scholarly journals Immunization with a Toll-Like Receptor 7 and/or 8 Agonist Vaccine Adjuvant Increases Protective Immunity against Leishmania major in BALB/c Mice

2008 ◽  
Vol 76 (8) ◽  
pp. 3777-3783 ◽  
Author(s):  
Wen-Wei Zhang ◽  
Greg Matlashewski
Keyword(s):  
Protective Immunity ◽  
Leishmania Major ◽  
Challenge Infection ◽  
Innate Immune ◽  
Infection Model ◽  
Vaccine Adjuvants ◽  
Th2 Response ◽  
Th1 Response ◽  
Potential Vaccine ◽  
Antigen Presenting

ABSTRACT Activation of Toll-like receptors (TLRs) on antigen-presenting cells of the innate immune system initiates, amplifies, and directs the antigen-specific acquired immune response. Ligands that stimulate TLRs therefore represent potential vaccine adjuvants. In the present study, we determined whether imiquimod and its related compound R848, which are TLR7 and/or TLR8 agonists, represent potential vaccine adjuvants when delivered topically, subcutaneously, or intramuscularly. Using the Leishmania major infection model in BALB/c mice, vaccination with crude Leishmania antigen was not protective against subsequent challenge infection unless it was administered with R848 or a topical application of imiquimod containing cream on the skin. Subcutaneous vaccination with these adjuvants mediated a TH1 response against L. major antigen, which appeared to suppress the TH2 response following a challenge infection. Protective immunity was generated following subcutaneous vaccination but not intramuscular vaccination. These observations suggest that topically administered imiquimod or subcutaneously injected R848 represent potential vaccine adjuvants to enhance the TH1 response, which can be used with existing or new vaccine formulations.

scholarly journals Cord Blood-Based Approach to Assess Candidate Vaccine Adjuvants Designed for Neonates and Infants

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 95
Author(s):  
Daisuke Tokuhara ◽  
Norikatsu Hikita
Keyword(s):  
Cord Blood ◽  
Protective Immunity ◽  
Current Knowledge ◽  
Current System ◽  
Innate Immune ◽  
Vaccine Adjuvants ◽  
Adult Humans ◽  
Neonates And Infants ◽  
Induced Immunity ◽  
Review Current

Neonates and infants are particularly susceptible to infections, for which outcomes tend to be severe. Vaccination is a key strategy for preventing infectious diseases, but the protective immunity achieved through vaccination typically is weaker in infants than in healthy adults. One possible explanation for the poor acquisition of vaccine-induced immunity in infants is that their innate immune response, represented by toll-like receptors, is immature. The current system for developing pediatric vaccines relies on the confirmation of their safety and effectiveness in studies involving the use of mature animals or adult humans. However, creating vaccines for neonates and infants requires an understanding of their uniquely immature innate immunity. Here we review current knowledge regarding the innate immune system of neonates and infants and challenges in developing vaccine adjuvants for those children through analyses of cord blood.

scholarly journals The Absence of Cutaneous Lymph Nodes Results in a Th2 Response and Increased Susceptibility to Leishmania major Infection in Mice

2008 ◽  
Vol 76 (9) ◽  
pp. 4241-4250 ◽  
Author(s):  
Jan M. Ehrchen ◽  
Johannes Roth ◽  
Kirsten Roebrock ◽  
Georg Varga ◽  
Wolfram Domschke ◽  
...  
Keyword(s):  
Lymph Nodes ◽  
Leishmania Major ◽  
Systemic Infection ◽  
Th2 Cells ◽  
Th2 Response ◽  
Local Skin ◽  
Critical Requirement ◽  
Β Receptor ◽  
Cellular Immune ◽  
Antigen Presenting

ABSTRACT Lymph nodes (LNs) are important sentinel organs where antigen-presenting cells interact with T cells to induce adaptive immune responses. In cutaneous infection of mice with Leishmania major, resistance depends on the induction of a T-helper-cell-1 (Th1)-mediated cellular immune response in draining, peripheral LNs. We investigated whether draining, peripheral LNs are absolutely required for resistance against L. major infection. We investigated the course of experimental leishmaniasis in wild-type (wt) mice lacking peripheral LNs (pLNs), which we generated by in utero blockade of membrane-bound lymphotoxin, and in mice lacking pLNs or all LNs due to genetic deletion of lymphotoxin ligands or receptors. wt mice of the resistant C57BL/6 strain without local skin-draining LNs were still able to generate specific T-cell responses, but this yielded Th2 cells. This switch to a Th2 response resulted in severe systemic infection. We also confirmed these results with mice lacking pLNs due to genetic depletion of lymphotoxin-β. The complete absence of LNs due to a genetic depletion of the lymphotoxin-β receptor also resulted in a marked deterioration of disease and a Th2 response. Thus, in the absence of pLNs, an L. major-specific Th2 response is induced in the remaining secondary lymphoid organs, such as the spleen and non-skin-draining LNs. This indicates a critical requirement for pLNs to induce protective Th1 immunity and suggests that whether Th1 or Th2 priming to the same antigen occurs depends on the site of the primary antigen recognition.

