33 research outputs found
Therapeutic and immunomodulatory activities of short-course treatment of murine visceral leishmaniasis with KALSOMEā¢10, a new liposomal amphotericin B
Visceral leishmaniasis (VL), a potentially fatal disease, is most prevalent in the Indian subcontinent,
East Africa and South America. Since the conventional antileishmanial drugs have many limitations we evaluated a
new ergosterol rich liposomal amphotericin B formulation, KALSOMEā¢10 for its leishmanicidal efficacy, tolerability
and immunomodulatory activity. Normal healthy mice were treated with 3.5 mg/kg single and 7.5 mg/kg single and double doses ofKALSOMEā¢10. Liver and kidney function tests were performed fourteen days after treatment. Next, normal mice were infected with Leishmania donovani amastigotes. Two months post infection they were treated with the above
mentioned doses of KALSOMEā¢10 and sacrificed one month after treatment for estimation of parasite burden in
the liver and spleen by Limiting Dilution Assay. Leishmanial antigen stimulated splenocyte culture supernatants were collected for cytokine detection through ELISA. Flow cytometric studies were performed on normal animals treated with KALSOMEā¢10, Amphotericin B (AmB) and AmBiosome to compare their immunomodulatory activities.
The drug was found to induce no hepato- or nephrotoxicities at the studied doses. Moreover, at all doses,
it led to significant reduction in parasite burden in two month infected BALB/c mice, with 7.5 mg/kg double dose
resulting in almost complete clearance of parasites from both liver and spleen. Interestingly, the drug at 7.5 mg/kg
double dose could almost completely inhibit the secretion of disease promoting cytokines, IL-10 and TGFĪ², and
significantly elevate the levels of IFNĪ³ and IL-12, cytokines required for control of the disease. Mice treated with KALSOMEā¢10 showed elevated levels of IFNĪ³ and suppressed IL-10 secretion from both CD4+ and CD8+ subsets
of T cells, as well as from culture supernatants of splenocytes, compared to that of normal, AmB and AmBisome
treated animal Treatment of infected mice with 7.5 mg/kg double dose of KALSOMEā¢10 was safe and effective in
clearing the parasites from the sites of infection. The drug maintains the inherent immunomodulatory activities of
AmB by effectively suppressing disease promoting cytokines IL-10 and TGFĪ², thereby boosting IL-12 and IFNĪ³ levels.
This emphasizes KALSOMEā¢10 as a promising drug alternative for lifelong protection from VL
Noninvasive Diagnosis of Visceral Leishmaniasis:Development and Evaluation of Two Urine-Based Immunoassays for Detection of Leishmania donovani Infection in India
Visceral leishmaniasis (VL), one of the most prevalent parasitic diseasesin the developing world causes serious health concerns. Post kala-azar dermal leishmaniasis (PKDL) is a skin disease which occurs after treatment as a sequel to VL. Parasitological diagnosis involves invasive tissue aspiration which is tedious and painful. Commercially available immunochromatographic rapid diagnostic test such as rK39-RDT is used for field diagnosis of VL, detects antibodiesin serum samples. Urine sample is however, much easier in
collection,storage and handling than serum and would be a better alternative where collection of tissue aspirate or blood is impractical. In this study, we have developed and evaluated the performance of two urine-based diagnostic assays, ELISA and dipstick test, and
compared the results with serologicalrK39-RDT. Our study shows the capability of urinebased tests in detecting anti-Leishmania antibodies effectively for both VL and PKDL diagnosis. The ability of dipstick test to demonstrate negative results after six months in
90% of the VL cases after treatment could be useful as a test of clinical cure. Urine-based
tests can therefore replace the need for invasive practices and ensure better diagnosi
Investigations on Immunomodulatory and ParasiticidaL Efficacies of Individualistic and Combinatorial Chemotherapeutic Agents against Visceral Leishmaniasis
Leishmaniasis is a collection of broad spectrum of diseases caused by obligate intracellular parasites belonging to genus Leishmania. It has emerged as the third most
prevalent parasite-borne disease worldwide after malaria and filariasis (Pourahmad et al., 2009). Manifestations of this disorder can range from less severe cutaneous leishmaniasis (CL) characterized by self-resolving local cutaneous lesions and mucocutaneous leishmaniasis (MCL) affecting the mucus membranes of mouth, nose and throat to the more serious visceral leishmaniasis (VL), which is potentially fatal. An estimated 12 million people worldwide have some form of leishmaniasis, and another 350 million
people are at risk (WHO Technical Report, 2010). There are approximately 0.2-0.4 million new cases of VL each year and over 90% of these occur in India, Bangladesh, Nepal, Brazil, Sudan and South Sudan, although these numbers are likely to be an underestimation since majority of the cases are not even reported in these and many of the other 88 endemic countries (Alvar et al., 2010). Post-kala-azar dermal leishmaniasis (PKDL), characterized by dispigmented macule, erythematous rashes, indurated plaques, papules and nodules, develops in a small percentage of Indian VL patients generally after 1 to 7 years, and in >50% Sudanese VL patients during or within 6 months of successful
antimonial therapy (Zijlstra et al., 2003). This chronic skin condition is probably a reservoir of parasites especially during inter-epidemic periods of kala-aza
Treatment of visceral leishmaniasis: anomalous pricing and distribution of AmBisome and emergence of an indigenous liposomal amphotericin B, FUNGISOME
Visceral leishmaniasis (VL) is one of the
severest forms of parasite borne diseases worldwide with a
mortality rate second only to malaria. Treatment of VL
patients with currently available chemotherapeutic agents
poses problems of large scale failure, toxicity, prolonged
hospitalization time, high treatment cost and drug resistance.
