatment in visceral infection, Th1 cytokine-driven responses were characterized in Leishmania donovani-infected BALB/c mice in which IL-10 was absent or overexpressed or its receptor (IL-10R) was blockaded. IL-10 knockout and normal mice treated prophylactically with anti-IL-10R demonstrated accelerated granuloma assembly and rapid parasite killing without untoward tissue inflammation; IL-12 and gamma interferon mRNA expression, inducible nitric oxide synthase reactivity, and responsiveness to antimony chemotherapy were also enhanced in knockout mice. In IL-10 transgenic mice, parasite replication was unrestrained, and except for antimony responsiveness, measured Th1 cell-dependent events were all initially impaired. Despite subsequent granuloma assembly, high-level infection persisted, and antimony-treated transgenic mice also relapsed. In normal mice with established infection, anti-IL-10R treatment was remarkably active, inducing near-cure by itself and synergism with antimony. IL-10's deactivating effects regulate outcome in experimental visceral leishmaniasis, and IL-10R blockade represents a potential immuno- and/or immunochemotherapeutic approach in this infection.

scholarly journals Enhanced Replication of Leishmania amazonensis Amastigotes in Gamma Interferon-Stimulated Murine Macrophages: Implications for the Pathogenesis of Cutaneous Leishmaniasis

2004 ◽  
Vol 72 (2) ◽  
pp. 988-995 ◽  
Author(s):  
Hai Qi ◽  
Jiaxiang Ji ◽  
Nanchaya Wanasen ◽  
Lynn Soong
Keyword(s):  
Leishmania Major ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Leishmania Amazonensis ◽  
Promoting Effect ◽  
Necrosis Factor Alpha ◽  
Different Temperatures ◽  
Ifn Γ

ABSTRACT During Leishmania major infection in mice, gamma interferon (IFN-γ) plays an essential role in controlling parasite growth and disease progression. In studies designed to ascertain the role of IFN-γ in Leishmania amazonensis infection, we were surprised to find that IFN-γ could promote L. amazonensis amastigote replication in macrophages (MΦs), although it activated MΦs to kill promastigotes. The replication-promoting effect of IFN-γ on amastigotes was independent of the source and genetic background of MΦs, was apparently not affected by surface opsonization of amastigotes, was not mediated by interleukin-10 or transforming growth factor β, and was observed at different temperatures. Consistent with the different fates of promastigotes and amastigotes in IFN-γ-stimulated MΦs, L. amazonensis-specific Th1 transfer helped recipient mice control L. amazonensis infection established by promastigotes but not L. amazonensis infection established by amastigotes. On the other hand, IFN-γ could stimulate MΦs to limit amastigote replication when it was coupled with lipopolysaccharides but not when it was coupled with tumor necrosis factor alpha. Thus, IFN-γ may play a bidirectional role at the level of parasite-MΦ interactions; when it is optimally coupled with other factors, it has a protective effect against infection, and in the absence of such synergy it promotes amastigote growth. These results reveal a quite unexpected aspect of the L. amazonensis parasite and have important implications for understanding the pathogenesis of the disease and for developing vaccines and immunotherapies.

scholarly journals Down-Modulation of Lung Immune Responses by Interleukin-10 and Transforming Growth Factor β (TGF-β) and Analysis of TGF-β Receptors I and II in Active Tuberculosis

2004 ◽  
Vol 72 (5) ◽  
pp. 2628-2634 ◽  
Author(s):  
M. Glória Bonecini-Almeida ◽  
John L. Ho ◽  
Neio Boéchat ◽  
Richard C. Huard ◽  
Sadhana Chitale ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cellular Response ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Active Tuberculosis ◽  
Alveolar Cells ◽  
Old Patients ◽  
Protein Levels ◽  
Ifn Γ

ABSTRACT Immune factors influencing progression to active tuberculosis (TB) remain poorly defined. In this study, we investigated the expression of immunoregulatory cytokines and receptors by using lung bronchoalveolar lavage cells obtained from patients with pulmonary TB, patients with other lung diseases (OLD patients), and healthy volunteers (VOL) by using reverse transcriptase PCR, a transforming growth factor β (TGF-β) bioactivity assay, and an enzyme immunoassay. TB patients were significantly more likely than OLD patients to coexpress TGF-β receptor I (RI) and RII mRNA, as well as interleukin-10 (IL-10) mRNA (thereby indicating the state of active gene transcription in the alveolar cells at harvest). In contrast, gamma interferon (IFN-γ) and IL-2 mRNA was seen in both TB and OLD patients. Likewise, significantly elevated pulmonary steady-state protein levels of IL-10, IFN-γ, and bioactive TGF-β were found in TB patients versus those in OLD patients and VOL. These data suggest that the combined production of the immunosuppressants IL-10 and TGF-β, as well as coexpression of TGF-β RI and RII (required for cellular response to TGF-β), may act to down-modulate host anti-Mycobacterium tuberculosis immunity and thereby allow uncontrolled bacterial replication and overt disease. Delineating the underlying mechanisms of M. tuberculosis-triggered expression of these immune elements may provide a molecular-level understanding of TB immunopathogenesis.

