scholarly journals Senescent BALB/c Mice Are Able To Develop Resistance to Leishmania major Infection

2004 ◽  
Vol 72 (9) ◽  
pp. 5106-5114 ◽  
Author(s):  
Jan Ehrchen ◽  
Anca Sindrilaru ◽  
Stephan Grabbe ◽  
Frank Schönlau ◽  
Christian Schlesiger ◽  
...  
Keyword(s):  
Immune Response ◽  
Leishmania Major ◽  
Hepatitis Virus ◽  
Interleukin 12 ◽  
No Production ◽  
Microbiological Analysis ◽  
Spontaneous Release ◽  
Th1 Response ◽  
Age Related ◽  
Young Mice

ABSTRACT Aging has been associated with a decline in immunocompetence and resistance to infections, partially due to dysregulated NO production by macrophages and deficits in mounting Th2 cell responses. We wondered if these alterations would reverse the immune response in experimental leishmaniasis. Bone-marrow-derived macrophages from 2- and 18-month-old (senescent) C57BL/6 or BALB/c mice showed no marked difference in leishmanicidal functions. In vivo infections of resistant C57BL/6 mice with Leishmania major revealed no difference between senescent and young mice. However, among susceptible BALB/c mice, senescent animals showed less foot-pad swelling than young mice, and 40 to 60% of them even showed healing of ulcers, reduced parasite dissemination, and a Th1 cell response. These changes were associated with a spontaneous release of interleukin-12 (IL-12) by macrophages from aged but not from young mice. Since exogenous microbial stimulation can influence immune responses during aging, we also infected senescent mice who were raised under specific-pathogen-free (SPF) conditions. They showed neither resistance nor a Th1 response, but their macrophages still spontaneously released IL-12. A microbiological analysis showed that conventionally kept mice, but not SPF mice, had experienced infection with murine hepatitis virus (MHV), an infection associated with a Th1-like response. We conclude that for the reversal of the immune response, senescence is the premier requirement but needs to be completed by another mandatory event such as microbial stimulation. One of the age-related, but not environment-related, factors is the spontaneous release of IL-12 by macrophages, while confrontation with MHV presents an environment-related difference, with both having the potential to support a Th1 response.

scholarly journals Aging dampens the intestinal innate immune response during Clostridioides difficile infection and is associated with altered intestinal eosinophil mobilization

2020 ◽  
Author(s):  
Lisa Abernathy-Close ◽  
Michael G. Dieterle ◽  
Kimberly C. Vendrov ◽  
Ingrid L. Bergin ◽  
Vincent B. Young
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Disease Severity ◽  
Advanced Age ◽  
Simultaneous Increase ◽  
Aged Mice ◽  
Age Related ◽  
Cellular Immune ◽  
The Impact ◽  
Young Mice

ABSTRACTClostridioides (formerly Clostridium) difficile is the most common cause of hospital-acquired infection, and advanced age is a risk factor for C. difficile infection. Disruption of the intestinal microbiota and immune responses contribute to host susceptibility and severity of C. difficile infection. However, the impact of aging on the cellular immune response associated with C. difficile infection in the setting of advanced age remains to be well described. This study explores the effect of age on cellular immune responses in C. difficile infection as well as disease severity. Young adult mice (2-3 months old) and aged mice (22-28 months old) were rendered susceptible to C. difficile infection with cefoperazone and then infected with C. difficile strains of varying disease-causing potential. Aged mice infected with C. difficile develop more severe clinical disease, compared to young mice. Tissue-specific CD45+ immune cell responses occurred at the time of peak disease severity in the cecum and colon of all mice infected with a high-virulence strain of C. difficile; however, significant deficits in intestinal neutrophils and eosinophils were detected in aged mice. Interestingly, while C. difficile infection in young mice was associated with a robust increase in cecal and colonic eosinophils, there was a complete lack of an intestinal eosinophil response in aged counterparts accompanied by a simultaneous increase in blood eosinophils with severe disease. These findings demonstrate that age-related alterations in immune responses are associated with significantly worse C. difficile infection and support a key role for intestinal eosinophils in mitigating C. difficile-mediated disease severity.

scholarly journals Effect of age on susceptibility to Salmonella Typhimurium infection in C57BL/6 mice