scholarly journals Polarized Helper-T-Cell Responses againstLeishmania major in the Absence of B Cells

1999 ◽  
Vol 67 (1) ◽  
pp. 266-270 ◽  
Author(s):  
Daniel R. Brown ◽  
Steven L. Reiner
Keyword(s):  
T Cell ◽  
B Cells ◽  
Leishmania Major ◽  
Immunoglobulin M ◽  
Wild Type ◽  
Th2 Response ◽  
Th1 Response ◽  
Cell Responses ◽  
Th Cell ◽  
Th2 Responses

ABSTRACT B-cell-to-T-cell signaling can shape helper T (Th) cell responses. During infection with Leishmania major, Th response is critical in determining the outcome of disease. Resistance depends on the generation of a protective Th1 response, while susceptibility is mediated by the generation of a Th2 response. In this study, we determined whether B cells are required for the development of polarized Th1 and Th2 responses during infection with L. major. Mice lacking B cells due to disruption of the immunoglobulin M locus (μMT) were infected with L. major, and disease progression and Th cell development were assessed. On the genetically resistant C57BL background, both wild-type and μMT mice controlled the infection and mounted a Th1 response. On the genetically susceptible BALB/c background, both wild-type and μMT mice were susceptible to infection and generated Th2 responses. Thus, duringL. major infection, neither direct antigen presentation or costimulation by B cells nor antibody-mediated effector functions are essential for the development of polarized Th responses.

scholarly journals Interleukin-12 p40 Secretion by Cutaneous CD11c+ and F4/80+ Cells Is a Major Feature of the Innate Immune Response in Mice That Develop Th1-Mediated Protective Immunity to Schistosomamansoni

2003 ◽  
Vol 71 (6) ◽  
pp. 3563-3571 ◽  
Author(s):  
Karen G. Hogg ◽  
Supeecha Kumkate ◽  
Sonia Anderson ◽  
Adrian P. Mountford
Keyword(s):  
Protective Immunity ◽  
Innate Immune ◽  
Interleukin 12 ◽  
Innate Immune Responses ◽  
Toll Like Receptor 4 ◽  
Inflammatory Protein ◽  
Antigen Presenting ◽  
Macrophage Inflammatory Protein ◽  
Large Granular Cells

ABSTRACT Radiation-attenuated (RA) schistosome larvae are potent stimulators of innate immune responses at the skin site of exposure (pinna) that are likely to be important factors in the development of Th1-mediated protective immunity. In addition to causing an influx of neutrophils, macrophages, and dendritic cells (DCs) into the dermis, RA larvae induced a cascade of chemokine and cytokine secretion following in vitro culture of pinna biopsy samples. While macrophage inflammatory protein 1α and interleukin-1β (IL-1β) were produced transiently within the first few days, the Th1-promoting cytokines IL-12 and IL-18 were secreted at high levels until at least day 14. Assay of C3H/HeJ mice confirmed that IL-12 secretion was not due to lipopolysaccharide contaminants binding Toll-like receptor 4. Significantly, IL-12 p40 secretion was sustained in pinnae from vaccinated mice but not in those from nonprotected infected mice. In contrast, IL-10 was produced from both vaccinated and infected mice. This cytokine regulates IL-12-associated dermal inflammation, since in vaccinated IL-10−/− mice, pinna thickness was greatly increased concurrent with elevated levels of IL-12 p40. A significant number of IL-12 p40+ cells were detected as emigrants from in vitro-cultured pinnae, and most were within a population of rare large granular cells that were Ia+, consistent with their being antigen-presenting cells. Labeling of IL-12+ cells for CD11c, CD205, CD8α, CD11b, and F4/80 indicated that the majority were myeloid DCs, although a proportion were CD11c− F4/80+, suggesting that macrophages were an additional source of IL-12 in the skin.

scholarly journals Chronic Aerobic Training at Different Volumes in the Modulation of Macrophage Function and in vivo Infection of BALB/c Mice by Leishmania major

