scholarly journals Interleukin 1α Promotes Th1 Differentiation and Inhibits Disease Progression in Leishmania major–susceptible BALB/c Mice

2003 ◽  
Vol 198 (2) ◽  
pp. 191-199 ◽  
Author(s):  
Esther von Stebut ◽  
Jan M. Ehrchen ◽  
Yasmine Belkaid ◽  
Susanna Lopez Kostka ◽  
Katharina Mölle ◽  
...  
Keyword(s):  
Disease Progression ◽  
Protective Immunity ◽  
Leishmania Major ◽  
Interferon Γ ◽  
Mouse Strains ◽  
Mrna Accumulation ◽  
Partial Explanation ◽  
Th2 Cytokine ◽  
Local Injections ◽  
Interleukin 1Α

Protective immunity against pathogens such as Leishmania major is mediated by interleukin (IL)-12–dependent Th1-immunity. We have shown previously that skin-dendritic cells (DCs) from both resistant C57BL/6 and susceptible BALB/c mice release IL-12 when infected with L. major, and infected BALB/c DCs effectively vaccinate against leishmaniasis. To determine if cytokines other than IL-12 might influence disease outcome, we surveyed DCs from both strains for production of a variety of cytokines. Skin-DCs produced significantly less IL-1α in response to lipopolysaccharide/interferon γ or L. major when expanded from BALB/c as compared with C57BL/6 mice. In addition, IL-1α mRNA accumulation in lymph nodes of L. major–infected BALB/c mice was ∼3-fold lower than that in C57BL/6 mice. Local injections of IL-1α during the first 3 d after infection led to dramatic, persistent reductions in lesion sizes. In L. major–infected BALB/c mice, IL-1α administration resulted in increased Th1- and strikingly decreased Th2-cytokine production. IL-1α and IL-12 treatments were similarly effective, and IL-1α efficacy was strictly IL-12 dependent. These data indicate that transient local administration of IL-1α acts in conjunction with IL-12 to influence Th-development in cutaneous leishmaniasis and prevents disease progression in susceptible BALB/c mice, perhaps by enhancing DC-induced Th1-education. Differential production of IL-1 by C57BL/6 and BALB/c mice may provide a partial explanation for the disparate outcomes of infection in these mouse strains.

scholarly journals Langerhans cells are negative regulators of the anti-Leishmania response

2011 ◽  
Vol 208 (5) ◽  
pp. 885-891 ◽  
Author(s):  
Kordula Kautz-Neu ◽  
Madelon Noordegraaf ◽  
Stephanie Dinges ◽  
Clare L. Bennett ◽  
Dominik John ◽  
...  
Keyword(s):  
Langerhans Cells ◽  
Protective Immunity ◽  
Low Dose ◽  
Leishmania Major ◽  
Interferon Γ ◽  
Cell Ablation ◽  
Selective Depletion ◽  
T Cell Immune Responses

Migratory skin dendritic cells (DCs) are thought to play an important role in priming T cell immune responses against Leishmania major, but DC subtypes responsible for the induction of protective immunity against this pathogen are still controversial. In this study, we analyzed the role of Langerin+ skin-derived DCs in the Leishmania model using inducible in vivo cell ablation. After physiologically relevant low-dose infection with L. major (1,000 parasites), mice depleted of all Langerin+ DCs developed significantly smaller ear lesions with decreased parasite loads and a reduced number of CD4+ Foxp3+ regulatory T cells (T reg cells) as compared with controls. This was accompanied by increased interferon γ production in lymph nodes in the absence of Langerin+ DCs. Moreover, selective depletion of Langerhans cells (LCs) demonstrated that the absence of LCs, and not Langerin+ dermal DC, was responsible for the reduced T reg cell immigration and the enhanced Th1 response, resulting in attenuated disease. Our data reveal a unique and novel suppressive role for epidermal LCs in L. major infection by driving the expansion of T reg cells. A better understanding of the various roles of different DC subsets in cutaneous leishmaniasis will improve the development of a potent therapeutic/prophylactic vaccine.

scholarly journals Vaccination with DNA Encoding the Immunodominant LACK Parasite Antigen Confers Protective Immunity to Mice Infected with Leishmania major

1997 ◽  
Vol 186 (7) ◽  
pp. 1137-1147 ◽  
Author(s):  
Sanjay Gurunathan ◽  
David L. Sacks ◽  
Daniel R. Brown ◽  
Steven L. Reiner ◽  
Hughes Charest ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Leishmania Major ◽  
Protective Efficacy ◽  
Dna Vaccination ◽  
Attractive Alternative ◽  
Dna Immunization ◽  
Dna Encoding ◽  
Ifn Γ

