Immune evasion within the tumor microenvironment supports malignant growth and is also a major obstacle for successful immunotherapy. Multiple cellular components and soluble factors coordinate to disrupt protective immune responses. Although stromal cells are well-known for their parenchymal supportive roles in cancer establishment and progression, we demonstrate for the first time, to our knowledge, that tumor-derived vascular pericytes negatively influence CD4+ T cell activation and proliferation, and promote anergy in recall response to Ag by CD4+CD44+ T cells via regulator of G protein signaling 5– and IL-6–dependent pathways. Our data support a new specific role for tumor-derived pericytes in the immune evasion paradigm within the tumor microenvironment and suggest the targeting of these cell populations in the context of successful immunotherapeutics for the treatment of cancer.
Visceral leishmaniasis is characterized by severe immunosuppression of the host cell, resulting in loss of the proinflammatory response. Toll-like receptor 2 (TLR2) is involved in myriad disease forms, including visceral leishmaniasis. During Leishmania donovani infection, the parasite modulates TLR2 to suppress interleukin 12 production, indicating the possible involvement of TLR2 in regulation of the immune response against L. donovani infection. Arabinosylated lipoarabinomannan (Ara-LAM) possesses immunomodulatory properties and induces proinflammatory responses via induction of TLR2-mediated signaling. Here, we found that pretreatment of L. donovani-infected macrophages with Ara-LAM caused a significant increase in TLR2 expression along with the activation of TLR2-mediated downstream signaling, facilitating active nuclear translocation of nuclear factor kappaB. These events culminated in up-regulation of the proinflammatory response, which was abrogated by treatment with TLR2-specific small interfering RNA. In vivo experiments were also suggestive of Ara-LAM playing a long-term protective role. This study demonstrates that Ara-LAM confers protection against leishmanial pathogenesis via TLR2 signaling-mediated induction of the proinflammatory response.
1. The effect of dietary vitamin E, selenium (Se) and their different combinations on body weight gain, food consumption, food conversion efficiency, leukocyte migration inhibition and antibody production was determined in broilers. 2. Chicks were fed on maize-soya bean based diets with concentrations of supplemental vitamin E varying from 0 to 300 IU/kg and selenium concentrations varying from 0 to 1 mg/kg either alone or in combination from 1 to 42 d of age. 3. The chicks were immunised for Newcastle Disease Virus (NDV) vaccine at 21 d. Per cent leukocyte migration inhibition (LMI) was studied on 42 d. Antibodies to NDV in serum were determined at 10 and 21 d post immunisation (PI). 4. Chicks receiving Se, 1 mg/kg and vitamin E 300 IU/kg had significantly higher cellular immune responses in terms of per cent LMI. 5. Maximum body weight gain and best efficiency of food utilisation were obtained in chicks fed diets containing 0.50 mg/kg Se and 300 IU/kg vitamin E. 6. Significantly higher antibody titres (HI and ELISA) at 10 d PI were attributed to 0.06 mg/kg and 150 IU/kg Se and vitamin E, respectively. 7. These data suggest that optimum growth and immune response may be achieved at supplemental level of Se of 0.06 mg/kg and vitamin E at 150 IU/kg. The vitamin E level is higher than that recommended by NRC (1984, 1994).
Visceral leishmaniasis, caused by the protozoan parasite Leishmania donovani, is characterized by the loss of ability of the host to generate an effective immune response. In the present study, the comparative potential of CXC chemokines, interferon-gamma-inducible protein-10 (IP-10) and interleukin-8 (IL-8) in restricting Leishmania donovani infection via the release of nitric oxide and proinflammatory cytokines was studied in an in vitro model. Nitric oxide, a crucial mediator for IP-10-mediated leishmanicidal activity, was found to be dependent on inducible nitric oxide synthase 2 (iNOS2) expression and was linked to the mitogen-activated protein kinases (MAPK) signaling pathway. Further, IP-10 was also able to abrogate the survival of Leishmania in an in vivo model of visceral leishmaniasis by restoration of Th1 cytokines and nitric oxide. Thus, this study strongly demonstrates that IP-10, like CC chemokines, is involved in rendering a protective response in visceral leishmaniasis via up-regulation of proinflammatory mediators.
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