2021 ◽  
Vol 12 ◽  
Author(s):  
T. T. Guimarães ◽  
S. M. R. Gomes ◽  
R. A. A. C. Albuquerque ◽  
A. K. C. Lima ◽  
G. F. Braga ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Aerobic Training ◽  
Clinical Manifestations ◽  
High Volume ◽  
Strenuous Exercise ◽  
Macrophage Infection ◽  
Th2 Response ◽  
Th1 Response ◽  
Very High

Physical inactivity is one of the main causes of chronic diseases; however, strenuous exercise can induce immunosuppression. Several studies suggest that moderate amounts of exercise lead to a Th1 response, favoring the resolution of infections caused by intracellular microorganisms, while high volumes of exercise tend to direct the response to Th2, favoring infection by them. Leishmaniasis is a parasitic disease promoted by parasites of the Leishmania genus, with clinical manifestations that vary according to the species of the parasite and the immune response of the host. The experimental Leishmania major–BALB/C mouse model provides a good model for the resistance (Th1 response) or susceptibility (Th2 response) that determines the progression of this infection. The aim of this study was to evaluate the effect of aerobic training at different volumes on modulation of in vitro macrophage infection by L. major, as well as to assess the effect of high volume (HV) aerobic training on the development of L. major in vivo in BALB/c mice. Uninfected animals were submitted to various exercise volumes: none (SED), light (LV), moderate (MV), high (HV), very high (VHV), and tapering (TAP). The macrophages of these animals were infected by L. major and the LV and MV groups showed a decrease in the infection factor, while the VHV showed an increase in the infection factor, when treated with LPS. The cytokine concentration pattern measured in the supernatants of these macrophages suggested a predominant Th1 response profile in the LV and MV groups, while the Th2 profile predominated in the VHV and TAP groups. Groups of BALB/C mice infected with L. major were subjected to high volume (iHV) or non-periodized high volume (iNPHV) exercise or kept sedentary (iSED). The exercised animals suffered a significant increase in injuries caused by the parasites. The animals in the group submitted to high volume exercise (iHV) showed visceralization of the infection. These data strongly suggest that a very high volume of aerobic training increased the susceptibility of BALB/C mice to L. major infection, while moderate distribution of training loads promoted immunological balance, better controlling the infection by this parasite.

scholarly journals Cutaneous leishmaniasis and related tissue helminthiasis (review)

2019 ◽  
Vol 11 (2) ◽  
pp. 20-25
Author(s):  
M. D. Akhmedova ◽  
J. A. Anvarov ◽  
U. T. Suvonkulov ◽  
D. B. Mirzajonova ◽  
S. O. Osipova
Keyword(s):  
Side Effects ◽  
Cutaneous Leishmaniasis ◽  
Amphotericin B ◽  
Protective Immunity ◽  
Antioxidant Properties ◽  
Th2 Response ◽  
Resistance Development ◽  
Th1 Response

Epidemiology of cutaneous leismaniasis is considered, CL morbidity remains rather high and it is increasing in Uzbekistan. The main medicines in leishmaniasis treatment are pentavalent antimonials which are characterized by toxicity and resistance development, and amphotericin B. Amphotericin B is toxic too and has a lot of contraindications and side effects. Medicines with reparative and antioxidant properties are assumed to positively influence the CL course, not only leishmanicidal preparations. Protective immunity in CL mediated by Th1 response is analyzed. Expediency of examination of patients with CL for helminthiases inducing opposite Th2-response as well as studies of concomitant helminthiases influence on the CL course are discussed. 

scholarly journals Early Enhanced Th1 Response after Leishmania amazonensis Infection of C57BL/6 Interleukin-10-Deficient Mice Does Not Lead to Resolution of Infection

2002 ◽  
Vol 70 (4) ◽  
pp. 2151-2158 ◽  
Author(s):  
Douglas E. Jones ◽  
Mark R. Ackermann ◽  
Ulrike Wille ◽  
Christopher A. Hunter ◽  
Phillip Scott
Keyword(s):  
Leishmania Major ◽  
Chronic Phase ◽  
Leishmania Amazonensis ◽  
Delayed Type Hypersensitivity ◽  
Cell Mediated Immunity ◽  
Th2 Response ◽  
Th1 Response ◽  
Response Expression ◽  
Deficient Mice

