Differentialin vitroCD4+/CD8+T-cell response to live vs. killedLeishmania major

Rostami, Mahmoud Nateghi; Valian, H. Keshavarz; Eskandari, Seyed Ebrahim; Mohammadi, Akram Miramin; Shahrestani, S. Tahereh; Sarrafnejad, Abdolfattah; Khamesipour, Ali

doi:10.1111/j.1365-3024.2009.01164.x

Cited by 19 publications

(17 citation statements)

References 56 publications

(69 reference statements)

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“…Macrophages upon activation produce nitric oxide (NO) which inhibits growth of intracellular pathogens. It is shown that during active lesion of CL due to L. major the proliferative response and IFN-γ production of PBMC was increased [12], [46] and T cells from healed CL produced a significantly higher level of IFN-γ but a low level of IL-10 than the cells from controls [14], [15], [40]. Similarly, studies in L. braziliensis infection demonstrated a Th1/Th2 mixed response in early stage of active CL [11], [42] and then a sustained Th1 response with elevated level of IFN-γ and down-regulation of IL-4 and IL-10 production were seen apparently associated with healing [11].…”

Section: Discussionmentioning

confidence: 94%

“…Promastigotes were harvested at day 5, washed 3 times with PBS (pH 7.2) and used for preparation of soluble Leishmania antigen (SLA) as previously described [14]. Briefly, protease inhibitor cocktail enzyme (Sigma, St. Louis, MO, USA) was added at 100 µl per 1×10 9 promastigotes, and then the parasites were freeze-thawed 10 times followed by sonication at 4°C with two 20-sec blasts.…”

Section: Methodsmentioning

confidence: 99%

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CD8+ T Cells as a Source of IFN-γ Production in Human Cutaneous Leishmaniasis

et al. 2010

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BackgroundIn human leishmaniasis Th1/Th2 dichotomy similar to murine model is not clearly defined and surrogate marker(s) of protection is not yet known. In this study, Th1/Th2 cytokines (IL-5, IL-10, IL-13 and IFN-γ) profile induced by purified CD4+/CD8+ T cells in response to Leishmania antigens were assessed at transcript and protein levels in 14 volunteers with a history of self-healing cutaneous leishmaniasis (HCL) and compared with 18 healthy control volunteers.Methodology/Principal FindingsCD4+/CD8+/CD14+ cells were purified from peripheral blood using magnetic beads; CD4+/CD8+ T cells were co-cultured with autologous CD14+ monocytes in the presence of soluble Leishmania antigens (SLA). Stimulation of either CD4+ T cells or CD8+ T cells of HCL volunteers with SLA induced a significantly (P<0.05) higher IFN-γ production compared with the cells of controls. Upregulation of IFN-γ gene expression in CD4+ cells (P<0.001) and CD8+ cells (P = 0.006) of HCL volunteers was significantly more than that of controls. Significantly (P<0.05) higher fold-expression of IFN-γ gene was seen in CD4+ cells than in CD8+ cells. In HCL volunteers a significantly (P = 0.014) higher number of CD4+ cells were positive for intracellular IFN-γ production than CD8+ cells.Conclusions/SignificanceCollectively, the volunteers have shown maintenance of specific long-term immune responses characterized by a strong reaction to leishmanin skin test and IFN-γ production. The dominant IFN-γ response was the result of expansion of both CD4+ and CD8+ T cells. The results suggested that immune response in protected individuals with a history of zoonotic cutaneous leishmaniasis (ZCL) due to L. major is mediated not only through the expansion of antigen-specific IFN-γ producing CD4+ Th1 cells, but also through IFN-γ producing CD8+ T cells.

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Section: Discussionmentioning

confidence: 94%

Section: Methodsmentioning

confidence: 99%

CD8+ T Cells as a Source of IFN-γ Production in Human Cutaneous Leishmaniasis

et al. 2010

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“…The results of phase 3 clinical trials using crude Leishmania as vaccine were not promising [4], [12], [23], [24]. It has been shown that in vitro CD4 + /CD8 + T-cell responses to live Leishmania major are significantly stronger than responses to dead parasites [25]. The only successful protective measure against CL has been shown to be leishmanization.…”

