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 Modulation of T-Cell Costimulation as Immunotherapy or Immunochemotherapy in Experimental Visceral Leishmaniasis

2003 ◽  
Vol 71 (11) ◽  
pp. 6453-6462 ◽  
Author(s):  
Henry W. Murray ◽  
Cristina M. Lu ◽  
Elaine B. Brooks ◽  
Richard E. Fichtl ◽  
Jennifer L. DeVecchio ◽  
...  
Keyword(s):  
T Cell ◽  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Cytotoxic T Lymphocyte ◽  
Acquired Resistance ◽  
Cd40 Ligand ◽  
Response To Treatment ◽  
Interleukin 12 ◽  
Ifn Γ ◽  
Visceral Infection

ABSTRACT CD40 ligand (CD40L)-deficient C57BL/6 mice failed to control intracellular Leishmania donovani visceral infection, indicating that acquired resistance involves CD40-CD40L signaling and costimulation. Conversely, in wild-type C57BL/6 and BALB/c mice with established visceral infection, injection of agonist anti-CD40 monoclonal antibody (MAb) induced killing of ∼60% of parasites within liver macrophages, stimulated gamma interferon (IFN-γ) secretion, and enhanced mononuclear cell recruitment and tissue granuloma formation. Comparable parasite killing was also induced by MAb blockade (inhibition) of cytotoxic T lymphocyte antigen-4 (CTLA-4) which downregulates separate CD28-B7 T-cell costimulation. Optimal killing triggered by both anti-CD40 and anti-CTLA-4 required endogenous IFN-γ and involved interleukin 12. CD40L−/− mice also failed to respond to antileishmanial chemotherapy (antimony), while in normal animals, anti-CD40 and anti-CTLA-4 synergistically enhanced antimony-associated killing. CD40L-CD40 signaling regulates outcome and response to treatment of experimental visceral leishmaniasis, and MAb targeting of T-cell costimulatory pathways (CD40L-CD40 and CD28-B7) yields macrophage activation and immunotherapeutic and immunochemotherapeutic activity.

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 Immunoadjuvant Chemotherapy of Visceral Leishmaniasis in Hamsters Using Amphotericin B-Encapsulated Nanoemulsion Template-Based Chitosan Nanocapsules

2013 ◽  
Vol 57 (4) ◽  
pp. 1714-1722 ◽  
Author(s):  
Shalini Asthana ◽  
Anil K. Jaiswal ◽  
Pramod K. Gupta ◽  
Vivek K. Pawar ◽  
Anuradha Dube ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Leishmania Donovani ◽  
Transforming Growth Factor ◽  
Treatment Options ◽  
Interleukin 12 ◽  
Necrosis Factor Alpha ◽  
Content Type

ABSTRACTThe accessible treatment options for life-threatening neglected visceral leishmaniasis (VL) disease have problems with efficacy, stability, adverse effects, and cost, making treatment a complex issue. Here we formulated nanometric amphotericin B (AmB)-encapsulated chitosan nanocapsules (CNC-AmB) using a polymer deposition technique mediated by nanoemulsion template fabrication. CNC-AmB exhibited good steric stabilityin vitro, where the chitosan content was found to be efficient at preventing destabilization in the presence of protein and Ca2+. A toxicity study on the model cell line J774A and erythrocytes revealed that CNC-AmB was less toxic than commercialized AmB formulations such as Fungizone and AmBisome. The results ofin vitro(macrophage-amastigote system; 50% inhibitory concentration [IC50], 0.19 ± 0.04 μg AmB/ml) andin vivo(Leishmania donovani-infected hamsters; 86.1% ± 2.08% parasite inhibition) experiments in conjunction with effective internalization by macrophages illustrated the efficacy of CNC-AmB at augmenting antileishmanial properties. Quantitative mRNA analysis by real-time PCR (RT-PCR) showed that the improved effect was synergized with the upregulation of tumor necrosis factor alpha (TNF-α), interleukin-12 (IL-12), and inducible nitric oxide synthase and with the downregulation of transforming growth factor β (TGF-β), IL-10, and IL-4. These research findings suggest that a cost-effective CNC-AmB immunoadjuvant chemotherapeutic delivery system could be a viable alternative to the current high-cost commercial lipid-based formulations.