2009 ◽  
Vol 58 (12) ◽  
pp. 1559-1567 ◽  
Author(s):  
Zhihong Ren ◽  
Raina Gay ◽  
Adam Thomas ◽  
Munkyong Pae ◽  
Dayong Wu ◽  
...  
Keyword(s):  
Immune Response ◽  
Ex Vivo ◽  
The Elderly ◽  
Mesenteric Lymph ◽  
Age Related ◽  
Serovar Typhimurium ◽  
Lymph Node Cells ◽  
Old Mice ◽  
Effect Of Age ◽  
Young Mice

Ageing is associated with a decline in immune function, which predisposes the elderly to a higher incidence of infections. Information on the mechanism of the age-related increase in susceptibility to Salmonella enterica serovar Typhimurium (S. Typhimurium) is limited. In particular, little is known regarding the involvement of the immune response in this age-related change. We employed streptomycin (Sm)-pretreated C57BL/6 mice to develop a mouse model that would demonstrate age-related differences in susceptibility and immune response to S. Typhimurium. In this model, old mice inoculated orally with doses of 3×108 or 1×106 c.f.u. S. Typhimurium had significantly greater S. Typhimurium colonization in the ileum, colon, Peyer's patches, spleen and liver than young mice. Old mice had significantly higher weight loss than young mice on days 1 and 2 post-infection. In response to S. Typhimurium infection, old mice failed to increase ex vivo production of IFN-γ and TNF-α in the spleen and mesenteric lymph node cells to the same degree as observed in young mice; this was associated with their inability to maintain the presence of neutrophils and macrophages at a ‘youthful’ level. These results indicate that Sm-pretreated C57BL/6 old mice are more susceptible to S. Typhimurium infection than young mice, which might be due to impaired IFN-γ and TNF-α production as well as a corresponding change in the number of neutrophils and macrophages in response to S. Typhimurium infection compared to young mice.

scholarly journals Differential Regulation of the Interleukin-12 Receptor during the Innate Immune Response to Leishmania major

1998 ◽  
Vol 66 (8) ◽  
pp. 3818-3824 ◽  
Author(s):  
Douglas Jones ◽  
M. Merle Elloso ◽  
Louise Showe ◽  
Donna Williams ◽  
Giorgio Trinchieri ◽  
...  
Keyword(s):  
Immune Response ◽  
Lymph Node ◽  
Mrna Expression ◽  
Innate Immune Response ◽  
Leishmania Major ◽  
Innate Immune ◽  
Interleukin 12 ◽  
C3h Mice ◽  
Lymph Node Cells ◽  
Mrna Expression Levels

ABSTRACT Previous studies have shown the central role of interleukin 12 (IL-12) in the development of resistance to Leishmania major infection in C3H mice. We now show that during the innate immune response the lymph node cells of L. major-infected C3H mice upregulate the IL-12 receptor on CD4+, CD8+, and B220+ cells. An increase in the ability of the lymph node cells to bind IL-12 correlates with 9.3- and 4.6-fold increases in the mRNA expression levels of the IL-12Rβ1 and -β2 subunits, respectively. In contrast, BALB/c mice, which are susceptible to L. major infection, have no increase in the ability of the lymph node cells to bind IL-12 and correspondingly smaller increases in the mRNA expression levels of the IL-12Rβ1 and -β2 subunits of 2- and 1.5-fold, respectively. Neutralizing IL-4 and the administration of exogenous IL-12 upregulate IL-12R expression in BALB/c mice, while the neutralization of IL-12 in C3H mice blocks increased IL-12 receptor expression. These experiments reveal an important role for the regulation of the IL-12 receptor during the innate immune response after infection of mice with a pathogen.

scholarly journals Vaccination with Plasmid DNA Encoding TSA/LmSTI1 Leishmanial Fusion Proteins Confers Protection against Leishmania major Infection in Susceptible BALB/c Mice

2002 ◽  
Vol 70 (6) ◽  
pp. 2828-2836 ◽  
Author(s):  
A. Campos-Neto ◽  
J. R. Webb ◽  
K. Greeson ◽  
R. N. Coler ◽  
Y. A. W. Skeiky ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Plasmid Dna ◽  
Leishmania Major ◽  
Acquired Resistance ◽  
Interleukin 12 ◽  
Dna Immunization ◽  
Dna Encoding ◽  
Primate Model ◽  
Fusion Construct

