Three Decades of Clinical Trials on Immunotherapy for Human Leishmaniases: a Systematic Review and Meta-Analysis

Mota, Camila Alves; Oyama, Jully; Monich, Mariana de Souza Terron; Brustolin, Aline Ávila; Souza, João Vítor Perez de; Murase, Letícia Sayuri; Lopes, Luciana Dias Ghiraldi; Santos, Thaís da Silva; Teixeira, Jorge Juarez Vieira; Silveira, Thaís Gomes Verzignassi

doi:10.2217/imt-2020-0184

Cited by 4 publications

(3 citation statements)

References 84 publications

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“…A significant in vivo leishmanicidal effect that induced subsequent resolution of lesions was evidenced both with Glucantime ® , the agent used to successfully treat the CL patient from whom the UA-946 L(V)p was isolated, and with Miltefosine, which has been increasingly used to treat CL in the New World ( Pinart et al, 2020 ). Likewise, since host-directed immunotherapeutic interventions have been used to treat leishmaniasis ( Mota et al, 2021 ) and are gaining special attention ( Novais et al, 2021 ), we also confirmed that low dose of the TLR9 agonist CpG protected mice clinically and parasitologically from L(V)p CL when co-delivered with the challenge or when used as an adjuvant of total L(V)p antigen in a vaccination setting ( Zimmermann et al, 1998 , 2008 ; Raman et al, 2012 ). Moreover, the model allowed us to identify a protective 28–30 kDa L(V)p subproteome (termed F9) via forward vaccinology and confirm that F9 induces a shift toward a Th1 response.…”

Section: Discussionsupporting

confidence: 78%

A Mouse Model of Ulcerative Cutaneous Leishmaniasis by Leishmania (Viannia) panamensis to Investigate Infection, Pathogenesis, Immunity, and Therapeutics

et al. 2022

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A mouse model of cutaneous leishmaniasis (CL) by Leishmania (Viannia) panamensis (L(V)p) that reproduces the characteristics of the human disease remains elusive. Here we report the development of a CL model that uses a mouse-adapted L(V)p isolate to reproducibly induce a dermal disease with a remarkable similarity to human CL. BALB/c mice infected intradermally in the ear with 105 stationary UA-946 L(V)p promastigotes develop a progressive cutaneous disease that exhibits the typical ulcerated lesions with indurated borders observed in CL patients. Although most of parasites in the inoculum die within the first week of infection, the survivors vigorously multiply at the infection site during the following weeks, paralleling disease appearance and aggravation. Regional lymphadenopathy as well as lymphatic dissemination of parasites to draining lymph nodes (dLN) was evidenced early after infection. Viable parasites were also isolated from spleen at later timepoints indicating systemic parasitic dissemination, but, strikingly, no signs of systemic disease were observed. Increasing numbers of myeloid cells and T lymphocytes producing IFNγ and IL-4 were observed in the dLN as disease progressed. A mixed adaptive L(V)p-specific T cell-mediated response was induced, since ex vivo recall experiments using dLN cells and splenocytes revealed the production of type 1 (IFNγ, IL-2), type 2 (IL-4, IL-13), regulatory (IL-10), and inflammatory (GM-CSF, IL-3) cytokines. Humoral adaptive response was characterized by early production of IgG1- followed by IgG2a-type of L(V)p-specific antibodies. IFNγ/IL-4 and IgG2a/IgG1 ratios indicated that the initial non-protective Th2 response was redirected toward a protective Th1 response. In situ studies revealed a profuse recruitment of myeloid cells and of IFNγ- and IL-4-producing T lymphocytes to the site of infection, and the typical histopathological changes induced by dermotropic Leishmania species. Evidence that this model is suitable to investigate pharmacological and immunomodulatory interventions, as well as for antigen discovery and vaccine development, is also presented. Altogether, these results support the validity and utility of this novel mouse model to study the pathogenesis, immunity, and therapeutics of L(V)p infections.

