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 Beryllium, an Adjuvant That Promotes Gamma Interferon Production

2000 ◽  
Vol 68 (7) ◽  
pp. 4032-4039 ◽  
Author(s):  
Julia Y. Lee ◽  
Olga Atochina ◽  
Benjamin King ◽  
Leslie Taylor ◽  
Merle Elloso ◽  
...  
Keyword(s):  
Lymph Node ◽  
Gamma Interferon ◽  
Effective Control ◽  
Interleukin 12 ◽  
Spleen Cells ◽  
Th2 Response ◽  
Th1 Response ◽  
Ifn Γ

ABSTRACT Beryllium is associated with a human pulmonary granulomatosis characterized by an accumulation of CD4+ T cells in the lungs and a heightened specific lymphocyte proliferative response to beryllium (Be) with gamma interferon (IFN-γ) release (i.e., a T helper 1 [Th1] response). While an animal model of Be sensitization is not currently available, Be has exhibited adjuvant effects in animals. The effects of Be on BALB/c mice immunized with soluble leishmanial antigens (SLA) were investigated to determine if Be had adjuvant activity for IFN-γ production, an indicator of the Th1 response. In this strain of Leishmania-susceptible BALB/c mice, a Th2 response is normally observed after in vivo SLA sensitization and in vitro restimulation with SLA. If interleukin-12 (IL-12) is given during in vivo sensitization with SLA, markedly increased IFN-γ production and decreased IL-4 production are detected. We show here that when beryllium sulfate (BeSO4) was added during in vivo sensitization of BALB/c mice with SLA and IL-12, significantly increased IFN-γ production and decreased IL-4 production from lymph node and spleen cells were detected upon in vitro SLA restimulation. No specific responses were observed to Be alone. Lymph node and spleen cells from all mice proliferated strongly and comparably upon in vitro restimulation with SLA and with SLA plus Be; no differences were noted among groups of mice that received different immunization regimens. In vivo, when Be was added to SLA and IL-12 for sensitization of BALB/c mice, more effective control ofLeishmania infection was achieved. This finding has implications for understanding not only the development of granulomatous reactions but also the potential for developing Be as a vaccine adjuvant.

scholarly journals Interdependency of Interleukin-10 and Interleukin-12 in Regulation of T-Cell Differentiation and Effector Function of Monocytes in Response to Stimulation withCryptococcus neoformans

2001 ◽  
Vol 69 (10) ◽  
pp. 6064-6073 ◽  
Author(s):  
Cinzia Retini ◽  
Thomas R. Kozel ◽  
Donatella Pietrella ◽  
Claudia Monari ◽  
Francesco Bistoni ◽  
...  
Keyword(s):  
T Cells ◽  
Critical Role ◽  
Principal Component ◽  
Interleukin 10 ◽  
Interleukin 12 ◽  
T Helper ◽  
Ifn Γ ◽  
Capsular Material ◽  
Type Response

ABSTRACT We previously demonstrated that the principal component of capsular material of Cryptococcus neoformans, glucuronoxylomannan (GXM), induces interleukin-10 (IL-10) secretion from human monocytes. Here we report that encapsulation of the yeast with GXM is able to down-regulate interleukin-12 (IL-12) production by monocytes that would normally occur in the absence of encapsulation. This phenomenon appeared to be the result of inhibition of the phagocytic process by encapsulation with GXM as well as of negative signals such as IL-10 secretion produced by interaction of GXM with leukocytes. Decreased secretion of IL-12 correlated with decreased release of gamma interferon (IFN-γ) from T cells, suggesting a role for encapsulation with GXM in hindering a T helper type 1 (Th1) response. This is supported by the ability of encapsulation with GXM to limit increased expression of B7-1 costimulatory molecules that otherwise might limit IL-10 secretion. Endogenous IL-10 played a critical role in modulatory activity associated with encapsulation with GXM. Blocking IL-10 with monoclonal antibody to IL-10 resulted in increased (i) IL-12 secretion, (ii) IFN-γ release from T cells, and (iii) killing of C. neoformans by monocytes. These results suggest that encapsulation with GXM limits development of a protective Th1-type response, an inhibitory process in which IL-10 plays a critical role. Scavengers of GXM and/or IL-10 could be useful in a protective Th1-type response in patients with cryptococcosis.

scholarly journals Pretreatment with Recombinant Flt3 Ligand Partially Protects against Progressive Cutaneous Leishmaniasis in Susceptible BALB/c Mice