To determine whether DNA immunization could elicit protective immunity to Leishmania major in susceptible BALB/c mice, cDNA for the cloned Leishmania antigen LACK was inserted into a euykaryotic expression vector downstream to the cytomegalovirus promoter. Susceptible BALB/c mice were then vaccinated subcutaneously with LACK DNA and challenged with L. major promastigotes. We compared the protective efficacy of LACK DNA vaccination with that of recombinant LACK protein in the presence or absence of recombinant interleukin (rIL)-12 protein. Protection induced by LACK DNA was similar to that achieved by LACK protein and rIL-12, but superior to LACK protein without rIL-12. The immunity conferred by LACK DNA was durable insofar as mice challenged 5 wk after vaccination were still protected, and the infection was controlled for at least 20 wk after challenge. In addition, the ability of mice to control infection at sites distant to the site of vaccination suggests that systemic protection was achieved by LACK DNA vaccination. The control of disease progression and parasitic burden in mice vaccinated with LACK DNA was associated with enhancement of antigen-specific interferon-γ (IFN-γ) production. Moreover, both the enhancement of IFN-γ production and the protective immune response induced by LACK DNA vaccination was IL-12 dependent. Unexpectedly, depletion of CD8+ T cells at the time of vaccination or infection also abolished the protective response induced by LACK DNA vaccination, suggesting a role for CD8+ T cells in DNA vaccine induced protection to L. major. Thus, DNA immunization may offer an attractive alternative vaccination strategy against intracellular pathogens, as compared with conventional vaccination with antigens combined with adjuvants.

The Magnitude of Interferon-γ Responses to Human Cytomegalovirus Is Predictive for HIV-1 Disease Progression

2008 ◽  
Vol 49 (5) ◽  
pp. 507-512 ◽  
Author(s):  
Laila Darwich ◽  
Cecilia Cabrera ◽  
Joan Romeu ◽  
Javier Martinez-Picado ◽  
José A Esté ◽  
...  
Keyword(s):  
Disease Progression ◽  
Human Cytomegalovirus ◽  
Interferon Γ ◽  
Hiv 1

scholarly journals Comparisons of Mutants Lacking the Golgi UDP-Galactose or GDP-Mannose Transporters Establish that Phosphoglycans Are Important for Promastigote but Not Amastigote Virulence in Leishmania major

2007 ◽  
Vol 75 (9) ◽  
pp. 4629-4637 ◽  
Author(s):  
Althea A. Capul ◽  
Suzanne Hickerson ◽  
Tamara Barron ◽  
Salvatore J. Turco ◽  
Stephen M. Beverley
Keyword(s):  
Golgi Apparatus ◽  
Protective Immunity ◽  
Leishmania Major ◽  
Protozoan Parasite ◽  
Macrophage Infection ◽  
Nucleotide Sugar ◽  
Infectious Cycle ◽  
Null Mutants

ABSTRACT Abundant surface Leishmania phosphoglycans (PGs) containing [Gal(β1,4)Man(α1-PO4)]-derived repeating units are important at several points in the infectious cycle of this protozoan parasite. PG synthesis requires transport of activated nucleotide-sugar precursors from the cytoplasm to the Golgi apparatus. Correspondingly, null mutants of the L. major GDP-mannose transporter LPG2 lack PGs and are severely compromised in macrophage survival and induction of acute pathology in susceptible mice, yet they are able to persist indefinitely and induce protective immunity. However, lpg2 − L. mexicana amastigotes similarly lacking PGs but otherwise normal in known glycoconjugates remain able to induce acute pathology. To explore this further, we tested the infectivity of a new PG-null L. major mutant, which is inactivated in the two UDP-galactose transporter genes LPG5A and LPG5B. Surprisingly this mutant did not recapitulate the phenotype of L. major lpg2 −, instead resembling the L. major lipophosphoglycan-deficient lpg1 − mutant. Metacyclic lpg5A −/lpg5B − promastigotes showed strong defects in the initial steps of macrophage infection and survival. However, after a modest delay, the lpg5A − /lpg5B − mutant induced lesion pathology in infected mice, which thereafter progressed normally. Amastigotes recovered from these lesions were fully infective in mice and in macrophages despite the continued absence of PGs. This suggests that another LPG2-dependent metabolite is responsible for the L. major amastigote virulence defect, although further studies ruled out cytoplasmic mannans. These data thus resolve the distinct phenotypes seen among lpg2 − Leishmania species by emphasizing the role of glycoconjugates other than PGs in amastigote virulence, while providing further support for the role of PGs in metacyclic promastigote virulence.