ABSTRACT We have recently shown that a cocktail containing two leishmanial recombinant antigens (LmSTI1 and TSA) and interleukin-12 (IL-12) as an adjuvant induces solid protection in both a murine and a nonhuman primate model of cutaneous leishmaniasis. However, because IL-12 is difficult to prepare, is expensive, and does not have the stability required for a vaccine product, we have investigated the possibility of using DNA as an alternative means of inducing protective immunity. Here, we present evidence that the antigens TSA and LmSTI1 delivered in a plasmid DNA format either as single genes or in a tandem digene construct induce equally solid protection against Leishmania major infection in susceptible BALB/c mice. Immunization of mice with either TSA DNA or LmSTI1 DNA induced specific CD4+-T-cell responses of the Th1 phenotype without a requirement for specific adjuvant. CD8 responses, as measured by cytotoxic-T-lymphocyte activity, were generated after immunization with TSA DNA but not LmSTI1 DNA. Interestingly, vaccination of mice with TSA DNA consistently induced protection to a much greater extent than LmSTI1 DNA, thus supporting the notion that CD8 responses might be an important accessory arm of the immune response for acquired resistance against leishmaniasis. Moreover, the protection induced by DNA immunization was specific for infection with Leishmania, i.e., the immunization had no effect on the course of infection of the mice challenged with an unrelated intracellular pathogen such as Mycobacterium tuberculosis. Conversely, immunization of BALB/c mice with a plasmid DNA that is protective against challenge with M. tuberculosis had no effect on the course of infection of these mice with L. major. Together, these results indicate that the protection observed with the leishmanial DNA is mediated by acquired specific immune response rather than by the activation of nonspecific innate immune mechanisms. In addition, a plasmid DNA containing a fusion construct of the two genes was also tested. Similarly to the plasmids encoding individual proteins, the fusion construct induced both specific immune responses to the individual antigens and protection against challenge with L. major. These results confirm previous observations about the possibility of DNA immunization against leishmaniasis and lend support to the idea of using a single polygenic plasmid DNA construct to achieve polyspecific immune responses to several distinct parasite antigens.

scholarly journals Interleukin-12 Regulates Chemokine Gene Expression during the Early Immune Response to Leishmania major

2003 ◽  
Vol 71 (3) ◽  
pp. 1587-1589 ◽  
Author(s):  
Colby Zaph ◽  
Phillip Scott
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Lymph Nodes ◽  
Leishmania Major ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
Chemokine Gene ◽  
Early Immune Response ◽  
Draining Lymph Nodes ◽  
Chemokine Gene Expression

ABSTRACT Following infection with Leishmania major, the chemokines XCL1, CXCL10, and CCL2 were preferentially expressed in draining lymph nodes of resistant mice. Neutralization of interleukin 12 (IL-12) or gamma interferon in resistant mice resulted in decreased chemokine expression, while administration of IL-12 to susceptible mice resulted in an increase in the level of chemokine gene expression.

scholarly journals Immunogenicity Evaluation of a Novel Lentiviral Vaccine Expressing Multi- Epitope Against of Leishmania Major in BALB/c Mice

2020 ◽  
Author(s):  
Mahsa Rabienia ◽  
Zahra Roudbari ◽  
Ali Ghanbariasad ◽  
Abbas Abdollahi ◽  
Alireaza Molazadeh ◽  
...  
Keyword(s):  
Immune Response ◽  
Humoral Immune Response ◽  
Leishmania Major ◽  
Main Group ◽  
Definitive Treatment ◽  
Control Groups ◽  
Epitope Vaccine ◽  
Th1 Response ◽  
Humoral Immune ◽  
Ifn Γ

Abstract Background: Nowadays, the prevention of parasitic diseases including leishmaniasis is one of the health concerns in the world, and cutaneous leishmaniasis is the most common type of these diseases. So far, no drug or vaccine has been approved for definitive treatment of this disease.Methods: In this study, the recombinant lentiviral vaccine containing a new multi-epitope of KMP11 and HASPB of the Leishmania major (L. major) was synthesized that had previously been designed in-silico. The designed multi-epitope was subcloned into the pCDH513 lentiviral vector, and the recombinant lentiviral multi-epitope vaccine (rLV-multi-epitope) was synthesized in the HEK293T cell by the packaging vectors. Also, the Western Blotting method was used to confirm the gene expression. Then, the rLV-multi-epitope vaccine was injected twice, along with two control groups, PBS, and rLV-empty to immunize the BALB /c mice. Twenty-one days after the second injection, the splenocytes of the mice were is­­­­olated and stimulated with the Leishmania lysate.Results: The results of the enzyme-linked immunoassay (ELISA) test not only showed the titer of IFN-γ and IL-4 was increased in the immunized group compared to the controls, but also indicated that the ratio of IFN-γ to IL-4 cytokines in the main group was increased significantly. As a result, the Th1 response was generated in the main group. Moreover, the humoral immune response was assessed and the results showed that the ratio of IgG2a to IgG1 antibody in the sera of the immunized mice was increased compared to the control groups. Also, the ratio of IgG2a to IgG1 was increased in the main group. Therefore, the humoral immune response was increased, which can also have a positive effect on increasing the Th1 response.Conclusions: Our results showed that immunization by the new rLV-multi-epitope vaccine could stimulate the immune system towards the Th1 through increasing the IFN-γ production.