2001 ◽  
Vol 69 (2) ◽  
pp. 673-680 ◽  
Author(s):  
Inger B. Kremer ◽  
Meetha P. Gould ◽  
Kevin D. Cooper ◽  
Frederick P. Heinzel
Keyword(s):  
Dendritic Cells ◽  
Lymph Node ◽  
Leishmania Major ◽  
Parasite Load ◽  
Interleukin 12 ◽  
Productive Capacity ◽  
Cutaneous Lesions ◽  
Cutaneous Infections ◽  
Ifn Γ ◽  
Cellular Immune

ABSTRACT Dendritic cells are potent antigen-presenting cells that also produce interleukin-12 (IL-12) during innate and adaptive cellular immune responses and that thereby promote the differentiation of gamma interferon (IFN-γ)-producing Th1-type CD4+ T lymphocytes. We hypothesized that expanded dendritic-cell populations in mice pretreated with the hematopoietic cytokine Flt3L would protect against cutaneous Leishmania major infection. Pretreatment of disease-susceptible BALB/c mice with 10 μg of recombinant Flt3L (rFlt3L) for 9 to 10 days before infection increased lymph node IL-12 p40 productive capacity 20-fold compared to that of saline-injected controls. Furthermore, 9 of 22 (40.9%) rFlt3L-pretreated BALB/c mice resolved their cutaneous infections, whereas none of the 22 control BALB/c mice healed. Healed, rFlt3L-pretreated mice did not develop disease following reinfection. Flt3L pretreatment also reduced parasite numbers 1,000-fold in the cutaneous lesions at 2 weeks after infection relative to numbers in lesions of untreated controls. However, Flt3L pretreatment did not significantly alter L. major-induced IFN-γ and IL-4 production in lymph node culture at 1, 2, and 4 weeks after infection. Despite the lack of Th immune deviation, Flt3L ligand-pretreated lymph nodes expressed up to 10-fold higher levels of IL-12 p40 and inducible (type 2) nitric oxide synthase mRNA at 7 days after infection. In contrast, treatment with rFlt3L after infection failed to protect against disease despite comparable expansions of dendritic cells and IL-12 p40 productive capacity in both infected and uninfected BALB/c mice treated with rFlt3L. We conclude that rFlt3L pretreatment before infection with L. major reduces parasite load and promotes healing of cutaneous lesions without stable cytokine deviation towards a dominant Th1 cytokine phenotype.

scholarly journals Evaluation of Immune Response against Leishmaniasis in BALB/c Mice Immunized with Cationic DOTAP/DOPE/CHOL Liposomes Containing Soluble Leishmania major Antigens

2019 ◽  
Author(s):  
Mansure HOJATIZADE ◽  
Ali BADIEE ◽  
Ali KHAMESIPOUR ◽  
Mahmoud Reza JAAFARI
Keyword(s):  
Immune Response ◽  
Leishmania Major ◽  
High Titer ◽  
Parasite Burden ◽  
Phase Iii ◽  
Th2 Response ◽  
Liposomal Form ◽  
Lipid Film ◽  
Phase Iii Clinical Trials ◽  
Ifn Γ

Background: Whole killed Leishmania vaccine reached phase III clinical trials but failed to display significant efficacy in human mainly due to limited Th1 inducer adjuvant. Liposomes consisting of 1, 2-dioleoyl-3trimethylammonium-propane (DOTAP) bearing an inherent adjuvanticity and 1, 2-dioleoyl-L-α-glycero-3-phosphatidylethanolamine (DOPE) is well known to intensify the efficacy of positively charged liposomes. Methods: Soluble Leishmania major antigens (SLA) encapsulated in cationic liposomes using lipid film method in 2016). BALB/c mice were immunized subcutaneously (SC), three times in a 2-wk interval, with Lip (DOTAP)-SLA+, Lip (DOTAP/DOPE)-SLA+, Lip (DOTAP/DOPE/CHO)-SLA+, Lip (DOTAP/DOPE/CHO), Lip (DOPE/CHO), SLA or HEPES buffer. At week 2 after the last booster injection, immunized mice have challenged SC in the footpad with L. major parasites. To investigate the rate of protection and the type of immune response generated in mice, lesions development was assessed, IL-4 and IFN-γ levels with the ratio of IgG2a/IgG1 isotype were studied to describe the type of generated immune response. Results: Mice immunized with all liposomal form of SLA showed smaller footpad swelling and lower parasite burden in the spleen and footpad compared to the group of mice received buffer. However, these formulations did not show protection against leishmaniosis because of a generated mixed Th1/Th2 response in mice characterized by high production of IFN-γ and IL4 and a high titer of IgG1 and IgG2a antibody. Conclusion: Immunization with Lip (DOTAP/DOPE/CHO)-SLA+ was not an appropriate strategy to protect mice against leishmaniosis.