scholarly journals Pathology of Plasmodium chabaudi chabaudi Infection and Mortality in Interleukin-10-Deficient Mice Are Ameliorated by Anti-Tumor Necrosis Factor Alpha and Exacerbated by Anti-Transforming Growth Factor β Antibodies

2003 ◽  
Vol 71 (9) ◽  
pp. 4850-4856 ◽  
Author(s):  
Ching Li ◽  
Latifu A. Sanni ◽  
Fakhreldin Omer ◽  
Eleanor Riley ◽  
Jean Langhorne
Keyword(s):  
Tumor Necrosis ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Plasmodium Chabaudi ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Factor Alpha ◽  
Ifn Γ ◽  
Necrosis Factor

ABSTRACT Interleukin-10 (IL-10)-deficient (IL-10−/−) mice infected with Plasmodium chabaudi (AS) suffer a more severe disease and exhibit a higher rate of mortality than control C57BL/6 mice. Here, we show that a drop in body temperature to below 28°C and pronounced hypoglycemia of below 3 mM are reliable indicators of a lethal infection. Elevated inflammatory responses have been shown to accompany pathology in infected IL-10−/− mice. We show that neutralization of tumor necrosis factor alpha (TNF-α) in IL-10−/− mice abolishes mortality and ameliorates the hypothermia, weight loss, and anemia but does not affect the degree of hypoglycemia. These data suggest that TNF-α is involved in some of the pathology associated with a P. chabaudi infection in IL-10−/− mice but other factors play a role. IL-10−/− mice that survive a primary infection have been shown to control gamma interferon (IFN-γ) and TNF-α production, indicating that other cytokines or mechanisms may be involved in their down-regulation. Significantly higher levels of transforming growth factor β (TGF-β), a cytokine with such properties, are present in the plasma of infected IL-10−/− mice at a time that coincides with the disappearance of IFN-γ and TNF-α from the blood. Neutralization of TGF-β in IL-10−/− mice resulted in higher circulating amounts of TNF-α and IFN-γ, and all treated IL-10−/− mice died within 12 days with increased pathology but with no obvious increase in parasitemia. Our data suggest that a tight regulation of the balance between regulatory cytokines such as IL-10 and TGF-β and inflammatory cytokines such as IFN-γ and TNF-α is critical for survival in a mouse malaria infection.

scholarly journals Cloning of Syrian Hamster (Mesocricetus auratus) Cytokine cDNAs and Analysis of Cytokine mRNA Expression in Experimental Visceral Leishmaniasis

1998 ◽  
Vol 66 (5) ◽  
pp. 2135-2142 ◽  
Author(s):  
Peter C. Melby ◽  
Victor V. Tryon ◽  
Bysani Chandrasekar ◽  
Gregory L. Freeman
Keyword(s):  
Sequence Analysis ◽  
Visceral Leishmaniasis ◽  
Syrian Hamster ◽  
Leishmania Donovani ◽  
Transforming Growth Factor ◽  
Interleukin 2 ◽  
Mesocricetus Auratus ◽  
Amino Acid Sequences ◽  
Intracellular Pathogens ◽  
Ifn Γ

ABSTRACT The Syrian golden hamster (Mesocricetus auratus) is uniquely susceptible to a variety of intracellular pathogens and is an excellent model for a number of human infectious diseases. The molecular basis for this high level of susceptibility is unknown, and immunological studies related to this model have been limited by the lack of available reagents. In this report we describe the cloning and sequence analysis of portions of the Syrian hamster interleukin 2 (IL-2), IL-4, gamma interferon (IFN-γ), tumor necrosis factor alpha, IL-10, IL-12p40, and transforming growth factor β cDNAs. In addition, we examined the cytokine response to infection with the intracellular protozoan Leishmania donovani in this animal model. Sequence analysis of the hamster cytokines revealed 69 to 93% homology with the corresponding mouse, rat, and human nucleotide sequences and 48 to 100% homology with the deduced amino acid sequences. The hamster IFN-γ, compared with the mouse and rat homologs, had an additional 17 amino acids at the C terminus that could decrease the biological activity of this molecule and thus contribute to the extreme susceptibility of this animal to intracellular pathogens. The splenic expression of these genes in response to infection with L. donovani, the cause of visceral leishmaniasis (VL), was determined by Northern blotting. VL in the hamster is a progressive, lethal disease which very closely mimics active human disease. In this model there was pronounced expression of the Th1 cytokine mRNAs, with transcripts being detected as early as 1 week postinfection. Basal expression of IL-4 in uninfected hamsters was prominent but did not increase in response to infection with L. donovani. IL-12 transcript expression was detected at low levels in infected animals and paralleled the expression of IFN-γ. Expression of IL-10, a potent macrophage deactivator, increased throughout the course of infection and could contribute to the progressive nature of this infection. These initial studies are the first to examine the molecular immunopathogenesis of a hamster model of VL infection and indicate that progressive disease in this model of VL is not associated with early polarization of the splenic cellular immune response toward a Th2 phenotype and away from a Th1 phenotype.

