scholarly journals gp63 in Stable Cationic Liposomes Confers Sustained Vaccine Immunity to Susceptible BALB/c Mice Infected with Leishmania donovani

2008 ◽  
Vol 76 (3) ◽  
pp. 1003-1015 ◽  
Author(s):  
Swati Bhowmick ◽  
Rajesh Ravindran ◽  
Nahid Ali
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Protective Efficacy ◽  
Cationic Liposomes ◽  
Interleukin 4 ◽  
Th2 Response ◽  
Parasitic Burden ◽  
Ifn Γ ◽  
Dose Dependent

ABSTRACT Visceral leishmaniasis is deadly if not treated, and development of a vaccine with long-term immunity remains a challenge. In this study, we showed that cationic distearoyl phosphatidylcholine (DSPC) liposomes, when used as vaccine adjuvant with the immunodominant 63-kDa glycoprotein (gp63) of Leishmania donovani promastigotes, induced significant protection against progressive visceral leishmaniasis in susceptible BALB/c mice. gp63 used without adjuvant elicited partial protection but in association with liposomes exhibited marked resistance in both the livers and spleens of the mice challenged 10 days after the last vaccination. The protective efficacy of liposomal gp63 vaccination was dose dependent, with 2.5 μg of protein showing optimal protection. The immunity conferred by this vaccine formulation was durable, as mice challenged 12 weeks after immunization were still protected, and the infection was controlled for at least 3 months postchallenge. Production of gamma interferon (IFN-γ) and interleukin-4 (IL-4) by splenic T cells, and of serum immunoglobulin G1 (IgG1) and IgG2a following immunization, suggested that a mixed Th1/Th2 response had been induced following immunization. However, control of disease progression and parasitic burden in mice vaccinated with gp63 in cationic DSPC liposomes was associated with enhancement of antigen-specific IFN-γ and downregulation of IL-4, demonstrating a Th1 bias. Long-term immunity elicited by this vaccine corresponded to, in addition to the presence of antigen-specific Th1, CD8+ T-cell responses. Our results demonstrated that stable cationic liposomes containing gp63 acted as a potent adjuvant for protein antigen to induce long-term protection against L. donovani that represents an alternative to DNA vaccination.

scholarly journals Behavior of  Visceral Leishmania donovani in an Experimentally Induced T Helper Cell 2 (Th2)-Associated Response Model

1997 ◽  
Vol 185 (5) ◽  
pp. 867-874 ◽  
Author(s):  
Henry W. Murray ◽  
June Hariprashad ◽  
Robert L. Coffman
Keyword(s):  
Leishmania Donovani ◽  
Systemic Infection ◽  
T Helper Cell ◽  
Interleukin 4 ◽  
Helper Cell ◽  
T Helper ◽  
Th2 Response ◽  
Ifn Γ ◽  
Type Response ◽  
Visceral Infection

Although implicated in the clinical expression of human visceral leishmaniasis, a disease-exacerbating T helper cell 2 (Th2)-associated immune response involving interleukin-4 (IL-4) and/ or IL-10 is not readily detectable in experimental visceral infection. To overcome this obstacle to analyzing visceral Leishmania donovani in this relevant immunopathogenetic environment, we sought a model in which a Th2 response induces noncuring infection. Four initial approaches were tested primarily in BALB/c mice which control intracellular L. donovani via an IL-12– and interferon-γ (IFN-γ)–dependent Th1 mechanism: (a) modifying the cytokine milieu when the parasite is first encountered (treatment with exogenous IL-4 or anti–IL-12), (b) providing sustained endogenous exposure to a Th2 cytokine (infection of IL-4 transgenic mice), (c) increasing the parasite challenge inoculum, and (d) injecting heat-killed L. major promastigotes (HKLMP) to induce a cross-reactive Th2 response to live L. donovani. Only the last approach generated a functional Th2-type response that induced disease exacerbation accompanied by inhibition of tissue granuloma assembly. In HKLMP-primed BALB/c mice, prophylaxis with anti–IL-4, anti–IL-10, or exogenous IL-12 (but not IFN-γ) readily restored resistance. In primed mice with established visceral infection, treatment with either IL-12 or IFN-γ also successfully induced antileishmanial activity. The results in this model (a) suggest that rather than acting alone, IL-4 and IL-10 may act in concert to prevent acquisition of resistance to L. donovani, (b) reemphasize the capacity of IL-12 to reverse early Th2-related effects, and (c) demonstrate that Th1 cytokines (IL-12, IFN-γ) have therapeutic action in an established systemic infection despite the presence of a disease-exacerbating Th2-type response.

