The immunology of post-kala-azar dermal leishmaniasis (PKDL)

Zijlstra, Eduard E.

doi:10.1186/s13071-016-1721-0

Cited by 108 publications

(106 citation statements)

References 73 publications

(97 reference statements)

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“…For example, therapeutic vaccination with ChAd3-NSmut/MVA-NSmut was unable to overcome the immune dysregulation associated with chronic Hepatitis C Virus (HCV) infection and vaccine-induced T cell responses were impaired compared to that seen in healthy vaccine recipients [71]. Although qualitatively similar immune dysregulation is observed in active VL and to a lesser extent in PKDL [19, 72], experimental data in models of established VL suggest that therapeutic vaccination with viral vectors can nevertheless lead to functional T cell activation and reduced parasite burden [12, 18]. Whether this can be recapitulated in humans with PKDL (for which there is no animal model) or in asymptomatic VL patients (where immune dysregulation may be less evident) remains to be tested in the clinic.…”

Section: Discussionmentioning

confidence: 99%

A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: First-in-human trial of ChAd63-KH

et al. 2017

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BackgroundVisceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells.MethodsWe conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry.FindingsChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects.ConclusionThe results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL.Trial registrationThis clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359).

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Section: Discussionmentioning

confidence: 99%

A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: First-in-human trial of ChAd63-KH

et al. 2017

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“…In Africa, the disease is often self‐limiting and cures spontaneously. In India, it persists indefinitely if not treated …”

Section: Discussionmentioning

confidence: 99%

“…In India, it persists indefinitely if not treated. [17][18][19][20][21] In South America, specifically in Paraguay and some states of Brazil, such as Rio de Janeiro, Mato Grosso do Sul and Minas Gerais, cases of cutaneous leishmaniasis caused by Leishmania (L.) infantum chagasi with peculiarities in its clinical presentation have been reported. These lesions ulcerate, evolve over time and do not present a hypopigmented halo.…”

Section: Discussionmentioning

confidence: 99%

Histopathological features of skin lesions in patients affected by non‐ulcerated or atypical cutaneous leishmaniasis in Honduras, Central America

Pacheco

Araujo

Ferreira³

et al. 2018

Int J Experimental Path

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Summary In Honduras visceral leishmaniasis and non‐ulcerated or atypical cutaneous leishmaniasis (NUCL) are caused by the species Leishmania (L.) infantum chagasi. NUCL is the most common clinical form in the southern regions of the country, mainly affecting the young. In view of the lack of knowledge about the pathogenesis of the disease pattern caused by L. (L) infantum chagasi in individuals affected by NUCL, the aim of the present study was to describe in detail the histopathological features of the skin lesion caused by the parasite. Biopsies from human NUCL lesions with a positive parasitological diagnosis were collected and processed using standard histological techniques. Paraffin sections stained by haematoxylin and eosin were used to examine the histopathological alterations seen in the skin. The lesions varied between 3 and 5 mm, and the majority of the patients (60%) had a single lesion. Lesions were more frequently seen in females (65%), with an average age of 33.4 years. Microscopically, the skin lesions were characterized by mononuclear inflammatory infiltrate in the dermis composed of lymphocytes, macrophages and a few plasma cells. The intensity of the infiltration varied from discrete to intense. In both cases, the parasitic infection was discrete. Granulomas were present in 60% of cases and were associated with intense inflammation. The data revealed by the histopathological alterations in the skin of individuals affected by NUCL suggest activation of a cellular immune response that potentially controls parasite spreading.

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“…PKDL takes an intermediate position with a dissociation of the immune response between the skin and the viscera with a Th2 and Th1 type of response, respectively. 5 Clinically, the morphology and distribution of the lesions closely simulate that of leprosy, creating confusion in differentiating it from the latter. 6 Papules, nodules, hypopigmented patches are the most common presentations of PKDL, which are often confused with Hansen's.…”

Section: Discussionmentioning

confidence: 99%