Dendritic cells activated with products released by schistosome larvae drive Th2-type immune responses, which can be inhibited by manipulation of CD40 costimulation

The early immune events in response to infective larvae of the parasitic helminth Schistosoma mansoni are poorly understood, but here for the first time we report on the potential of products released by schistosome larvae (material released in the first 3 It after transformation [0-3hRP]) to stimulate the maturation of dendritic cells (DC) and alter their T-cell-polarizing function. This was performed in comparison with lipopolysaccharide (LPS) and zymosan A, which classically activate DC to prime for Th1- and Th2-type responses, respectively. In our study, immature bone marrow-derived DC stimulated in vitro with 0-3hRP exhibited up-regulated expression of major histocompatibility complex class II, CD40, and CD86 and increased production of interleukin 12p40 (IL-12p40) and IL-6, albeit at lower levels than in response to LPS or zymosan A. Using an in vitro ovalbumin peptide-restricted priming assay, DC matured with 0-3hRP exhibited a potent capacity to drive Th2 polarization of CD4(+) cells from DO11.10 transgenic mice. This was characterized by increased IL-4 production (but not gamma interferon) of a magnitude similar to that primed by DC matured with zymosan A. Inoculation of DO11.10 mice with 0-3hRP-activated DC pulsed with ovalbumin peptide also led to the development of a Th2-type polarized response in the skin-draining lymph nodes and spleen. However, ligation of CD40 on DC by anti-CD40 antibody treatment reversed the ability of 0-3hRP-activated DC to prime for Th2-type responses and instead caused the induction of a more Th1-type response

On large deviation regimes for random media models

The focus of this article is on the different behavior of large deviations of random subadditive functionals above the mean versus large deviations below the mean in two random media models. We consider the point-to-point first passage percolation time $a_n$ on $\mathbb{Z}^d$ and a last passage percolation time $Z_n$. For these functionals, we have $\lim_{n\to\infty}\frac{a_n}{n}=\nu$ and $\lim_{n\to\infty}\frac{Z_n}{n}=\mu$. Typically, the large deviations for such functionals exhibits a strong asymmetry, large deviations above the limiting value are radically different from large deviations below this quantity. We develop robust techniques to quantify and explain the differences.Comment: Published in at http://dx.doi.org/10.1214/08-AAP535 the Annals of Applied Probability (http://www.imstat.org/aap/) by the Institute of Mathematical Statistics (http://www.imstat.org

Interleukin-12 p40 secretion by cutaneous CD11c(+) and F4/80(+) cells is a major feature of the innate immune response in mice that develop Th1-mediated protective immunity to Schistosoma mansoni

Radiation-attenuated (RA) schistosome larvae are potent stimulators of innate immune responses at the skin site of exposure (pinna) that are likely to be important factors in the development of Th1-mediated protective immunity. In addition to causing an influx of neutrophils, macrophages, and dendritic cells (DCs) into the dermis, RA larvae induced a cascade of chemokine and cytokine secretion following in vitro culture of pinna biopsy samples. While macrophage inflammatory protein 1alpha and interleukin-1beta (IL-1beta) were produced transiently within the first few days, the Th1-promoting cytokines IL-12 and IL-18 were secreted at high levels until at least day 14. Assay of C3H/HeJ mice confirmed that IL-12 secretion was not due to lipopolysaccharide contaminants binding Toll-like receptor 4. Significantly, IL-12 p40 secretion was sustained in pinnae from vaccinated mice but not in those from nonprotected infected mice. In contrast, IL-10 was produced from both vaccinated and infected mice. This cytokine regulates IL-12-associated dermal inflammation, since in vaccinated IL-10(-/-) mice, pinna thickness was greatly increased concurrent with elevated levels of IL-12 p40. A significant number of IL-12 p40(+) cells were detected as emigrants from in vitro-cultured pinnae, and most were within a population of rare large granular cells that were Ia(+), consistent with their being antigen-presenting cells. Labeling of IL-12(+) cells for CD11c, CD205, CD8alpha, CD11b, and F4/80 indicated that the majority were myeloid DCs, although a proportion were CD11c(-) F4/80(+), suggesting that macrophages were an additional source of IL-12 in the skin

Inhibition of MDR1 does not sensitize primitive chronic myeloid leukemia CD34⁺ cells to imatinib

<p><b>Objective:</b> To investigate the interaction of imatinib mesylate (IM) with the clinically relevant adenosine triphosphate-binding cassette efflux transporter MDR1 (ABCB1) in cells from patients with chronic myeloid leukemia (CML) and to explore whether inhibition of this transporter would improve IM's efficacy in the elimination of CML CD34<sup>+</sup> cells by increasing cell-associated drug accumulation.</p> <p><b>Materials and Methods:</b> Cells from newly diagnosed chronic-phase CML patients were harvested by leukapheresis and enriched to >95% CD34<sup>+</sup>. Expression of the transporter gene MDR1 was performed by quantitative reverse transcription polymerase chain reaction. Interaction of IM with MDR1 was analyzed by substrate (rhodamine 123) displacement assay. Cell-associated levels of IM in CML CD34<sup>+</sup> cells were measured by high-pressure liquid chromatography. Intracellular phospho-CrkL levels, apoptosis in total CML CD34<sup>+</sup> cells and high-resolution tracking of cell division were assayed by flow cytometry.</p> <p><b>Results:</b> Measurements of cell-associated IM uptake showed significantly lower drug levels in CD34<sup>+</sup> cells, particularly the CD38<sup>-</sup> subpopulation, as compared to IM-sensitive K562 cells. MDR1 was expressed at low level and dye efflux studies demonstrated very little MDR1 activity in CML CD34<sup>+</sup> cells. Furthermore, combination treatment of primitive CML cells with IM and the MDR1 inhibitor PSC833 did not result in elevated cell-associated IM levels. Although we observed slightly enhanced cytostasis with IM when combined with PSC833, this was independent of BCR-ABL inhibition because no associated decrease in phospho-CrkL was observed.</p> <p><b>Conclusions:</b> Our findings demonstrate that inhibition of MDR1 neither enhances the effect of IM against BCR-ABL activity, nor significantly potentiates IM's efficiency in eliminating primitive CML cells.</p&gt

Contact process under renewals I

Motivated by questions regarding long range percolation, we investigate a non-Markovian analogue of the Harris contact process in $\mathbb{Z}^d$: an individual is attached to each site $x \in \mathbb{Z}^d$, and it can be infected or healthy; the infection propagates to healthy neighbors just as in the usual contact process, according to independent exponential times with a fixed rate $\lambda$; nevertheless, the possible recovery times for an individual are given by the points of a renewal process with heavy tail; the renewal processes are assumed to be independent for different sites. We show that the resulting processes have a critical value equal to zero.Comment: 13 page