scholarly journals Efficacy of the Triazole SCH 56592 againstLeishmania amazonensis and Leishmania donovani in Experimental Murine Cutaneous and Visceral Leishmaniases

1999 ◽  
Vol 43 (12) ◽  
pp. 2910-2914 ◽  
Author(s):  
Hail M. Al-Abdely ◽  
John R. Graybill ◽  
David Loebenberg ◽  
Peter C. Melby
Keyword(s):  
Visceral Leishmaniasis ◽  
Amphotericin B ◽  
Oral Therapy ◽  
Leishmania Donovani ◽  
Parasite Burden ◽  
Current Therapy ◽  
Cutaneous Infection ◽  
Unit Reduction ◽  
Visceral Infection ◽  
Draining Lymph Nodes

ABSTRACT Current therapy for leishmaniasis is unsatisfactory. Efficacious and safe oral therapy would be ideal. We examined the efficacy of SCH 56592, an investigational triazole antifungal agent, against cutaneous infection with Leishmania amazonensis and visceral infection with Leishmania donovani in BALB/c mice. Mice were infected in the ear pinna and tail with L. amazonensispromastigotes and were treated with oral SCH 56592 or intraperitoneal amphotericin B for 21 days. At doses of 60 and 30 mg/kg/day, SCH 56592 was highly efficacious in treating cutaneous disease, and at a dose of 60 mg/kg/day, it was superior to amphotericin B at a dose of 1 mg/kg/day. The means of tail lesion sizes were 0.32 ± 0.12, 0.11 ± 0.06, 0.17 ± 0.07, and 0.19 ± 0.08 mm for controls, SCH 56592 at 60 and 30 mg/kg/day, and amphotericin B recipients, respectively (P = 0.0003, 0.005, and 0.01, respectively). Parasite burden in draining lymph nodes confirmed these efficacy findings. In visceral leishmaniasis due to L. donovani infection, mice treated with SCH 56592 showed a 0.5- to 1-log-unit reduction in parasite burdens in the liver and the spleen compared to untreated mice. Amphotericin B at 1 mg/kg/day was superior to SCH 56592 in the treatment of visceral infection, with a 2-log-unit reduction in parasite burdens in both the liver and spleen. These studies indicate very good activity of SCH 56592 against cutaneous leishmaniasis due to L. amazonensis infection and, to a lesser degree, against visceral leishmaniasis due to L. donovani infection in susceptible BALB/c mice.

scholarly journals Antagonizing Deactivating Cytokines To Enhance Host Defense and Chemotherapy in Experimental Visceral Leishmaniasis

2005 ◽  
Vol 73 (7) ◽  
pp. 3903-3911 ◽  
Author(s):  
Henry W. Murray ◽  
Kathleen C. Flanders ◽  
Debra D. Donaldson ◽  
Joseph P. Sypek ◽  
Philip J. Gotwals ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Leishmania Donovani ◽  
Transforming Growth Factor ◽  
Therapeutic Potential ◽  
Transforming Growth Factor Β ◽  
Interleukin 10 ◽  
Th1 Cell ◽  
Pentavalent Antimony ◽  
Ifn Γ ◽  
Liver Infection

ABSTRACT In experimental visceral leishmaniasis, inhibition of interleukin 10 (IL-10) signaling enhances Th1-cell-associated responses, promoting gamma interferon (IFN-γ) secretion, granuloma assembly, macrophage activation with substantial liver parasite killing, and synergy with pentavalent antimony (Sb) chemotherapy. To determine if inhibiting other suppressive cytokines has similar therapeutic potential, Leishmania donovani-infected BALB/c mice were injected with anti-IL-4 monoclonal antibody or receptor fusion antagonists of IL-13 or transforming growth factor β (TGF-β). Targeting IL-13 or TGF-β enabled inhibition of L. donovani replication but little parasite killing; anti-IL-4 had no effect. None of the three antagonists promoted IFN-γ production, granuloma maturation, or Sb efficacy. Excess IL-13 and TGF-β exacerbated liver infection; however, effects were transient. Among IL-10, IL-4, IL-13, and TGF-β, cytokines capable of disabling Th1-cell mechanisms (including those which support chemotherapy), IL-10 appears to be the appropriate target for therapeutic inhibition in visceral L. donovani infection.