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Section: Discussionsupporting

confidence: 78%

A Mouse Model of Ulcerative Cutaneous Leishmaniasis by Leishmania (Viannia) panamensis to Investigate Infection, Pathogenesis, Immunity, and Therapeutics

et al. 2022

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“…The toxicity and mortality caused by these drugs justify the recommendation to administer liposomal amphotericin B over pentavalent antimonials in individuals with VL and HIV (35). The combination of pentavalent antimonials with recombinant interferon-gamma showed cure rates ranging from 69% to 100%, but further studies are needed to confirm this combination is superior to antimonials alone (39). On the other hand, the combination of pentavalent antimonials with paromomycin, evaluated in Ethiopia, produced a therapeutic success of 90.1% (37).…”

Section: Treatmentmentioning

confidence: 99%

Evidence map of diagnosis, treatment, prognosis, prevention, and control in visceral leishmaniasis

Ibiapina¹,

Batista²,

Aguiar³

et al. 2022

Revista Panamericana De Salud Pública

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Objective. To develop an evidence map on visceral leishmaniasis prevention, control, diagnosis, treatment, and prognosis. Methods. Systematic reviews on visceral leishmaniasis were searched using MEDLINE/PubMed and Virtual Health Library. After selection, each included systematic review was assessed, characterized, and categorized by intervention type and by outcomes, according to the methodology offered by the PAHO/WHO Latin American and Caribbean Center on Health Sciences Information (BIREME). The methodological quality was assessed using the AMSTAR2 tool to determine the confidence level of the evidence obtained. Results. Among the prevention and control interventions, insecticide spraying, bednets, dog collars, and dog culling were the most assessed, emphasizing that insecticidal dog collars can reduce visceral leishmaniasis incidence in dogs. Regarding diagnosis, polymerase chain reaction (PCR), rK39 immunochromatographic test (rK39 ICT), and direct agglutination test (DAT) presented high sensitivity and specificity. As for treatment, pentavalent antimonials and amphotericin B were the most analyzed drugs and showed therapeutic success; however, serious adverse events can occur due to their use. The prognostic factors identified were anemia, edema, bleeding, jaundice, age, and HIV coinfection. Conclusions. The evidence map developed shows rK39 ICT and DAT as promising diagnostic alternatives and reinforces the efficacy of liposomal amphotericin B and pentavalent antimonials. Insecticide-impregnated dog collars appear as a promising measure for the control of visceral leishmaniasis, but there is also a need for future studies and reviews with higher methodological quality, especially on prevention and control interventions.

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“…Another approach is to use combined therapy, associating immunotherapeutics with classic drugs to improve patient outcomes [26,27]. A few clinical trials, conducted in the last three decades, have shown positive results, with combined immunotherapy reducing the healing time for patients, but more studies are needed before these combinations receive market approval [27].…”

Section: Clinical Forms and Treatmentmentioning

confidence: 99%

Ruthenium Complexes, an Emerging Class of Leishmanicidal Drug Candidates

Braga

2022

Applied Biosciences

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This review addresses the search for activity enhancement of leishmanicidal organic compounds through their coordination chemistry with ruthenium. In an introduction to leishmaniasis, its clinical manifestations, geographical distribution, available forms of treatment, and challenges to disease management are presented. Ruthenium complexes, owing to their physico-chemical and biological properties, are introduced as a suitable molecular library from which to find alternatives to current medicines. The main sections of the review describe complexes reported in the literature, organised into two main groups: organometallics and inorganic complexes. The activity of the ruthenium complexes is presented compared with that of the ligands for a critical assessment of their utility in future clinical application.

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Three Decades of Clinical Trials on Immunotherapy for Human Leishmaniases: a Systematic Review and Meta-Analysis

Cited by 4 publications

References 84 publications

A Mouse Model of Ulcerative Cutaneous Leishmaniasis by Leishmania (Viannia) panamensis to Investigate Infection, Pathogenesis, Immunity, and Therapeutics

A Mouse Model of Ulcerative Cutaneous Leishmaniasis by Leishmania (Viannia) panamensis to Investigate Infection, Pathogenesis, Immunity, and Therapeutics

Evidence map of diagnosis, treatment, prognosis, prevention, and control in visceral leishmaniasis

Ruthenium Complexes, an Emerging Class of Leishmanicidal Drug Candidates

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