scholarly journals Cross-reactive, natural IgG recognizing L. major promote parasite internalization by dendritic cells and promote protective immunity

2021 ◽  
Author(s):  
Filiz Dermicik ◽  
Susanna Lopez Kostka ◽  
Stefan Tenzer ◽  
Ari Waisman ◽  
Esther Von Stebut
Keyword(s):  
Dendritic Cells ◽  
B Cell ◽  
Protective Immunity ◽  
Normal Mouse ◽  
Leishmania Major ◽  
Mouse Serum ◽  
List Type ◽  
Susceptibility To Infection ◽  
Large Numbers

Abstract In cutaneous leishmaniasis, infection of dendritic cells (DC) is essential for generation of T cell-dependent protective immunity. DC acquires Leishmania major through Fc receptor (FcR)-mediated uptake of complexes comprising antibodies bound to parasites. We now assessed the development of the initial B cell and DC response to the parasite itself and if natural IgG play a role. L. major parasites display large numbers of phospholipids on their surface. Parasites were opsonized with normal mouse serum (NMS), or serum containing anti-phospholipid IgG (PL). We found that L. major bound to PL which significantly enhanced parasite phagocytosis by DC as compared to NMS. Similar results were obtained with cross-reactive human PL antibodies using myeloid primary human DC. In addition, mice infected with PL-opsonized parasites showed significantly improved disease outcome compared to mice infected with NMS-opsonized parasites. Finally, IgMi mice, which produce membrane-bound IgM only and no secreted antibodies, displayed increased susceptibility to infection as compared to wild types. Interestingly, once NMS was administered to IgMi mice, their phenotype was normalized to that of wild types. Upon incubation with IgG-opsonized parasite (IgG derived from infected mice or using PL antibodies), also the IgMi mice were able to show superior immunity. Our findings suggest that “natural” cross-reactive antibodies (e.g., anti-PL Ab) in NMS bind to pathogens to facilitate phagocytosis, which leads to induction of protective immunity via preferential DC infection. Prior L. major-specific B cell-priming does not seem to be absolutely required to facilitate clearance of this important human pathogen in vivo. Key messages We found that anti-phospholipid (anti-PL) antibodies enhance phagocytosis of L. major by DCs. We also found that normal mouse sera have natural antibodies that can imitate PL specific antibodies. Using different genetically modified mice, we found that these antibodies can be IgG, not only IgM.

Effect of Ninjin-Youei-To on Th1/Th2 Type Cytokine Production in Different Mouse Strains

2002 ◽  
Vol 30 (02n03) ◽  
pp. 215-223 ◽  
Author(s):  
Tsutomu Nakada ◽  
Kenji Watanabe ◽  
Guang-Bi Jin ◽  
Kazuo Toriizuka ◽  
Toshihiko Hanawa
Keyword(s):  
Oral Administration ◽  
Cytokine Production ◽  
Interferon Γ ◽  
Interleukin 4 ◽  
Mouse Strains ◽  
Enzyme Linked Immunosorbent Assay ◽  
Herbal Formula ◽  
Beneficial Effects ◽  
Ifn Γ ◽  
Th1 And Th2

Ninjin-Youei-To (NYT; Ren-Shen-Yang-Rong-Tang in Chinese) is a traditional herbal formula, which is widely used in Japan, Korea and China to modulate physiological immunity. The effects of oral administration of NYT on cytokine production from splenocytes were investigated in both C57BL/6 and BALB/c mice in which Th1 and Th2 were dominant, respectively. Splenocytes from C57BL/6 and BALB/c mice, which took NYT orally for four weeks, were cultured with anti-mouse CD3 mAb, and the supernatant was examined for cytokine production using enzyme-linked immunosorbent assay (ELISA). Administration of NYT to C57BL/6 mice, increased the production of interleukin-4 (IL-4) significantly, and slightly decreased interferon-γ (IFN-γ) production from splenocytes. In contrast, the same treatment significantly increased IFN-γ secretion from splenocytes of BALB/c mice. No remarkable changes of IL-12 production from splenocytes were observed in either strain of mice. These results suggest that oral administration of NYT ameliorates the excessive inclination of Th1 and Th2 type cytokine production, and NYT may provide a beneficial effects for the treatment of diseases caused by a skewed Th1-Th2 balance in the immune system.