scholarly journals MicroRNA 155 Contributes to Host Immunity against Leishmania donovani but Is Not Essential for Resolution of Infection

2019 ◽  
Vol 87 (8) ◽  
Author(s):  
Sanjay Varikuti ◽  
Gayathri Natarajan ◽  
Greta Volpedo ◽  
Bhawana Singh ◽  
Omar Hamza ◽  
...  
Keyword(s):  
Leishmania Donovani ◽  
Interleukin 4 ◽  
Cytokine Signaling ◽  
T Helper 1 ◽  
Content Type ◽  
Inflammatory Monocytes ◽  
Organ Specific ◽  
Src Homology ◽  
Ifn Γ ◽  
Src Homology 2 Domain

ABSTRACT CD4+ T helper 1 (Th1) cells producing interferon gamma (IFN-γ) are critical for the resolution of visceral leishmaniasis (VL). MicroRNA 155 (miR155) promotes CD4+ Th1 responses and IFN-γ production by targeting suppressor of cytokine signaling-1 (SOCS1) and Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP-1) and therefore could play a role in the resolution of VL. To determine the role of miR155 in VL, we monitored the course of Leishmania donovani infection in miR155 knockout (miR155KO) and wild-type (WT) C57BL/6 mice. miR155KO mice displayed significantly higher liver and spleen parasite loads than WT controls and showed impaired hepatic granuloma formation. However, parasite growth eventually declined in miR155KO mice, suggesting the induction of a compensatory miR155-independent antileishmanial pathway. Leishmania antigen-stimulated splenocytes from miR155KO mice produced significantly lower levels of Th1-associated IFN-γ than controls. Interestingly, at later time points, levels of Th2-associated interleukin-4 (IL-4) and IL-10 were also lower in miR155KO splenocyte supernatants than in WT mice. On the other hand, miR155KO mice displayed significantly higher levels of IFN-γ, iNOS, and TNF-α gene transcripts in their livers than WT mice, indicating that distinct organ-specific antiparasitic mechanisms were involved in control of L. donovani infection in miR155KO mice. Throughout the course of infection, organs of miR155KO mice showed significantly more PDL1-expressing Ly6Chi inflammatory monocytes than WT mice. Conversely, blockade of Ly6Chi inflammatory monocyte recruitment in miR155KO mice significantly reduced parasitic loads, indicating that these cells contributed to disease susceptibility. In conclusion, we found that miR155 contributes to the control of L. donovani but is not essential for infection resolution.

scholarly journals Fusion Cytokines IL-7-Linker-IL-15 Promote Mycobacterium Tuberculosis Subunit Vaccine to Induce Central Memory like T Cell-Mediated Immunity

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 715
Author(s):  
Chunxiang Bai ◽  
Lijun Zhou ◽  
Junxia Tang ◽  
Juanjuan He ◽  
Jiangyuan Han ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Immune Responses ◽  
Protective Efficacy ◽  
Central Memory ◽  
Control Group ◽  
Cell Mediated Immunity ◽  
Protein Subunit ◽  
Subunit Vaccines ◽  
Ifn Γ