scholarly journals Designing Therapies against Experimental Visceral Leishmaniasis by Modulating the Membrane Fluidity of Antigen-Presenting Cells

2009 ◽  
Vol 77 (6) ◽  
pp. 2330-2342 ◽  
Author(s):  
Subha Banerjee ◽  
June Ghosh ◽  
Subha Sen ◽  
Rajan Guha ◽  
Ranjan Dhar ◽  
...  
Keyword(s):  
T Cell ◽  
Visceral Leishmaniasis ◽  
Membrane Fluidity ◽  
Transforming Growth Factor Beta ◽  
Leishmania Donovani ◽  
Transforming Growth Factor ◽  
Antigen Presenting Cells ◽  
Cell Mediated Immunity ◽  
Ifn Γ ◽  
Antigen Presenting

ABSTRACT The membrane fluidity of antigen-presenting cells (APCs) has a significant bearing on T-cell-stimulating ability and is dependent on the cholesterol content of the membrane. The relationship, if any, between membrane fluidity and defective cell-mediated immunity in visceral leishmaniasis has been investigated. Systemic administration of cholesterol by liposome delivery (cholesterol liposomes) in Leishmania donovani-infected hamsters was found to cure the infection. Splenic macrophages as a prototype of APCs in infected hamsters had decreased membrane cholesterol and an inability to drive T cells, which was corrected by cholesterol liposome treatment. The effect was cholesterol specific because liposomes made up of the analogue 4-cholesten-3-one provided almost no protection. Infection led to increases in interleukin-10 (IL-10), transforming growth factor beta, and IL-4 signals and concomitant decreases in gamma interferon (IFN-γ), tumor necrosis factor alpha, and inducible NO synthase signals, which reverted upon cholesterol liposome treatment. The antileishmanial T-cell repertoire, whose expansion appeared to be associated with protection, was presumably type Th1, as shown by enhanced IFN-γ signals and the predominance of the immunoglobulin G2 isotype. The protected group produced significantly more reactive oxygen species and NO than the infected groups, which culminated in killing of L. donovani parasites. Therefore, cholesterol liposome treatment may be yet another simple strategy to enhance the cell-mediated immune response to L. donovani infection. To our knowledge, this is the first report on the therapeutic effect of cholesterol liposomes in any form of the disease.

scholarly journals TGF-β and IL-10 regulation of IFN-γ produced in Th2-type schistosome granulomas requires IL-12

2001 ◽  
Vol 281 (4) ◽  
pp. G940-G946 ◽  
Author(s):  
Khurram Qadir ◽  
Ahmed Metwali ◽  
Arthur M. Blum ◽  
Jie Li ◽  
David E. Elliott ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Interferon Γ ◽  
T Helper 2 ◽  
Subunit Mrna ◽  
Cba Mice ◽  
Neutralizing Monoclonal Antibody ◽  
Ifn Γ ◽  
Egg Antigen

Interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) regulate CD4+T cell interferon-γ (IFN-γ) secretion in schistosome granulomas. The role of IL-12 was determined using C57BL/6 and CBA mice. C57BL/6 IL-4 −/− granuloma cells were stimulated to produce IFN-γ when cultured with IL-10 or TGF-β neutralizing monoclonal antibody. In comparison, C57BL/6 wild-type (WT) control granuloma cells produced less IFN-γ. IL-12, IL-18, and soluble egg antigen stimulated IFN-γ release from C57BL/6 IL-4 −/− and WT mice. IFN-γ production in C57 IL-4 −/− and WT granulomas was IL-12 dependent, because IL-12 blockade partly abrogated IFN-γ secretion after stimulation. All granuloma cells released IL-12 (p70 and p40), and IL-12 production remained constant after anti-TGF-β, anti-IL-10, recombinant IL-18, or antigen stimulation. C57 WT and IL-4 −/− mouse granuloma cells expressed IL-12 receptor (IL-12R) β1-subunit mRNA but little β2 mRNA. TGF-β or IL-10 blockade did not influence β1 or β2 mRNA expression. CBA mouse dispersed granuloma cells released no measurable IFN-γ, produced IL-12 p70 and little p40, and expressed IL-12R β2 and little β1 mRNA. In T helper 2 (Th2) granulomas of C57BL/6 WT and IL-4 −/− mice, cells produce IL-12 (for IFN-γ production) and IL-10 and TGF-β modulate IFN-γ secretion via mechanisms independent of IL-12 and IL-12R mRNA regulation. We found substantial differences in control of granuloma IFN-γ production and IL-12 circuitry in C57BL/6 and CBA mice.

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