scholarly journals Interleukin-12 Is Capable of Generating an Antigen-Specific Th1-Type Response in the Presence of an Ongoing Infection-Driven Th2-Type Response

1999 ◽  
Vol 67 (5) ◽  
pp. 2166-2171 ◽  
Author(s):  
Lisa R. Schopf ◽  
Judy L. Bliss ◽  
Liz M. Lavigne ◽  
Charles L. Chung ◽  
Stanley F. Wolf ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Keyhole Limpet Hemocyanin ◽  
Interleukin 12 ◽  
Th2 Response ◽  
Th1 Response ◽  
Specific Immunoglobulin ◽  
Ifn Γ ◽  
Type Response ◽  
Visceral Disease ◽  
Ongoing Infection

ABSTRACT Previously we demonstrated that recombinant murine interleukin-12 (rmIL-12) administration can promote a primary Th1 response while suppressing the Th2 response in mice primed with 2,4,6-trinitrophenyl–keyhole limpet hemocyanin (TNP-KLH). The present studies examined the capacity of rmIL-12 to drive a Th1 response to TNP-KLH in the presence of an ongoing Th2-mediated disease. To establish a distinct Th2 response, we used a murine model of leishmaniasis. Susceptible BALB/c mice produce a strong Th2 response when infected with Leishmania major and develop progressive visceral disease. On day 26 postinfection, when leishmaniasis was well established, groups of mice were immunized with TNP-KLH in the presence or absence of exogenous rmIL-12. Even in the presence of overt infection, TNP-KLH-plus-rmIL-12-immunized mice were still capable of generating KLH-specific gamma interferon (IFN-γ) as well as corresponding TNP-specific immunoglobulin G2a (IgG2a) titers. In addition, the KLH-specific IL-4 was suppressed in infected mice immunized with rmIL-12. However, parasite-specific IL-4 and IgG1 production with a lack of parasite-specific IFN-γ secretion were maintained in all infected groups of mice including those immunized with rmIL-12. These data show that despite the ongoing infection-driven Th2 response, rmIL-12 was capable of generating an antigen-specific Th1 response to an independent immunogen. Moreover, rmIL-12 administered with TNP-KLH late in infection did not alter the parasite-specific cytokine or antibody responses.

scholarly journals CD4+ Th1 Cells Induced by Dendritic Cell-Based Immunotherapy in Mice Chronically Infected with Leishmania amazonensis Do Not Promote Healing

2004 ◽  
Vol 72 (8) ◽  
pp. 4455-4463 ◽  
Author(s):  
Yannick F. Vanloubbeeck ◽  
Amanda E. Ramer ◽  
Fei Jie ◽  
Douglas E. Jones
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Leishmania Amazonensis ◽  
Interleukin 12 ◽  
Mrna Levels ◽  
Antigen Presenting Cell ◽  
Th1 Response ◽  
Ifn Γ ◽  
Antigen Presenting

ABSTRACT The susceptibility of mice to Leishmania amazonensis infection is thought to result from an inability to develop a Th1 response. Our data show that the low levels of gamma interferon (IFN-γ) produced by the draining lymph node (DLN) cells of chronically infected mice could be enhanced in vitro and in vivo with L. amazonensis antigen-pulsed bone marrow-derived dendritic cells (BM-DC) and the Th1-promoting cytokine interleukin-12 (IL-12). Given intralesionally to chronically infected mice, this treatment induced the upregulation of mRNA levels for IFN-γ, the transcription factor T-box expressed in T cells, and IL-12 receptor β2 in CD4+ T cells from the DLN and an increase in parasite-specific immunoglobulin G2a in the serum. However, this Th1 response was not associated with healing, and the antigen-specific enhancement of IFN-γ production remained impaired in the DLN. However, addition of IL-12 to the in vitro recall response was able to recover this defect, suggesting that antigen-presenting cell-derived IL-12 production may be limited in infected mice. This was supported by the fact that L. amazonensis amastigotes limited the production of IL-12p40 from BM-DC in vitro. Altogether, our data indicate that the immune response of mice chronically infected with L. amazonensis can be enhanced towards a Th1 phenotype but that the presence of Th1 CD4+ T cells does not promote healing. This suggests that the phenotype of the CD4+ T cells may not always be indicative of protection to L. amazonensis infection. Furthermore, our data support growing evidence that antigen-presenting cell function, such as IL-12 production, may limit the immune response in L. amazonensis-infected mice.