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tuberculosis), is among the most serious infectious diseases worldwide. Adjuvanted protein subunit vaccines have been demonstrated as a kind of promising novel vaccine. This study proposed to investigate whether cytokines interliukine-7 (IL-7) and interliukine-15 (IL-15) help TB subunit vaccines induce long-term cell-mediated immune responses, which are required for vaccination against TB. In this study, mice were immunized with the M. tuberculosis protein subunit vaccines combined with adnovirus-mediated cytokines IL-7, IL-15, IL-7-IL-15, and IL-7-Linker-IL-15 at 0, 2, and 4 weeks, respectively. Twenty weeks after the last immunization, the long-term immune responses, especially the central memory-like T cells (TCM like cell)-mediated immune responses, were determined with the methods of cultured IFN-γ-ELISPOT, expanded secondary immune responses, cell proliferation, and protective efficacy against Mycobacterium bovis Bacilli Calmette-Guerin (BCG) challenge, etc. The results showed that the group of vaccine + rAd-IL-7-Linker-IL-15 induced a stronger long-term antigen-specific TCM like cells-mediated immune responses and had higher protective efficacy against BCG challenge than the vaccine + rAd-vector control group, the vaccine + rAd-IL-7 and the vaccine + rAd-IL-15 groups. This study indicated that rAd-IL-7-Linker-IL-15 improved the TB subunit vaccine’s efficacy by augmenting TCM like cells and provided long-term protective efficacy against Mycobacteria.

Kinetic Th1/Th2 responses of transgenic mice with bacterial meningitis induced by Haemophilus influenzae

2006 ◽  
Vol 111 (4) ◽  
pp. 253-263 ◽  
Author(s):  
Shyi-Jou Chen ◽  
Mong-Ling Chu ◽  
Chia-Jen Wang ◽  
Ching-Len Liao ◽  
Shie-Liang Hsieh ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Haemophilus Influenzae ◽  
Clinical Symptoms ◽  
Specific Antigen ◽  
Clinical Severity ◽  
Interleukin 4 ◽  
Th2 Cells ◽  
Th1 Cells ◽  
Th2 Response ◽  
Ifn Γ

To investigate the kinetic Th1/Th2 immunopathogenic mechanisms of Haemophilus influenzae meningitis, we established a murine experimental model of meningitis and elucidated the Th1/Th2 immune responses in T1/T2 doubly transgenic mice based on a BALB/c background under the control of the IFN-γ (interferon-γ)/IL-4 (interleukin-4) promoters respectively. NTHi (non-typeable Haemophilus influenzae) meningitis was induced in these mice by inoculation with either a colonized (CNTHi) or invasive (INTHi) strain of NTHi. Mice inoculated with CNTHi displayed a less severe degree of disease in terms of clinical symptoms, mortality rate and brain histopathology. Conversely, INTHi-inoculated mice had more severe clinical symptoms. CNTHi-inoculated mice had a more significant Th1 response in terms of a higher percentage and longer maintenance of Th1 cells, and more production of IFN-γ from strain-specific antigen-stimulated splenocytes than INTHi-inoculated mice. In contrast, INTHi-inoculated mice had a more significant Th2 response. This was due to a significant increase in IL-4-producing CD4+ T-cells (Th2 cells) and more production of IL-4 from strain-specific antigen-stimulated splenocytes accompanied by a rapid decline of Th1 cells in INTHi-inoculated mice. In conclusion, the preferential Th1/Th2 trend in this murine model of NTHi meningitis is correlated with clinical severity as well as isolated characteristics of the pathogens themselves.

scholarly journals Intracellular Antimicrobial Activity in the Absence of Interferon-γ: Effect of Interleukin-12 in Experimental Visceral Leishmaniasis in Interferon-γ Gene-disrupted Mice

1997 ◽  
Vol 185 (7) ◽  
pp. 1231-1240 ◽  
Author(s):  
Alice P. Taylor ◽  
Henry W. Murray
Keyword(s):  
Antimicrobial Activity ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Gene Knockout ◽  
Interferon Γ ◽  
Interleukin 12 ◽  
Tnf Α ◽  
Ifn Γ ◽  
Independent Effects ◽  
Factor Α