ABSTRACT C3H and C57BL/6 mice are resistant to Leishmania major but develop chronic lesions with persistent parasite loads when they are infected with Leishmania amazonensis. These lesions develop in the absence of interleukin-4 (IL-4), indicating that susceptibility to this parasite is not a result of development of a Th2 response. Expression of the cytokine IL-10 during infection could account for the lack of IL-12 expression and poor cell-mediated immunity towards the parasite. Therefore, we tested the hypothesis that IL-10 plays a central role in downmodulating the Th1 response after L. amazonensis infection. Infection of C57BL/6 IL-10-deficient mice indicated that in the absence of IL-10 there was early enhancement of a Th1 response, which was downregulated during the more chronic stage of infection. In addition, although there were 1- to 2-log reductions in the parasite loads within the lesions, the parasites continued to persist, and they were associated with chronic lesions whose size was similar to that of the control lesions. These experiments indicated that L. amazonensis resistance to killing in vivo is only partially dependent on expression of host IL-10. However, IL-10-deficient mice had an enhanced delayed-type hypersensitivity response during the chronic phase of infection, indicating that there were Th1 type effector cells in vivo at this late stage of infection. These results indicate that although IL-10 plays a role in limiting the Th1 response during the acute infection phase, other immunomodulatory factors are responsible for limiting the Th1 response during the chronic phase.

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 Dendritic Cells Are Responsible for the Capacity of CpG Oligodeoxynucleotides to Act as an Adjuvant for Protective Vaccine Immunity Against Leishmania major in Mice

2003 ◽  
Vol 198 (2) ◽  
pp. 281-291 ◽  
Author(s):  
Javeed A. Shah ◽  
Patricia A. Darrah ◽  
David R. Ambrozak ◽  
Tara N. Turon ◽  
Susana Mendez ◽  
...  
Keyword(s):  
Protective Immunity ◽  
Leishmania Major ◽  
Cellular Mechanism ◽  
Cpg Odn ◽  
Cpg Oligodeoxynucleotides ◽  
Plasmacytoid Dcs ◽  
Ifn Γ ◽  
Adjuvant Effects ◽  
Antigen Presenting

Vaccination with leishmanial Ag and CpG oligodeoxynucleotides (ODN) confers sustained cellular immunity and protection to infectious challenge up to 6 mo after immunization. To define the cellular mechanism by which CpG ODN mediate their adjuvant effects in vivo, the functional capacity of distinct dendritic cell (DC) subsets was assessed in the lymph nodes (LNs) of BALB/c mice, 36 h after immunization with the leishmanial antigen (LACK) and CpG ODN. After this immunization, there was a striking decrease in the frequency of the CD11c+B220+ plasmacytoid DCs with a proportionate increase in CD11c+CD8−B220− cells. CD11c+CD8+B220− cells were the most potent producers of interleukin (IL)-12 p70 and interferon (IFN)-γ, while plasmacytoid DCs were the only subset capable of secreting IFN-α. In terms of antigen presenting capacity, plasmacytoid DCs were far less efficient compared with the other DC subsets. To certify that DCs were responsible for effective vaccination, we isolated CD11c+ and CD11c− cells 36 h after immunization and used such cells to elicit protective immunity after adoptive transfer in naive, Leishmania major susceptible BALB/c mice. CD11c+ cells but not 10-fold higher numbers of CD11c− cells from such immunized mice mediated protection. Therefore, the combination of LACK antigen and CpG ODN adjuvant leads to the presence of CD11c+ DCs in the draining LN that are capable of vaccinating naive mice in the absence of further antigen or adjuvant.

scholarly journals Low Dose Leishmania major Promotes a Transient T Helper Cell Type 2 Response That Is Down-regulated by Interferon γ–producing CD8+ T Cells

2004 ◽  
Vol 199 (11) ◽  
pp. 1559-1566 ◽  
Author(s):  
Jude E. Uzonna ◽  
Karen L. Joyce ◽  
Phillip Scott
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Low Dose ◽  
Leishmania Major ◽  
Interferon Γ ◽  
Th2 Response ◽  
Th1 Response ◽  
Th Cell

An unresolved issue in the field of T helper (Th) cell development relates to the findings that low doses of antigen promote Th2 cell development in vitro, whereas several classic in vivo studies suggest the opposite. Here we resolve this paradox by studying the early immune response in mice after infection with different doses of Leishmania major. We found that low parasite doses induced a Th2 response in C57BL/6 (B6) mice, whereas high doses induced a Th1 response. However, the Th2 response in low dose–infected mice was transient and the animals healed. The appearance of a Th1 response after low dose infection was dependent upon the concomitant activation of interferon γ–producing CD8+ T cells. In the absence of CD8+ T cells, the Th2 response was maintained. However, either neutralization of interleukin (IL)-4 or administration of IL-12 promoted a Th1 response after low dose infection of CD8-deficient mice, indicating that the required role for CD8+ T cells was limited to modulation of CD4+ T cell responses. Thus, the discrepant results seen between in vivo and in vitro studies on the effects of antigen dose on Th cell differentiation may depend upon whether CD8+ T cells participate in the immune response.

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