Section: Discussionmentioning

confidence: 99%

A Dual Drug Sensitive L. major Induces Protection without Lesion in C57BL/6 Mice

et al. 2014

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Leishmaniasis is a major health problem in some endemic areas and yet, no vaccine is available against any form of the disease. Historically, leishmanization (LZ) which is an inoculation of individual with live Leishmania, is the most effective control measure at least against cutaneous leishmaniasis (CL). Due to various reasons, LZ is not used today. Several live attenuated Leishmania have been developed but their use is limited. Previously, we developed a transgenic strain of L. major that harbors two suicide genes tk and cd genes (lmtkcd+/+) for use as a challenge strain in vaccine studies. These genes render the parasite susceptible to Ganciclovir (GCV) and 5-flurocytosine (5-FC). The dual drug sensitive strain of L. major was developed using gene targeting technology using a modified Herpes Simplex Virus thymidine kinase gene (hsv-tk) sensitive to Ganciclovir antibiotic and Saccharomyces cerevisae cytosine deaminase gene (cd sensitive to 5-flurocytosine) that were stably introduced into L. major chromosome. BALB/c mice inoculated with lmtkcd+/+ developed lesions which upon treatment with GCV and 5-FC completely healed. In the current study, the transgenic lmtkcd+/+strain was assessed as a live vaccine model to determine the time necessary to develop a protective immune response. C57BL/6 mice were inoculated with the transgenic lmtkcd+/+strain, and treated at the time of inoculation (day0) or at day 8 after inoculation. Immunized animals were challenged with wild-type L. major, and complete protection was induced in mice that were treated at day 8. The results show that in contrast to leishmanization, in group of mice inoculated with a dual sensitive L. major development and persistence of lesion is not necessary to induce Th1 response and protection.

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“…Although effective against VL in several experimental models, recent human clinical trials of killed vaccines have been found to be safe but not as effective as leishmanization, having low efficacies (54%) when tested in humans (Sharifi et al, 1998; Momeni et al, 1999; Armijos et al, 2004; Vélez et al, 2005) and dogs (Genaro et al, 1996; Mohebali et al, 2004). The success of leishmanization over killed vaccines in CL can possibly be explained by an in vitro study evaluating human T cell function when simulated by live vs. killed parasites (Nateghi Rostami et al, 2010). In addition to increased IFN-γ from CD4 + T cells, live parasites could also stimulate CD8 + T cells to secrete IFN-γ.…”

Section: Vl Vaccine Development: Conventional Approachesmentioning

confidence: 99%

“…Killed parasites, however, could stimulate CD4 + T cells only. This probably accounts for better immunologic memory leading to sustained immunity after healing of live infections (Okwor and Uzonna, 2008; Nateghi Rostami et al, 2010). Promising enough, a very recent approach have generated a killed but metabolically active L. infantum chagasi promastigotes after treating them with amotosalen and low-dose UV radiation that resulted in replication-deficient parasites that could protect mice against experimental VL (Bruhn et al, 2012).…”

Section: Vl Vaccine Development: Conventional Approachesmentioning

confidence: 99%

Vaccine Development Against Leishmania donovani

Das¹,

Ali²

2012

Front. Immun.

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Visceral leishmaniasis (VL) caused by Leishmania donovani and Leishmania infantum/chagasi represents the second most challenging infectious disease worldwide, leading to nearly 500,000 new cases and 60,000 deaths annually. Zoonotic VL caused by L. infantum is a re-emergent canid zoonoses which represents a complex epidemiological cycle in the New world where domestic dogs serve as a reservoir host responsible for potentially fatal human infection and where dog culling is the only measure for reservoir control. Life-long immunity to VL has motivated development of prophylactic vaccines against the disease but very few have progressed beyond the experimental stage. No licensed vaccine is available till date against any form of leishmaniasis. High toxicity and increasing resistance to the current chemotherapeutic regimens have further complicated the situation in VL endemic regions of the world. Advances in vaccinology, including recombinant proteins, novel antigen-delivery systems/adjuvants, heterologous prime-boost regimens and strategies for intracellular antigen presentation, have contributed to recent advances in vaccine development against VL. Attempts to develop an effective vaccine for use in domestic dogs in areas of canine VL should be pursued for preventing human infection. Studies in animal models and human patients have revealed the pathogenic mechanisms of disease progression and features of protective immunity. This review will summarize the accumulated knowledge of pathogenesis, immune response, and prerequisites for protective immunity against human VL. Authors will discuss promising vaccine candidates, their developmental status and future prospects in a quest for rational vaccine development against the disease. In addition, several challenges such as safety issues, renewed and coordinated commitment to basic research, preclinical studies and trial design will be addressed to overcome the problems faced in developing prophylactic strategies for protection against this lethal infection.

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Differentialin vitroCD4⁺/CD8⁺T-cell response to live vs. killedLeishmania major

Cited by 19 publications

References 56 publications

CD8+ T Cells as a Source of IFN-γ Production in Human Cutaneous Leishmaniasis

CD8+ T Cells as a Source of IFN-γ Production in Human Cutaneous Leishmaniasis

A Dual Drug Sensitive L. major Induces Protection without Lesion in C57BL/6 Mice

Vaccine Development Against Leishmania donovani

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