Despite permitting uncontrolled intracellular visceral infection for 8 wk, interferon-γ (IFN-γ) gene knockout (GKO) mice infected with Leishmania donovani proceeded to reduce liver parasite burdens by 50% by week 12. This late-developing IFN-γ–independent antileishmanial mechanism appeared to be dependent largely on endogenous tumor necrosis factor-α (TNF-α): L. donovani infection induced TNF-α mRNA expression in parasitized GKO livers and neutralization of TNF-α reversed control at week 12. 7 d of treatment of infected GKO mice with interleukin-12 (IL-12) readily induced leishmanicidal activity and also partially restored the near-absent tissue granulomatous response, observations that for the first time expand the antimicrobial repertoire of IL-12 to include IFN-γ–independent effects. The action of IL-12 against L. donovani was TNF-α dependent and required the activity of inducible nitric oxide synthase. These results point to the presence of an IFN-γ–independent antimicrobial mechanism, mediated by TNF-α, which remains quiescent until activated late in the course of experimental visceral leishmaniasis. However, as judged by the effect of exogenous IL-12 this quiescent mechanism can readily be induced to rapidly yield enhanced intracellular antimicrobial activity.

scholarly journals Absence of Interleukin-4 Determines Less Severe Pulmonary Paracoccidioidomycosis Associated with Impaired Th2 Response

2004 ◽  
Vol 72 (4) ◽  
pp. 2369-2378 ◽  
Author(s):  
Adriana Pina ◽  
Rita C. Valente-Ferreira ◽  
Eugênia E. W. Molinari-Madlum ◽  
Celidéia A. C. Vaz ◽  
Alexandre C. Keller ◽  
...  
Keyword(s):  
Paracoccidioides Brasiliensis ◽  
Fungal Growth ◽  
Protective Role ◽  
Yeast Cells ◽  
Interleukin 4 ◽  
Delayed Type Hypersensitivity ◽  
Th2 Response ◽  
Leukocyte Influx ◽  
Ifn Γ

ABSTRACT Host resistance to paracoccidiodomycosis, the main deep mycosis in Latin America, is mainly due to cellular immunity and gamma interferon (IFN-γ) production. To assess the role of interleukin-4 (IL-4), a Th2-inducing cytokine, pulmonary paracoccidioidomycosis was studied in IL-4-deficient (IL-4−/−) and wild-type (WT) C57BL/6 mice at the innate and acquired phases of immune response. Forty-eight hours after infection, equivalent numbers of viable Paracoccidioides brasiliensis yeast cells were recovered from the lungs of IL-4−/− and WT mice intratracheally infected with one million fungal cells. Alveolar macrophages from infected IL-4−/− mice controlled in vitro fungal growth more efficiently than macrophages from WT mice and secreted higher levels of nitric oxide. Compared with WT mice, IL-4−/− animals presented increased levels of pulmonary IFN-γ and augmented polymorphonuclear leukocyte influx to the lungs. Decreased pulmonary fungal loads were characterized in deficient mice at week 2 postinfection, concomitant with diminished presence of IL-10. At week 8, lower numbers of yeasts were recovered from lungs and liver of IL-4−/− mice associated with increased production of IFN-γ but impaired synthesis of IL-5 and IL-10. However, a clear shift to a Th1 pattern was not characterized, since IL-4−/− mice did not alter delayed-type hypersensitivity anergy or IL-2 levels. In addition, IL-4 deficiency resulted in significantly reduced levels of pulmonary IL-12, granulocyte-macrophage colony-stimulating factor, IL-3, monocyte chemotactic protein 1, and specific antibody isotypes. In IL-4−/− mice, well-organized granulomas restraining fungal cells replaced the more extensive lesions containing high numbers of fungi and inflammatory leukocytes developed by IL-4-sufficient mice. These results clearly showed that genetically determined deficiency of IL-4 can exert a protective role in pulmonary paracoccidioidomycosis.

scholarly journals Immunoenhancement Combined with Amphotericin B as Treatment for Experimental Visceral Leishmaniasis

