Oral tolerance to cancer can be abrogated by T regulatory cell inhibition

Oral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue – JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups - this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut

Lepton Acceleration in Pulsar Wind Nebulae

Pulsar Wind Nebulae (PWNe) act as calorimeters for the relativistic pair winds emanating from within the pulsar light cylinder. Their radiative dissipation in various wavebands is significantly different from that of their pulsar central engines: the broadband spectra of PWNe possess characteristics distinct from those of pulsars, thereby demanding a site of lepton acceleration remote from the pulsar magnetosphere. A principal candidate for this locale is the pulsar wind termination shock, a putatively highly-oblique, ultra-relativistic MHD discontinuity. This paper summarizes key characteristics of relativistic shock acceleration germane to PWNe, using predominantly Monte Carlo simulation techniques that compare well with semi-analytic solutions of the diffusion-convection equation. The array of potential spectral indices for the pair distribution function is explored, defining how these depend critically on the parameters of the turbulent plasma in the shock environs. Injection efficiencies into the acceleration process are also addressed. Informative constraints on the frequency of particle scattering and the level of field turbulence are identified using the multiwavelength observations of selected PWNe. These suggest that the termination shock can be comfortably invoked as a principal injector of energetic leptons into PWNe without resorting to unrealistic properties for the shock layer turbulence or MHD structure.Comment: 19 pages, 5 figures, invited review to appear in Proc. of the inaugural ICREA Workshop on "The High-Energy Emission from Pulsars and their Systems" (2010), eds. N. Rea and D. Torres, (Springer Astrophysics and Space Science series

A comparison of filtration rates among pelagic tunicates using kinematic measurements

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Marine Biology 157 (2010): 755-764, doi:10.1007/s00227-009-1359-y.Salps have higher filtration rates than most other holoplankton, and are capable of packaging and exporting primary production from surface waters. A method of kinematic analysis was employed to accurately measure salp feeding rates. The data were then used to explain how diverse body morphologies and swimming motions among species and lifecycle stages influence salp feeding performance. We selected five species, representing a range of morphologies and swimming styles, and used digitized outlines from video frames to measure body-shape change during a pulse cycle. Time-varying body volume was then calculated from the digitized salp outlines to estimate the amount of fluid passing through the filtering mesh. This non-invasive method produced higher feeding rates than other methods and revealed that body volume, pulse frequency and degree of contraction are important factors for determining volume filtered. Each species possessed a unique combination of these three characteristics that resulted in comparable filtration (range: 0.44 - 15.33 ml s-1) and normalized filtration rates (range: 0.21 – 1.27 s-1) across species. The convergence of different species with diverse morphologies on similar normalized filtration suggests a tendency towards a flow optimum.This work was supported by NSF project OCE-0647723

Repeated Methamphetamine Administration Differentially Alters Fos Expression in Caudate-Putamen Patch and Matrix Compartments and Nucleus Accumbens

Background: The repeated administration of psychostimulant drugs produces a persistent and long-lasting increase (‘‘sensitization’’) in their psychomotor effects, which is thought to be due to changes in the neural circuitry that mediate these behaviors. One index of neuronal activation used to identify brain regions altered by repeated exposure to drugs involves their ability to induce immediate early genes, such as c-fos. Numerous reports have demonstrated that past drug experience alters the ability of drugs to induce c-fos in the striatum, but very few have examined Fos protein expression in the two major compartments in the striatum—the so-called patch/striosome and matrix. Methodology/Principal Findings: In the present study, we used immunohistochemistry to investigate the effects of pretreatment with methamphetamine on the ability of a subsequent methamphetamine challenge to induce Fos protein expression in the patch and matrix compartments of the dorsolateral and dorsomedial caudate-putamen and in the ventral striatum (nucleus accumbens). Animals pretreated with methamphetamine developed robust psychomotor sensitization. A methamphetamine challenge increased the number of Fos-positive cells in all areas of the dorsal and ventral striatum. However, methamphetamine challenge induced Fos expression in more cells in the patch than in the matrix compartment in the dorsolateral and dorsomedial caudate-putamen. Furthermore, past experience with methamphetamine increased the number of methamphetamine-induced Fos positive cells in the patch compartment of the dorsal caudate putamen, but no

Analysis of proliferative activity in oral gingival epithelium in immunosuppressive medication induced gingival overgrowth

BACKGROUND: Drug-induced gingival overgrowth is a frequent adverse effect associated principally with administration of the immunosuppressive drug cyclosporin A and also certain antiepileptic and antihypertensive drugs. It is characterized by a marked increase in the thickness of the epithelial layer and accumulation of excessive amounts of connective tissue. The mechanism by which the drugs cause gingival overgrowth is not yet understood. The purpose of this study was to compare proliferative activity of normal human gingiva and in cyclosporine A-induced gingival overgrowth. METHODS: Gingival samples were collected from 12 generally healthy individuals and 22 Cyclosporin A-medicated renal transplant recipients. Expression of proliferating cell nuclear antigen was evaluated in formalin-fixed, paraffin-embedded gingival samples using an immunoperoxidase technique and a monoclonal antibody for this antigen. RESULTS: There were differences between the Cyclosporin A group and control group in regard to proliferating cell nuclear antigen and epithelial thickness. In addition, the degree of stromal inflammation was higher in the Cyclosporin A group when compared with the control group. CONCLUSION: The results suggest that the increased epithelial thickness observed in Cyclosporin A-induced gingival overgrowth is associated with increased proliferative activity in keratinocytes