13 research outputs found
Interleukin 10 inhibits pro-inflammatory cytokine responses and killing of Burkholderia pseudomallei.
Melioidosis, caused by Burkholderia pseudomallei, is endemic in northeastern Thailand and Northern Australia. Severe septicemic melioidosis is associated with high levels of pro-inflammatory cytokines and is correlated with poor clinical outcomes. IL-10 is an immunoregulatory cytokine, which in other infections can control the expression of pro-inflammatory cytokines, but its role in melioidosis has not been addressed. Here, whole blood of healthy seropositive individuals (nâ=â75), living in N. E. Thailand was co-cultured with B. pseudomallei and production of IL-10 and IFN-Îł detected and the cellular sources identified. CD3- CD14+ monocytes were the main source of IL-10. Neutralization of IL-10 increased IFN-Îł, IL-6 and TNF-α production and improved bacteria killing. IFN-Îł production and microbicidal activity were impaired in individuals with diabetes mellitus (DM). In contrast, IL-10 production was unimpaired in individuals with DM, resulting in an IL-10 dominant cytokine balance. Neutralization of IL-10 restored the IFN-Îł response of individuals with DM to similar levels observed in healthy individuals and improved killing of B. pseudomallei in vitro. These results demonstrate that monocyte derived IL-10 acts to inhibit potentially protective cell mediated immune responses against B. pseudomallei, but may also moderate the pathological effects of excessive cytokine production during sepsis
Phenotypic and Functional Characterization of Human Memory T Cell Responses to Burkholderia pseudomallei
The Gram-negative bacterium, Burkholderia pseudomallei, is a public health problem in southeast Asia and northern Australia and a Centers for Disease Control and Prevention listed Category B potential bioterrorism agent. It is the causative agent of melioidosis, and clinical manifestations vary from acute sepsis to chronic localized and latent infection, which can reactivate decades later. B. pseudomallei is the major cause of community-acquired pneumonia and septicemia in northeast Thailand. In spite of the medical importance of B. pseudomallei, little is known about the mechanisms of pathogenicity and the immunological pathways of host defense. There is no available vaccine, and the mortality rate in acute cases can exceed 40% with 10â15% of survivors relapsing or being reinfected despite prolonged and complete treatments. In this article, we describe cell-mediated immune responses to B. pseudomallei in humans living in northeast Thailand and demonstrate clear evidence of T cell priming in healthy seropositive individuals and patients who recovered from melioidosis. This is the most detailed study yet performed on the cell types that produce interferon-gamma to B. pseudomallei in humans and the antigens that they recognize and the first to study large sample numbers in the primary endemic focus of melioidosis in the world
1α,25âdihydroxyvitamin D3 in combination with transforming growth factorâÎČ increases the frequency of Foxp3+ regulatory T cells through preferential expansion and usage of interleukinâ2
A high prevalence of vitamin D insufficiency and deficiency exists worldwide, which is associated with an increased incidence and severity of a range of immuneâmediated diseases. This has resulted in considerable interest in the immunodulatory functions of vitamin D. The active form of vitamin D, 1α,25âdihydroxyvitamin D3 [1,25(OH)2D3], has been shown to increase the frequency of Foxp3+ CD4+ T regulatory (Treg) cells when present at high concentrations or under strong Tâcell stimulation in culture. Supporting evidence exists in vivo for a positive association between serum 25(OH)D and Foxp3+ Treg cell numbers in humans. The aim of this work was to identify the cytokine milieu required in vitro to promote Foxp3+ Treg cells in cultures containing 1,25(OH)2D3 at more moderate concentrations (10â7 m). Stimulation of human CD4+ T cells with a combination of 1,25(OH)2D3 and transforming growth factorâÎČ (TGFâÎČ) greatly increased the frequency of Foxp3+ Treg cells, which is proposed to result from the preferential expansion of Foxp3+ Treg cells, as compared with the Foxp3â effector T cells, in culture. The differential effect on proliferation may result from enhanced availability and usage of interleukinâ2 by the Foxp3+ Treg cells compared with Foxp3â effector T cells. In summary, modulation of the cytokine environment to one high in TGFâÎČ in the presence of 1,25(OH)2D3 (10â7 m) significantly increased Foxp3+ Treg cell frequency. These data provide additional evidence for the important immunomodulatory properties of 1,25(OH)2D3 that exist and may help to control inflammatory diseases