Splenic Cytokine Responses in Indian Kala‐Azar before and after Treatment

Kenney, Richard T.; Sacks, David L.; Gam, Albert A.; Murray, Henry W.; Sundar, Shyam

doi:10.1086/517817

Cited by 118 publications

(129 citation statements)

References 14 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…There is little data directly supporting this view, however, since it is difficult to obtain tissue samples from patients with the active disease. However, IFN-g mRNA expression is, as expected, present and high in bone marrow 36 , lymph node 27 , and spleen 38,50 aspirates.…”

Section: Immunoactivation In Lymphoid Organssupporting

confidence: 80%

Immunoactivation and immunopathogeny during active visceral leishmaniasis

Goto

Prianti

2009

Rev. Inst. Med. trop. S. Paulo

101

View full text Add to dashboard Cite

SUMMARYVisceral leishmaniasis is caused by protozoan parasites of the Leishmania donovani complex. During active disease in humans, high levels of IFN-g and TNF-a detected in blood serum, and high expression of IFN-g mRNA in samples of the lymphoid organs suggest that the immune system is highly activated. However, studies using peripheral blood mononuclear cells have found immunosuppression specific to Leishmania antigens; this poor immune response probably results from Leishmania antigen-engaged lymphocytes being trapped in the lymphoid organs. To allow the parasites to multiply, deactivating cytokines IL-10 and TGF-b may be acting on macrophages as well as anti-Leishmania antibodies that opsonize amastigotes and induce IL-10 production in macrophages. These high activation and deactivation processes are likely to occur mainly in the spleen and liver and can be confirmed through the examination of organ samples. However, an analysis of sequential data from studies of visceral leishmaniasis in hamsters suggests that factors outside of the immune system are responsible for the early inactivation of inducible nitric oxide synthase, which occurs before the expression of deactivating cytokines. In active visceral leishmaniasis, the immune system actively participates in non-lymphoid organ lesioning. While current views only consider immunocomplex deposition, macrophages, T cells, cytokines, and immunoglobulins by diverse mechanism also play important roles in the pathogenesis. KEYWORDS:Visceral leishmaniasis; Human; Immunosuppression; Immunoactivation; Cytokines; Immunopathogenesis.Visceral leishmaniasis is caused by protozoa of the genus Leishmania that are transmitted to mammalian hosts, including humans, by phlebotomine sandflies. The disease is present in 66 countries in tropical and subtropical regions, and 90% of cases occur in India, Sudan, Bangladesh, Nepal, and Brazil. It is estimated that there are 500,000 new cases a year worldwide 68 , and 3,000 new cases occur each year in Brazil 48 . Until recently, the disease was thought to be caused by three species of the Leishmania donovani complex: Leishmania (Leishmania) donovani, L. (L.) infantum, and Leishmania (L.) chagasi (a species present in Brazil). There is now debate, however, over whether L. (L). infantum and Leishmania (L.) chagasi are the same 44 or different 60 species. In this review, the names of the three species will be used as in the original publications. Leishmania (Leishmania) donovani is present in East Africa, India, and parts of the Middle East, while L. (L.) infantum in Europe, North Africa, and South and Central America. Human infections can be asymptomatic or can manifest as oligosymptomatic and progressive diseases; progressive cases can involve hepatosplenomegaly, fever, pancytopenia, hypergammaglobulinemia, and serious weight loss 4 . During active visceral leishmaniasis, the parasite multiplies within the cells of the mononuclear phagocyte system in the spleen, liver, and bone marrow, and the disease is fatal if untreated.Studies...

show abstract

Section: Immunoactivation In Lymphoid Organssupporting

confidence: 80%

Immunoactivation and immunopathogeny during active visceral leishmaniasis

Goto

Prianti

2009

Rev. Inst. Med. trop. S. Paulo

101

View full text Add to dashboard Cite

show abstract

“…One possible explanation is that new parasites are constantly being seeded into the spleen from other highly infected tissues, where IFN-γ is not elevated. High splenic IFN-γ was also detected in people infected with L. donovani [19,21,23]. In contrast to HVL, IL-10 mRNA expression was not elevated in the spleen of L. infantum-infected dogs in this study, as was the amount of IL-10 protein in a different study [12].…”

Section: Discussioncontrasting

confidence: 50%

“…Moreover, researchers were unable to clearly associate a Th2 polarity with non-healing, reactivating, or systemic leishmaniasis in humans. Interestingly, the severity of human visceral leishmaniasis (HVL) has not been associated with increased levels of IL-4 but of IL-10, which was also detected in the spleen of infected patients [23]. Similarly, elevated levels of IFN-γ were found in biopsies taken from the spleen, lymph nodes and bone marrow of infected people [19,21,23], indicating that an unfavorable disease prognosis in humans is not related to a defect in Th1 cell response but rather to a concurrent expression of the cytokine IL-10.…”

