scholarly journals Influence of Parasite Load on the Ability of Type 1 T Cells To Control Leishmania major Infection

2002 ◽  
Vol 70 (2) ◽  
pp. 498-503 ◽  
Author(s):  
Brian Hondowicz ◽  
Phillip Scott
Keyword(s):  
Cell Population ◽  
Leishmania Major ◽  
Parasite Load ◽  
Interleukin 12 ◽  
Block Type ◽  
Cell Transfer ◽  
Parasite Replication ◽  
High Parasite

ABSTRACT BALB/c mice infected with Leishmania major developed a type 2 immune response which failed to control parasite replication. We found that scid mice that received splenocytes from BALB/c mice that had been infected for 3 weeks with L. major (a type 2 cell population) and that were subsequently infected with L. major were protected when they were treated with interleukin 12 (IL-12). In contrast, IL-12 was ineffective at protecting BALB/c mice infected for 3 weeks, suggesting that a high parasite load regulates the development of protective immunity. To determine how this regulation operates, we performed a series of adoptive transfers of naïve, type 1 or type 2 splenocytes into scid mice. The recipient scid mice were infected either for 5 weeks prior to cell transfer (and thus had a high parasite load) or at the time of cell transfer. scid mice that were infected for 5 weeks and received a type 1 cell population were able to cure their lesions. However, when 5-week-infected scid mice received both type 1 and 2 cell populations, they were unable to control their infections. In contrast, the same type 1 and 2 cells transferred to naïve scid mice, which were subsequently infected, provided protection. In addition, we found that naïve cells mediated protection in scid mice with established lesions. These results show that high parasite numbers do not block type 1 protective responses or the development of type 1 responses. Instead, the influence of a high parasite load is dependent on the presence of a type 2 cell population.

scholarly journals Immunization with Leishmania major Exogenous Antigens Protects Susceptible BALB/c Mice against Challenge Infection with L. major

2004 ◽  
Vol 72 (10) ◽  
pp. 5654-5661 ◽  
Author(s):  
Willy K. Tonui ◽  
J. Santiago Mejia ◽  
Lisa Hochberg ◽  
M. Lamine Mbow ◽  
Jeffrey R. Ryan ◽  
...  
Keyword(s):  
Western Blot ◽  
Leishmania Major ◽  
Challenge Infection ◽  
Lymphoid Cells ◽  
Interleukin 12 ◽  
Protective Response ◽  
Type 2 Cytokines

ABSTRACT The potential of Leishmania major culture-derived soluble exogenous antigens (SEAgs) to induce a protective response in susceptible BALB/c mice challenged with L. major promastigotes was investigated. Groups of BALB/c mice were immunized with L. major SEAgs alone, L. major SEAgs coadministered with either alum (aluminum hydroxide gel) or recombinant murine interleukin-12 (rmIL-12), L. major SEAgs coadministered with both alum and rmIL-12, and L. major SEAgs coadministered with Montanide ISA 720. Importantly and surprisingly, the greatest and most consistent protection against challenge with L. major was seen in mice immunized with L. major SEAgs alone, in the absence of any adjuvant. Mice immunized with L. major SEAgs had significantly smaller lesions that at times contained more than 100-fold fewer parasites. When lymphoid cells from L. major SEAg-immunized mice were stimulated with leishmanial antigen in vitro, they proliferated and secreted a mixed profile of type 1 and type 2 cytokines. Finally, analyses with Western blot analyses and antibodies against three surface-expressed and secreted molecules of L. major (lipophosphoglycan, gp46/M2/PSA-2, and gp63) revealed that two of these molecules are present in L. major SEAgs, lipophosphoglycan and the molecules that associate with it and gp46/M2/PSA-2.

scholarly journals Immunomodulatory Effects of the Lutzomyia longipalpis Salivary Gland Protein Maxadilan on Mouse Macrophages

2007 ◽  
Vol 75 (5) ◽  
pp. 2359-2365 ◽  
Author(s):  
Tess M. Brodie ◽  
Matthew C. Smith ◽  
Robin V. Morris ◽  
Richard G. Titus
Keyword(s):  
Leishmania Major ◽  
Parasite Load ◽  
Sand Fly ◽  
Lutzomyia Longipalpis ◽  
No Production ◽  
Intracellular Pathogens ◽  
Tnf Α ◽  
Parasite Survival