Leishmania major H-line attenuated under pressure of gentamicin, induces a Th1 response which protects susceptible BALB/c mice against infection with virulent L. major

Parasitology ◽  
2009 ◽  
Vol 136 (11) ◽  
pp. 1243-1250 ◽  
Author(s):  
HAMID DANESHVAR ◽  
RICHARD BURCHMORE ◽  
PAUL HAGAN ◽  
R. STEPHEN PHILLIPS
Keyword(s):  
Immune Response ◽  
Lymph Node ◽  
Cell Line ◽  
Leishmania Major ◽  
Wild Type ◽  
Th1 Response ◽  
Th2 Responses ◽  
Draining Lymph Node ◽  
Ifn Γ

SUMMARYAn attenuated line of Leishmania major (L. major H-line) has been established by culturing promastigotes in vitro under gentamicin pressure. A modification of the previously described method for the generation of attenuated L. major is described, giving rise to attenuated parasites after 8 rather than 12 subpassages. No lesions developed in BALB/c mice infected with L. major H-line, whereas L. major wild-type (WT) induced a Th2 like response with progressive lesions. Analysis of splenocyte IFN-γ and IL-4 production following stimulation with promastigotes shows that the L. major H-line preferentially induces Th1-like responses and possibly down-regulates Th2 responses in BALB/c mice. L. major H-line parasites remained localized in the skin and draining lymph node, whereas L. major WT parasites disseminated into the visceral organs of BALB/c mice. Mice infected with L. major H-line acquired some resistance against L. major WT. These results show that the attenuated cell line of L. major is not only avirulent but that it may also modulate the host immune response.

scholarly journals Evolution of Lesion Formation, Parasitic Load, Immune Response, and Reservoir Potential in C57BL/6 Mice following High- and Low-Dose Challenge with Leishmania major

2000 ◽  
Vol 68 (9) ◽  
pp. 5176-5182 ◽  
Author(s):  
Rosalia Lira ◽  
Mark Doherty ◽  
Govind Modi ◽  
David Sacks
Keyword(s):  
Immune Response ◽  
Low Dose ◽  
Leishmania Major ◽  
Rapid Development ◽  
Parasite Clearance ◽  
Parasite Growth ◽  
Interleukin 12 ◽  
Lesion Formation ◽  
Metacyclic Promastigotes ◽  
Ifn Γ

ABSTRACT A model of cutaneous leishmaniasis using 102 Leishmania major metacyclic promastigotes inoculated into the footpads of genetically resistant C57BL/6 mice was studied in order to more accurately reproduce the evolution of lesion formation and the kinetics of parasite growth and immune response as they might occur in naturally exposed reservoirs and in human hosts. In contrast to the more conventional experimental model employing 106metacyclic promastigotes, in which the rapid development of footpad lesions was associated with an increasing number of amastigotes in the site, the low-dose model revealed a remarkably “silent” phase of parasite growth, lasting approximately 6 weeks, during which peak parasitic loads were established in the absence of any overt pathology. Footpad swelling was observed after 6 weeks, coincident with the onset of parasite clearance and with production of high levels of interleukin-12 (IL-12) and gamma interferon (IFN-γ) in draining lymph nodes. Low-dose challenge of IL-12- and IFN-γ-depleted or -deficient mice provided strong evidence that the induction or expression of cellular immunity is essentially absent during the first 6 to 8 weeks of intracellular growth, since the concentration of amastigotes in the site was not enhanced compared to that for wild-type animals during this time. By monitoring the ability of infected mice to transmit parasites to vector sand flies, it was observed that following low-dose challenge, footpads without apparent lesions provided an efficient source of parasites for exposed flies and that the low-dose challenge actually extended the duration of parasite transmissibility during the course of infection.

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