2003 ◽  
Vol 47 (8) ◽  
pp. 2513-2517 ◽  
Author(s):  
Henry W. Murray ◽  
Elaine B. Brooks ◽  
Jennifer L. DeVecchio ◽  
Frederick P. Heinzel
Keyword(s):  
Visceral Leishmaniasis ◽  
Total Dose ◽  
Amphotericin B ◽  
Leishmania Donovani ◽  
Low Dose ◽  
Interleukin 12 ◽  
Th1 Cell ◽  
Killing Effect ◽  
Ifn Γ ◽  
Visceral Infection

ABSTRACT To determine if stimulation of Th1-cell-associated immune responses, mediated by interleukin 12 (IL-12) and gamma interferon (IFN-γ), enhance the antileishmanial effect of amphotericin B (AMB), Leishmania donovani-infected BALB/c mice were first treated with (i) exogenous IL-12 to induce IFN-γ, (ii) agonist anti-CD40 monoclonal antibody (MAb) to maintain IL-12 and induce IFN-γ, or (iii) anti-IL-10 receptor (IL-10R) MAb to blockade suppression of IL-12 and IFN-γ. In animals with established visceral infection, low-dose AMB alone (two injections of 1 mg/kg of body weight; total dose, 2 mg/kg) killed 15 to 29% of liver parasites; by themselves, the immunointerventions induced 16 to 33% killing. When the interventions were combined, the leishmanicidal activities increased 3.4-fold (anti-CD40), 6.3-fold (anti-IL-10R), and 9-fold (IL-12) compared with the activities of AMB plus the control preparations; and overall killing (76 to 84%) approximated the 84 to 92% killing effect of 7.5-fold more AMB alone (three injections of 5 mg/kg; total dose, 15 mg/kg). These results suggest that strengthening the host Th1-cell response may be a strategy for the development of AMB-sparing regimens in visceral leishmaniasis.

scholarly journals Preexisting Inflammation Due to Mycobacterium bovis BCG Infection Differentially Modulates T-Cell Priming against a Replicating or Nonreplicating Immunogen

2002 ◽  
Vol 70 (4) ◽  
pp. 1957-1964 ◽  
Author(s):  
Renu Dudani ◽  
Yvan Chapdelaine ◽  
Henk van Faassen ◽  
Dean K. Smith ◽  
Hao Shen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Inflammatory Responses ◽  
Protective Efficacy ◽  
T Cell Response ◽  
Boost Vaccine ◽  
Ifn Γ ◽  
T Cell Priming

ABSTRACT Induction of T-cell memory by vaccination ensures long-term protection against pathogens. We determined whether on-going inflammatory responses during vaccination influenced T-cell priming. A preexposure of mice to Mycobacterium bovis BCG impaired their subsequent ability to prime T cells against Listeria monocytogenes. This was characterized by a decrease in L. monocytogenes-specific gamma interferon (IFN-γ)-secreting CD4+ and CD8+ T cells. The intensity of T-cell priming towards L. monocytogenes depended on the extent of L. monocytogenes expansion, and a cessation of this expansion caused by M. bovis BCG-induced inflammation resulted in impairment in T-cell priming. A challenge of M. bovis BCG-infected mice with a higher L. monocytogenes dose increased L. monocytogenes survival and restored T-cell priming towards L. monocytogenes. Impairment in T-cell priming towards L. monocytogenes due to M. bovis BCG-induced inflammation resulted in a compromised protective efficacy in the long term after mice were rechallenged with L. monocytogenes. Preexisting inflammation selectively impaired T-cell priming for replicating immunogens as CD8+ T-cell response to ovalbumin administered as an inert antigen (ovalbumin-archaeosomes) was enhanced by M. bovis BCG preimmunization, whereas priming towards ovalbumin administered as a live immunogen (L. monocytogenes-ovalbumin) was impaired. Thus, depending on the nature of the immunogen, the presence of prior inflammatory responses may either impede or boost vaccine efficacy.

scholarly journals Antibody and cytokine levels in visceral leishmaniasis patients with varied parasitemia before, during, and after treatment in patients admitted to Arba Minch General Hospital, southern Ethiopia