ABSTRACT Infection with Leishmania major is enhanced when the sand fly Lutzomyia longipalpis salivary peptide maxadilan (MAX) is injected along with the parasite. Here we determined the effect that MAX has on the secretion of cytokines and nitric oxide (NO) and on parasite survival in macrophages (MΦs). The cytokines produced by MΦs can enhance a type 1 response, which will increase NO and the killing of intracellular pathogens such as L. major, or a type 2 response, leading to antibody production that is ineffective against intracellular pathogens such as L. major. A mouse macrophage cell line (RAW 264.7) was stimulated with various concentrations of MAX and lipopolysaccharide (LPS), and the supernatants were collected after 1, 2, and 3 days. Supernatants were assayed for interleukin-12p70 (IL-12p70), IL-10, IL-6, transforming growth factor β (TGF-β), NO, and tumor necrosis factor alpha (TNF-α). Our results indicate that the addition of MAX upregulates the cytokines associated with a type 2 response (IL-10, IL-6, and TGF-β) but downregulates type 1 cytokines (IL-12p70 and TNF-α) and NO. MAX was also added to L. major-infected mouse peritoneal exudate cells (PECs), and the parasite load increased significantly. The enhanced parasite load correlated with decreased NO production by PECs that were stimulated with LPS and gamma interferon in the presence of MAX. The ability of MAX to foster a type 2 response, to enhance parasite survival, and to decrease NO argues that MAX may be crucial for the early survival of Leishmania in the vertebrate host, and therefore, MAX holds considerable promise as an antigenic component for a vaccine against Leishmania.

scholarly journals Protective Effect of Vaccination with a Combination of Recombinant Surface Antigen 1 and Interleukin-12 against Toxoplasmosis in Mice

1998 ◽  
Vol 66 (9) ◽  
pp. 4503-4506 ◽  
Author(s):  
Valerie Letscher-Bru ◽  
Odile Villard ◽  
Bernhard Risse ◽  
Michael Zauke ◽  
Jean-Paul Klein ◽  
...  
Keyword(s):  
Immune Response ◽  
Toxoplasma Gondii ◽  
Protective Effect ◽  
Surface Antigen ◽  
Parasite Load ◽  
Interleukin 12 ◽  
Humoral And Cellular Immunity ◽  
The Brain

ABSTRACT We studied the immune response induced in mice by recombinantToxoplasma gondii surface antigen 1 (rSAG1) protein, alone or combined with interleukin-12 (IL-12) as an adjuvant, and the protective effect against toxoplasmosis. Immunization with rSAG1 alone induced a specific humoral type 2 immunity and did not protect the animals from infection. In contrast, immunization with rSAG1 plus IL-12 redirected humoral and cellular immunity toward a type 1 pattern and reduced the brain parasite load by 40%.

scholarly journals Type 1 Immunity Provides Optimal Protection against Both Mucosal and Systemic Trypanosoma cruzi Challenges

2002 ◽  
Vol 70 (12) ◽  
pp. 6715-6725 ◽  
Author(s):  
D. F. Hoft ◽  
C. S. Eickhoff
Keyword(s):  
Trypanosoma Cruzi ◽  
Neutralizing Antibody ◽  
Secretory Iga ◽  
Immune Memory ◽  
Interleukin 12 ◽  
Intracellular Pathogens ◽  
Protective Effects ◽  
Culture Techniques

ABSTRACT Chagas' disease results from infection with Trypanosoma cruzi, a protozoan parasite that establishes systemic intracellular infection after mucosal invasion. We hypothesized that ideal vaccines for mucosally invasive, intracellular pathogens like T. cruzi should induce mucosal type 2 immunity for optimal induction of protective secretory immunoglobulin A (IgA) and systemic type 1 immunity protective against intracellular replication. However, differential mucosal and systemic immune memory could be difficult to induce because of reciprocal inhibitory actions between type 1 and type 2 responses. To test our hypotheses, we investigated the protective effects of type 1 and type 2 biased vaccines against mucosal and systemic T. cruzi challenges. Intranasal vaccinations were given with recombinant interleukin-12 (IL-12)- and IL-4-neutralizing antibody (Ab) for type 1 immune bias, or recombinant IL-4 and gamma interferon-neutralizing Ab for type 2 immune bias. Cytokine RNA and protein studies confirmed that highly polarized memory immune responses were induced by our vaccination protocols. Survival after virulent subcutaneous T. cruzi challenge was used to assess systemic protection. Mucosal protection was assessed by measuring the relative inhibition of parasite replication in mucosal tissues early after oral T. cruzi challenge, using both PCR and quantitative culture techniques. As expected, only type 1 responses protected against systemic challenges (P < 0.01). However, contrary to our original hypothesis, type 1 responses optimally protected against mucosal challenges as well (P < 0.05). Type 1 and type 2 biased vaccines induced similar secretory IgA responses. We conclude that future vaccines for T. cruzi and possibly other mucosally invasive, intracellular pathogens should induce both mucosal and systemic type 1 immunity.