Section: Zoonotic Visceral Leishmaniasis (Zvl) Is Caused By Parasitesmentioning

confidence: 99%

“…Interestingly, the severity of human visceral leishmaniasis (HVL) has not been associated with increased levels of IL-4 but of IL-10, which was also detected in the spleen of infected patients [23]. Similarly, elevated levels of IFN-γ were found in biopsies taken from the spleen, lymph nodes and bone marrow of infected people [19,21,23], indicating that an unfavorable disease prognosis in humans is not related to a defect in Th1 cell response but rather to a concurrent expression of the cytokine IL-10. Interleukin-10, traditionally thought to be produced mainly by macrophages, is secreted by naturally occurring CD4+CD25+ T regulatory (Treg) cells in lesions of low dose L. major infected C57BL/6 mice.…”

Section: Zoonotic Visceral Leishmaniasis (Zvl) Is Caused By Parasitesmentioning

confidence: 99%

See 1 more Smart Citation

Splenic immune responses during canine visceral leishmaniasis

Strauss-Ayali

Baneth

Jaffe³

2007

Vet. Res.

View full text Add to dashboard Cite

-Dogs are the main reservoir host for zoonotic visceral leishmaniasis caused by Leishmania infantum. In this study we investigated the immune response in spleens of L. infantum-infected dogs by measuring the mRNA expression levels for a wide panel of cytokines, transcription factors and chemokines. mRNA levels and parasite load were followed during 7 months of experimental infection and 14 months post-treatment, and were compared to naturally-infected (NI) dogs. Similarly, serum anti-Leishmania IgG and IgG subclass levels were measured during experimental infection. An increase in IFN-γ, T-bet, IP-10 and RANTES was found in the experimentally and NI dogs, implicating a substantial type-1 immune response during canine visceral leishmaniasis. IL-4, a type-2 associated cytokine, increased as early as one month after experimental infection, while IL-5 was high at later stages. Interestingly, the expression levels of the Treg-associated cytokines, IL-10 and TGF-β, did not change during the infection. Total anti-Leishmania IgG and IgG subclasses increased during the experimental infection. However, no association with specific cytokine patterns was observed. Parasite load in the spleens increased as early as one month postinfection and remained high until treatment. The load was higher in the polysymptomatic NI dogs than in the experimentally-infected dogs. This study indicates that both type-1 and type-2 immune responses occur in the spleen during canine L. infantum infection, and suggests that the early elevation of IL-4 might have a role in the persistence of parasites in the presence of high IFN-γ expression.canine visceral leishmaniasis / IFN-γ / IL-4 / T-bet / IP-10

show abstract

“…At baseline, mRNA for IFN-g was detected in 86% patients, and mRNA for IL-10 and IL-4 was detected in 100% and 48% patients, respectively, thereby suggesting that polarized Th 2 celltype responses do not appear to develop in Kala-azar; instead there is an initial mixed Th 1-and Th 2-cell response. With successful treatment in the sodium antimony gluconate and amphotericin B lipid complex groups, levels of IFN-g and IL-10 mRNA decreased significantly, indicating that after resolution of infection, both components (Th1 and Th 2) of the immune response appear to involute [29]. It would be interesting to study IFN-g production in patients who do not respond to therapy and thus are unable to control the infection.…”

Section: Discussionmentioning

confidence: 99%

Reactive oxygen intermediates, nitrite and IFN-γin Indian visceral leishmaniasis

Kumar

Pai

Sundar

2001

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SUMMARY Reactive oxygen intermediates (ROI), nitrite and interferon-gamma (IFN-γ) production were investigated at different times during treatment in 10 patients with visceral leishmaniasis (VL). Hydrogen peroxide (H2O2), superoxide (O2−) and IFN-γ production by cultured monocytes from patients with active VL were significantly lower compared with the healthy controls. In contrast, nitrite levels in the supernatants from monocyte cultures of VL patients were comparable to healthy controls and increased significantly during antileishmanial therapy. On day 20 of treatment, a significant increase in the release of H2O2, O2− and IFN-γ was observed. However, at follow-up, 4 months after the end of treatment, the production of H2O2, O2−, IFN-γ and nitrite had declined significantly. Thus, the impairment in hydrogen peroxide and superoxide production suggests that down-regulation of these mediators may be involved in the reduced killing of parasites by monocytes of active VL patients. Furthermore, the monocytes regained respiratory burst activity as the antileishmanial therapy progressed, suggesting that an immune-based mechanism is involved in successful drug therapy.

show abstract

Splenic Cytokine Responses in Indian Kala‐Azar before and after Treatment

Cited by 118 publications

References 14 publications

Immunoactivation and immunopathogeny during active visceral leishmaniasis

Immunoactivation and immunopathogeny during active visceral leishmaniasis

Splenic immune responses during canine visceral leishmaniasis

Reactive oxygen intermediates, nitrite and IFN-γin Indian visceral leishmaniasis

Contact Info

Product

Resources

About