scholarly journals Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract

2006 ◽  
Vol 203 (4) ◽  
pp. 843-849 ◽  
Author(s):  
Alexander M. Owyang ◽  
Colby Zaph ◽  
Emma H. Wilson ◽  
Katherine J. Guild ◽  
Terrill McClanahan ◽  
...  
Keyword(s):  
Gastrointestinal Tract ◽  
Intestinal Inflammation ◽  
Severe Infection ◽  
Interferon Γ ◽  
Mouse Strains ◽  
Dual Function ◽  
Type 2 Immunity ◽  
Interleukin 25 ◽  
Chronic Intestinal Inflammation

The cytokine interleukin (IL) 25 has been implicated in the initiation of type 2 immunity by driving the expression of type 2 cytokines such as IL-5 and IL-13, although its role in the regulation of immunity and infection-induced inflammation is unknown. Here, we identify a dual function for IL-25: first, in promoting type 2 cytokine-dependent immunity to gastrointestinal helminth infection and, second, in limiting proinflammatory cytokine production and chronic intestinal inflammation. Treatment of genetically susceptible mice with exogenous IL-25 promoted type 2 cytokine responses and immunity to Trichuris. IL-25 was constitutively expressed by CD4+ and CD8+ T cells in the gut of mouse strains that are resistant to Trichuris, and IL-25–deficient mice on a genetically resistant background failed to develop a type 2 immune response or eradicate infection. Furthermore, chronically infected IL-25−/− mice developed severe infection-induced intestinal inflammation associated with heightened expression of interferon-γ and IL-17, identifying a role for IL-25 in limiting pathologic inflammation at mucosal sites. Therefore, IL-25 is not only a critical mediator of type 2 immunity, but is also required for the regulation of inflammation in the gastrointestinal tract.

scholarly journals Lipopolysaccharide-induced interleukin-8 gene expression in human granulocytes: transcriptional inhibition by interferon-γ

1995 ◽  
Vol 310 (3) ◽  
pp. 751-755 ◽  
Author(s):  
M A Cassatella ◽  
S Gasperini ◽  
F Calzetti ◽  
P P McDonald ◽  
G Trinchieri
Keyword(s):  
Gene Expression ◽  
Interferon Γ ◽  
Interleukin 8 ◽  
Polymorphonuclear Leucocytes ◽  
Mrna Accumulation ◽  
Ifn Gamma ◽  
Potent Inducer ◽  
Transcriptional Inhibition ◽  
Human Granulocytes ◽  
New Protein

We recently showed that lipopolysaccharide (LPS) is a potent inducer of interleukin-8 (IL-8) expression in human polymorphonuclear leucocytes (PMN), at the level of both mRNA and protein, and that interferon-gamma (IFN gamma) inhibits IL-8 mRNA accumulation in stimulated PMN. To further define the molecular basis of the regulation of IL-8 gene expression in PMN, we investigated the effects of LPS and IFN gamma at both the transcriptional and post-transcriptional levels. As determined by Northern blot analysis, new protein synthesis was not required for the induction of IL-8 mRNA expression by LPS. Neither did the half-life of IL-8 mRNA in LPS-treated PMN differ from that observed in untreated cells. However, nuclear run-on analysis revealed that LPS increased the transcription of the IL-8 and IL-1 beta genes and that, in LPS-activated cells, IFN gamma markedly inhibited the rate of IL-8 gene transcription, but not that of IL-1 beta. IFN gamma did not affect IL-8 mRNA stability in LPS-treated PMN, indicating that the cytokine does not regulate LPS-induced IL-8 gene expression through post-transcriptional events. These results provide the first evidence that human granulocytes can actively transcribe the IL-8 gene, and that transcriptional inhibition is the mechanism by which IFN gamma inhibits IL-8 gene expression in PMN.

Protective immunity against Leishmania major induced by Leishmania tropica infection of BALB/c mice

2011 ◽  
Vol 127 (2) ◽  
pp. 448-453 ◽  
Author(s):  
Hamid Mahmoudzadeh-Niknam ◽  
Simin Sadat Kiaei ◽  
Davood Iravani
Keyword(s):  
Protective Immunity ◽  
Leishmania Major ◽  
Leishmania Tropica
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