scholarly journals Leishmania-Derived Trimannose Modulates the Inflammatory Response To Significantly Reduce Leishmania major-Induced Lesions

2017 ◽  
Vol 86 (1) ◽  
Author(s):  
Tara L. Grinnage-Pulley ◽  
Daniel E. K. Kabotso ◽  
Chelsea L. Rintelmann ◽  
Rajarshi Roychoudhury ◽  
Robert G. Schaut ◽  
...  
Keyword(s):  
Leishmania Major ◽  
Parasite Load ◽  
Mannose Receptor ◽  
Lesion Size ◽  
Wild Type ◽  
Cutaneous Lesions ◽  
Content Type ◽  
Latex Beads

ABSTRACTLeishmanialipophosphoglycan (LPG) is a key virulence factor, initiating inflammation resulting in cutaneous lesions. LPG is capped by various oligosaccharides. How these glycans are recognized and how they alter the course ofLeishmaniainfection are poorly understood. Previous studies synthesized α-1,2-trimannose cap sugars on latex beads and demonstrated that C57BL/6 mice coinoculated withLeishmania majorand trimannose-coated beads produced significantly higher levels of interleukin-12p40 (IL-12p40) and other proinflammatory, type 1 cytokines than mice inoculated withL. majoralone within the first 48 h of infection. However, asL. majorinfection typically progress over weeks to months, the role of trimannose in altering disease progression over the course of infection was unknown. Wild-type mice were inoculated with either trimannose-coated or carrier (uncoated) beads, infected withL. majoralone, coinoculated with carrier beads andL. major, or coinoculated with trimannose-coated beads andL. major. Trimannose treatment ofL. major-infected mice decreased the parasite load and significantly decreased the lesion size at 14 days postinfection (p.i.) compared to results for nontreated, infected mice. Infected, trimannose-treated mice had decreased IL-12p40 and IL-10 secretion and increased interferon gamma secretion at 14 days p.i. Mannose receptor knockout (MR−/−) mice lack the ability to detect trimannose. When MR−/−mice were infected withL. majorand treated with trimannose beads, they did not have decreased lesion size.Leishmania-derived trimannose represents a novel immunomodulator that provides early type 1-skewed cytokine production to control the parasite load and alter the course of cutaneous leishmaniasis.

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 Modulation of Cytokine Profiles by the Mycoplasma SuperantigenMycoplasma arthritidis Mitogen Parallels Susceptibility to Arthritis Induced by M. arthritidis

2000 ◽  
Vol 68 (3) ◽  
pp. 1142-1149 ◽  
Author(s):  
Hong-Hua Mu ◽  
Allen D. Sawitzke ◽  
Barry C. Cole
Keyword(s):  
Interleukin 12 ◽  
Mouse Strains ◽  
Mild Disease ◽  
Cytokine Profiles ◽  
C Cell ◽  
Severe Arthritis

ABSTRACT Mycoplasma arthritidis mitogen (MAM) is a potent superantigen secreted by M. arthritidis, an agent of murine arthritis. Here we compare the abilities of MAM to induce a panel of cytokines in vitro and in vivo in BALB/c and C3H/HeJ mouse strains that differ in susceptibility to mycoplasmal arthritis. Splenocytes from both mouse strains produced high levels of all cytokines by 24 h following in vitro exposure to MAM. No differences in cytokine profiles were seen irrespective of the MAM dose. However, there were striking differences in cytokine profiles present in supernatants of splenocytes that had been collected from mice after intravenous (i.v.) injection of MAM and subsequently rechallenged with MAM in vitro. Splenocytes collected 24 and 72 h after i.v. injection of MAM and challenged in vitro with MAM showed the most marked divergence in the secreted cytokines. Type 1 cytokines were markedly elevated in C3H/HeJ cell supernatants, whereas they were depressed or remained low in BALB/c cell supernatants. In contrast, the levels of type 2 cytokines were all greatly increased in BALB/c cell cultures but were decreased or remained low in C3H/HeJ supernatants. Interleukin-12 mRNA and protein was also markedly elevated in C3H/HeJ mice, as were the levels of immunoglobulin G2a. The data indicate a major skewing in cytokine profiles to a type 1 inflammatory response in C3H/HeJ mice but to a protective type 2 response in BALB/c mice. These cytokine changes appear to be associated with the severe arthritis in C3H/HeJ mice following injection of M. arthritidis in comparison to the mild disease seen in injected BALB/c mice.

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