2021 ◽  
Vol 15 (8) ◽  
pp. e0009632
Author(s):  
Dagimawie Tadesse ◽  
Alemseged Abdissa ◽  
Mekidim Mekonnen ◽  
Tariku Belay ◽  
Asrat Hailu
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Serum Levels ◽  
High Serum ◽  
Eastern Africa ◽  
Southern Ethiopia ◽  
Ifn Γ ◽  
A Prospective Study ◽  
Antibody Levels ◽  
Tgf Β1

Background Visceral leishmaniasis is a disease caused by disseminated Leishmania donovani infection which affects almost half a million people annually. Most of the patients are reported from the Indian sub-continent, Eastern Africa and Brazil. In this study, we aimed to determine the levels of antibodies and cytokines in visceral leishmaniasis patients and to examine associations of parasitemia with the clinical states of patients. A prospective study was carried out, enrolling a total of 48 active VL patients who were evaluated before, during different time points and, three months after treatment. Serum cytokine concentrations, antibody levels, parasitemia, laboratory (hematologic and biochemical) measurements, and clinical parameters were assessed. Results Counts of WBC and platelets, and measurements of hemoglobin (Hb) increased during treatment (P ≤ 0.05). Elevated levels of circulating IL-10, IFN-γ, and TGF-β1 were measured before treatment. The observed increase in serum IL-10 remarkably declined within 7 days after the start of treatment. Anti-leishmanial antibody index (AI) was high in all VL patients irrespective of spleen aspirate parasite grade before treatment and at different times during treatment. However, a significant (P ≤ 0.05) decrease of AI was observed 120 days post-treatment. IL-2 serum levels were below the detection limit at all sampling points. Conclusions The present results suggest that IL-10, IFN-γ, and TGF-β1 can be used as markers of active visceral leishmaniasis. In addition, measuring circulating cytokines concentrations, particularly IL-10, in combination with other clinical evaluations, could be used as criteria for the cure. The observation that a high serum concentration of IFN-gamma at baseline was associated with low parasitemia deserves further investigations.

scholarly journals Astaxanthin from Shrimp Cephalothorax Stimulates the Immune Response by Enhancing IFN-γ, IL-10, and IL-2 Secretion in Splenocytes of Helicobacter Pylori-Infected Mice

Marine Drugs ◽  
2019 ◽  
Vol 17 (7) ◽  
pp. 382 ◽  
Author(s):  
Davinelli ◽  
Melvang ◽  
Andersen ◽  
Scapagnini ◽  
Nielsen
Keyword(s):  
Helicobacter Pylori ◽  
Interleukin 2 ◽  
Gastrointestinal Diseases ◽  
Th2 Response ◽  
Frequent Consumption ◽  
Ifn Γ ◽  
H Pylori ◽  
To Receive ◽  
Dose Dependent Increase ◽  
Dose Dependent

Infection with Helicobacter pylori is a critical cause of gastrointestinal diseases. A crucial host response associated with H. pylori infection includes gastric inflammation, which is characterized by a sustained recruitment of T-helper (Th) cells to the site of infection and distinct patterns of cytokine production. Adequate nutritional status, especially frequent consumption of dietary antioxidants, appears to protect against infection with H. pylori. The aim of the present study was to investigate whether astaxanthin (AXT) from shrimp cephalothorax may modulate cytokine release of splenocytes in H. pylori-infected mice (n = 60). Six- to eight-week-old female mice were divided into three groups (n = 20 per group) to receive a daily oral dose of 10 or 40 mg of AXT for six weeks. After six weeks, a trend toward interferon gamma (IFN-γ) upregulation was found (40 mg; p < 0.05) and a significant dose-dependent increase of interleukin 2 (IL-2) and IL-10 (both p < 0.05) was observed. These results suggest that AXT induces higher levels of IL-2 and a shift to a balanced Th1/Th2 response by increasing IFN-γ and augmenting IL-10. We concluded that AXT may influence the pattern of cytokines during H. pylori infection.

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