scholarly journals Expression of the Nitric Oxide Synthase 2 Gene Is Not Essential for Early Control of Mycobacterium tuberculosis in the Murine Lung

2000 ◽  
Vol 68 (12) ◽  
pp. 6879-6882 ◽  
Author(s):  
Andrea M. Cooper ◽  
John E. Pearl ◽  
Jason V. Brooks ◽  
Stefan Ehlers ◽  
Ian M. Orme
Keyword(s):  
Nitric Oxide ◽  
Mycobacterium Tuberculosis ◽  
Nitric Oxide Synthase ◽  
Low Dose ◽  
Interleukin 12 ◽  
Infection Model ◽  
Rapid Progression ◽  
Ifn Γ ◽  
Nitric Oxide Synthase 2 ◽  
Oxide Synthase

ABSTRACT The interleukin-12 and gamma interferon (IFN-γ) pathway of macrophage activation plays a pivotal role in controlling tuberculosis. In the murine model, the generation of supplementary nitric oxide by the induction of the nitric oxide synthase 2 (NOS2) gene product is considered the principal antimicrobial mechanism of IFN-γ-activated macrophages. Using a low-dose aerosol-mediated infection model in the mouse, we have investigated the role of nitric oxide in controllingMycobacterium tuberculosis in the lung. In contrast to the consequences of a systemic infection, a low dose of bacteria introduced directly into the lungs of mice lacking the NOS2 gene is controlled almost as well as in intact animals. This is in contrast to the rapid progression of disease in mice lacking IFN-γ or a key member of the IFN signaling pathway, interferon regulatory factor 1. Thus while IFN-γ is pivotal in early control of bacterial growth in the lung, this control does not completely depend upon the expression of the NOS2 gene. The absence of inducible nitric oxide in the lung does, however, result in increased polymorphonuclear cell involvement and eventual necrosis in the pulmonary granulomas of the infected mice lacking the NOS2 gene.

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 Use of an Attenuated Leishmanial Parasite as an Immunoprophylactic and Immunotherapeutic Agent against Murine Visceral Leishmaniasis

2000 ◽  
Vol 7 (2) ◽  
pp. 233-240 ◽  
Author(s):  
Srirupa Mukhopadhyay ◽  
Sandip Bhattacharyya ◽  
Ramdhan Majhi ◽  
Tripti De ◽  
Khudiram Naskar ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Elevated Level ◽  
Leishmania Donovani ◽  
Peritoneal Macrophages ◽  
Delayed Type Hypersensitivity ◽  
Self Healing ◽  
Immunotherapeutic Agent ◽  
Virulent Challenge ◽  
Visceral Infection

ABSTRACT The ability of the leishmanial parasite UR6 to act as an immunoprophylactic and immunotherapeutic agent against Leishmania donovani infection in BALB/c mice was investigated. Unlike the virulent L. donovani AG83 (MOHOM/IN/1983/AG83), UR6 given through intracardiac route failed to induce visceral infection, but when it was injected subcutaneously, UR6 induced a short-lived and localized self-healing skin lesion. Priming of peritoneal macrophages with UR6 in vitro induced superoxide (O2 −) generation, whereas similar experiments with virulent AG83 inhibited O2 − generation. It was observed that priming of mice with either live or sonicated UR6 in the absence of any adjuvant provided strong protection against subsequent virulent challenge. Further, UR6-primed infected mice not only displayed a strong antileishmanial delayed-type hypersensitivity (DTH) response but also showed an elevated level of the serum antileishmanial immunoglobulin G2a (IgG2a) isotype, whereas infected mice failed to mount any antileishmanial DTH response and showed an elevated level of IgG1. This indicates that UR6 priming and subsequent L. donovani infection allowed the expansion of Th1 cells. Our studies indicate that UR6 has potential to be used as an immunoprophylactic and immunotherapeutic agent against experimental visceral leishmaniasis.

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.

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