Global Inhibition of DC Priming Capacity in the Spleen of Self-Antigen Vaccinated Mice Requires IL-10

DC in the spleen are highly activated following intravenous vaccination with a foreign antigen, promoting expansion of effector T cells, but remain phenotypically and functionally immature after vaccination with a self-antigen. Up-regulation or suppression of expression of a cohort of pancreatic enzymes 24-72 hours post-vaccination can be used as a biomarker of stimulatory versus toleragenic DC, respectively. Here we show, using MUC1 transgenic mice (MUC1.Tg) and a vaccine based on the MUC1 peptide which these mice perceive as a self-antigen, that the difference in enzyme expression that predicts whether DC will promote immune response or immune tolerance, is seen as early as 4-8 hours following vaccination. We also identify early production of IL-10 as a predominant factor that both correlates with this early time point and controls DC function. Pre-treating mice with an antibody against the IL-10 receptor (IL-10R) prior to vaccination results in DC that up-regulate CD40, CD80, and CD86 and promote stronger IFNγ+ T cell responses. This study suggests that transient inhibition of IL-10 prior to vaccination could improve responses to cancer vaccines that utilize self-tumor antigens

Regulation by IL-10 of innate immune responses to MUC1 as a self-antigen in MUC1 transgenic mice

Immune responses against a peptide derived from the MUC1 extracellular domain are inhibited in mice which transgenically express the human tumor antigen MUC1 (MUC1.Tg mice). One of the hallmarks of this tolerance is an inability to generate robust CD4 T cell responses. However, this tolerance is not due to a lack of MUC1 specific effector T cells in these animals, as it is evident even after naïve MUC1 specific CD4 T cells have been adoptively transferred in prior to vaccination. Here we show that immediately following intravenous MUC1 vaccination in MUC1.Tg mice, splenic dendritic cell (DC) activation is suppressed. This is measureable both by reduced levels, compared to DC from vaccinated WT mice, of MHC Class II, CD40, and CD86 on the surface of these DC, as well as by the level of a new marker of DC activation: expression of traditional pancreatic enzymes. These enzymes, exemplified by trypsin 1 and carboxypeptidase B1, are up-regulated in splenic DC following MUC1 vaccination in WT, but not MUC1.Tg mice. Their suppression in MUC1.Tg mice requires the activity of both regulatory T cells and IL-10. IL-10’s role in this system appears to be antigen specific as it is produced in the spleens of MUC1 vaccinated MUC1.Tg mice at higher levels than in the spleens of similarly treated WT animals. Furthermore, removal of IL-10 signaling from the system by pretreating animals with an antibody against the IL-10 receptor prior to MUC1 vaccination increases the MUC1 specific CD4 T cell response in MUC1.Tg, but not WT mice. The cellular source of this IL-10 was identified by flow cytometry as being natural killer (NK) cells. In addition to producing IL-10, NK cells from the spleens of MUC1.Tg mice post MUC1 vaccination are more cytotoxic and poorer at maturing DC in co-culture than NK cells from similarly treated WT mice. Depletion of these NK cells improves the quality of the MUC1 specific CD4 response in MUC1.Tg mice. Together, this data identifies a number of previously unidentified early factors which are responsible for the observed inability of MUC1.tg mice to generate robust MUC1 specific CD4 T cell responses

A New Formulation of the Initial Value Problem for Nonlocal Theories

There are a number of reasons to entertain the possibility that locality is violated on microscopic scales, for example through the presence of an infinite series of higher derivatives in the fundamental equations of motion. This type of nonlocality leads to improved UV behaviour, novel cosmological dynamics and is a generic prediction of string theory. On the other hand, fundamentally nonlocal models are fraught with complications, including instabilities and complications in setting up the initial value problem. We study the structure of the initial value problem in an interesting class of nonlocal models. We advocate a novel new formulation wherein the Cauchy surface is "smeared out" over the underlying scale of nonlocality, so that the the usual notion of initial data at t=0 is replaced with an "initial function" defined over -M^{-1} \leq t \leq 0 where M is the underlying scale of nonlocality. Focusing on some specific examples from string theory and cosmology, we show that this mathematical re-formulation has surprising implications for the well-known stability problem. For D-brane decay in a linear dilaton background, we are able to show that the unstable directions in phase space cannot be accessed starting from a physically sensible initial function. Previous examples of unstable solutions in this model therefore correspond to unphysical initial conditions, an observation which is obfuscated in the old formulation of the initial value problem. We also discuss implication of this approach for nonlocal cosmological models.Comment: 36 pages, 9 figures. Accepted for publication in Nuclear Physics

Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.

Tumor-associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited anti-tumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma-associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated downregulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this crosstalk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects

DECISION-MAKING IN THE NEBRASKA UNICAMERAL LEGISLATURE FOR THE 1959, 1961, AND 1963 SESSIONS

Abstract not availabl