However, most of these problems can be overcome
by the use of liposomal formulations of Amphotericin B
(L-AmB). Of the two L-AmBs currently available in Indian
market, AmBisome is imported and FUNGISOME is
indigenous. Initially AmBisome remained exorbitantly
costly and therefore inaccessible to most of the VL
patients. However, with the launch of FUNGISOME in
India, Gilead in agreement with WHO started a donation
program of AmBisome in developing countries through a
slashed price of US 18 per
vial. FUNGISOME, on the other hand, produced consistently
good results against VL both clinically and experimentally.
In the context of unavailability and price
anomaly of AmBisome, successful emergence of FUNGISOME
could mark it as the major L-AmB against VL
Translating immune cell cross-talk into a treatment opportunity for visceral leishmaniasis
Results from both murine and human studies suggest the emergence of immunotherapy, involving different agonists and antagonists to the cytokines and cells involved in the course of disease progression, as a promising treatment option against visceral leishmaniasi
Current diagnosis and treatment of visceral leishmaniasis
Human visceral leishmaniasis (VL), a potentially fatal disease, is most prevalent in the Indian subcontinent, East Africa and South America. Definite diagnosis and effective treatment are the primary needs for the control of VL. Diagnosis of VL has typically relied on microscopic
examination of bone marrow/splenic aspirate, but serology and molecular methods are now better alternatives. The conventional drugs for treatment of VL have limitations including unresponsiveness, relapse, specific toxicities and parenteral administration lasting for long durations. Moreover, they are less effective in HIVāVL-coinfected patients. Registration of miltefosine and paromomycin, and preferential pricing of AmBisome has offered more choices
for monotherapy and combination therapy for VL. Combination therapy will increase treatment efficacy and prevent the development of resistance. In addition, active case finding and vector control strategies will also have a positive impact in the control of VL. This article critically
addresses the currently available diagnostic and treatment regimens for the control of VL
Situs inversus of the optic disc
A case of bilateral sites inversus of the optic disc, presenting with marked impairment of vision due to asso-ciated optic neuritis in one eve has been reported
Translating immune cell cross-talk into a treatment opportunity for visceral leishmaniasis
HIV-1 induction of tolerogenic dendritic cells is mediated by cellular interaction with suppressive T cells
HIV-1 infection gives rise to a multi-layered immune impairment in most infected individuals. The chronic presence of HIV-1 during the priming and activation of T cells by dendritic cells (DCs) promotes the expansion of suppressive T cells in a contact-dependent manner. The mechanism behind the T cell side of this HIV-induced impairment is well studied, whereas little is known about the reverse effects exerted on the DCs. Herein we assessed the phenotype and transcriptome profile of mature DCs that have been in contact with suppressive T cells. The HIV exposed DCs from cocultures between DCs and T cells resulted in a more tolerogenic phenotype with increased expression of e.g., PDL1, Gal-9, HVEM, and B7H3, mediated by interaction with T cells. Transcriptomic analysis of the DCs separated from the DC-T cell coculture revealed a type I IFN response profile as well as an activation of pathways involved in T cell exhaustion. Taken together, our data indicate that the prolonged and strong type I IFN signaling in DCs, induced by the presence of HIV during DC-T cell cross talk, could play an important role in the induction of tolerogenic DCs and suppressed immune responses seen in HIV-1 infected individuals.Funding Agencies|Swedish International Development Cooperation Agency; SIDA SARC; VINNMER for Vinnova; Linkoping University Hospital Research Fund; Swedish Society of Medicine; Molecular Infection Medicine Sweden; ALF; Swedish Research Council [AI52731]; Physicians against AIDS Research Foundation</p