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 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 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 Combined Treatment with Interleukin-12 and Indomethacin Promotes Increased Resistance in BALB/c Mice with Established Leishmania major Infections

2002 ◽  
Vol 70 (10) ◽  
pp. 5715-5720 ◽  
Author(s):  
Jian Li ◽  
Udaikumar M. Padigel ◽  
Phillip Scott ◽  
Jay P. Farrell
Keyword(s):  
Leishmania Major ◽  
Combined Treatment ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Interleukin 12 ◽  
Th2 Response ◽  
Enhanced Production ◽  
Time Of Infection

ABSTRACT Following infection of susceptible BALB/c mice with Leishmania major, early production of interleukin-4 (IL-4) is associated with the development of a nonprotective Th2 response and the development of progressive disease. Treatment of mice with IL-12 at the time of infection can promote the activation of a protective Th1 response; however, IL-12 treatment of mice with established infections has little effect on the progress of lesion development. This may be due to a down-regulation of the IL-12 receptor β2 chain (IL-12Rβ2) that accompanies the expansion of IL-4-producing Th2 cells. We have examined whether prostaglandins function to regulate in vivo responsiveness to IL-12. Mice treated with indomethacin are responsive to treatment with exogenous IL-12 through at least the first 2 weeks of infection and, unlike control mice treated with IL-12, develop an enhanced Th1-type response associated with increased enhanced resistance to infection. Cells from indomethacin-treated mice also exhibit enhanced production of gamma interferon (IFN-γ) following in vitro stimulation with IL-12. Although in vivo indomethacin treatment did not appear to influence IL-12 production in infected mice, cells from indomethacin-treated mice did express higher levels of IL-12Rβ2, suggesting that prostaglandins may play a role in the loss of IL-12 responsiveness observed during nonhealing L. major infections.

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 Control of Borrelia burgdorferi-Specific CD4+-T-Cell Effector Function by Interleukin-12- and T-Cell Receptor-Induced p38 Mitogen-Activated Protein Kinase Activity

2006 ◽  
Vol 74 (10) ◽  
pp. 5713-5717 ◽  
Author(s):  
Michael N. Hedrick ◽  
Chris M. Olson ◽  
Dietrich B. Conze ◽  
Tonya C. Bates ◽  
Mercedes Rincón ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Map Kinase ◽  
Kinase Activity ◽  
Cell Receptor ◽  
P38 Map Kinase ◽  
Interleukin 12 ◽  
Th1 Response ◽  
Mitogen Activated Protein ◽  
Ifn Γ

ABSTRACT Infection with Borrelia burgdorferi, the causative agent of Lyme disease, results in a Th1 response and proinflammatory cytokine production. Mice deficient for MKK3, an upstream activator of p38 mitogen-activated protein (MAP) kinase, develop a lower Th1 response and exhibit an impaired ability to produce proinflammatory cytokines upon infection with the spirochete. We investigated the contribution of p38 MAP kinase activity in gamma interferon (IFN-γ) production in CD4+ T cells in response to specific antigen through T-cell receptor (TCR)- and interleukin-12 (IL-12)-mediated signals. The specific inhibition of p38 MAP kinase in T cells and the administration of a pharmacological inhibitor of the kinase during the course of infection with the spirochete resulted in reduced levels of IFN-γ in the sera of infected mice. Our results also demonstrate that although p38 MAP kinase activity is not required for the differentiation of B. burgdorferi-specific CD4+ T cells, the production of IFN-γ by Th1 effector cells is regulated by the kinase. Both TCR engagement and IL-12 induced the production of the Th1 cytokine through the activation of the p38 MAP kinase pathway. Thus, the inhibition of this pathway in vitro resulted in decreased levels of IFN-γ during restimulation of B. burgdorferi-specific T cells in response to anti-CD3 and IL-12 stimulation. These results clarify the specific contribution of the p38 MAP kinase in the overall immune response to the spirochete and its role in the effector function of B. burgdorferi-specific T cells.

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