Highly polarized T h17 cells induce EAE via a T ‐bet independent mechanism

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/101823/1/eji2739-sup-0001-FigureS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/101823/2/eji2739-sup-0001-FigS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/101823/3/eji2739-sup-0002-S1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/101823/4/eji2739-sup-0002-PRC.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/101823/5/eji2739.pd

Immunotherapeutic targeting of membrane Hsp70-expressing tumors using recombinant human granzyme B

Background: We have previously reported that human recombinant granzyme B (grB) mediates apoptosis in membrane heat shock protein 70 (Hsp70)-positive tumor cells in a perforin-independent manner

Der Einfluß eines fötal exprimierten Autoantigens auf die Induktion von Autoimmunität während der Schwangerschaft

Ein Fötus exprimiert während der Schwangerschaft paternale Antigene, die für die Mutter fremd sind. Es wurde gezeigt, daß der Fötus eine spezifische, systemische Toleranz in der Mutter gegenüber diesen paternalen Antigenen induziert. Während der Schwangerschaft kommt es häufig zu Remissionen bestimmter Autoimmunkrankheiten. Es wurde die Hypothese aufgestellt, daß die Expression von Autoantigenen durch den Fötus zu den beobachteten Remissionen beiträgt. Um diese Hypothese zu prüfen, sollte ein neues transgenes Mausmodell entwickelt werden. Als Autoimmunkrankheit wurde EAE (Experimentelle Autoimmune Enzephalomyelitis) als Tiermodell für Multiple Sklerose ausgewählt. Es wurden transgene Mäuse entwickelt, die das Autoantigen Myelin Basic Protein 1-10, kovalent gebunden an MHC Klasse II exprimieren. Die Transgene, unter der Kontrolle eines MHC Klasse II Promotors, wurden sowohl von fötalen Zellen, als auch im adulten Tier MHC Klasse II-spezifisch exprimiert. Die Expression der Transgene führte zur Toleranz gegenüber dem Autoantigen in vitro und je nach Mauslinie wurden sowohl Tiere mit einem normalen T-Zellrepertoire, als auch Tiere, die einen transgenen T-Zell Rezeptor exprimieren, weitgehend tolerant gegen die Induktion von EAE. Um zu testen, ob die fötale Expression der Transgene einen Einfluß auf die Induktion von EAE in der Schwangerschaft hat, wurden transgene Männchen mit B10.PL- oder TCR.Tg4-Weibchen verpaart, und in den schwangeren Weibchen EAE induziert. Die Schwangerschaft selbst mit nichttransgenen Föten führte zu einer Verzögerung des EAE-Beginns. EAE brach erst nach der Geburt oder dem Abort aus. Obwohl die Transgene in Plazenta und im Fötus exprimiert wurden, konnte in Verpaarungen mit Männchen der transgenen Linien kein Einfluß auf den Verlauf der Autoimmunkrankheit festgestellt werden

TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>Experimental autoimmune encephalomyelitis (EAE) depends on the initial activation of CD4⁺ T cells responsive to myelin autoantigens. The key antigen presenting cell (APC) population that drives the activation of naïve T cells most efficiently is the dendritic cell (DC). As such, we should be able to trigger EAE by transfer of DC that can present the relevant autoantigen(s). Despite some sporadic reports, however, models of DC-driven EAE have not been widely adopted. We sought to test the feasibility of this approach and whether activation of the DC by toll-like receptor (TLR)-4 ligation was a sufficient stimulus to drive EAE.</p> <p>Findings</p> <p>Host mice were seeded with myelin basic protein (MBP)-reactive CD4+ T cells and then were injected with DC that could present the relevant MBP peptide which had been exposed to lipopolysaccharide as a TLR-4 agonist. We found that this approach induced robust clinical signs of EAE.</p> <p>Conclusions</p> <p>DC are sufficient as APC to effectively drive the differentiation of naïve myelin-responsive T cells into autoaggressive effector T cells. TLR-4-stimulation can activate the DC sufficiently to deliver the signals required to drive the pathogenic function of the T cell. These models will allow the dissection of the molecular requirements of the initial DC-T cell interaction in the lymphoid organs that ultimately leads to autoimmune pathology in the central nervous system.</p

Autoimmunity and COPD: clinical implications.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Long term cigarette smoking is the cause of more than 90% of COPD in Westernized countries. However, only a fraction of chronic heavy smokers develop symptomatic COPD by the age of 80 years. COPD is characterized by an abnormal immune response in the lower airways and its progression is associated with infiltration of the lung by innate and adaptive inflammatory immune cells that form lymphoid follicles. There is growing evidence that both cellular- and antibody-mediated autoimmunity has a fundamental role in the pathogenesis of stable COPD. In particular, carbonyl-modified proteins may help to drive autoimmunity in COPD and to cause the characteristic small airways abnormalities and even contribute to the pathogenesis of pulmonary emphysema. Although direct, indirect, and circumstantial evidence of a role for autoimmunity in stable COPD patients has been identified, no cause-and-effect relationship between autoimmunity and the mechanisms of COPD has been firmly established in man. As such the potential contribution of an autoimmune response to the pathogenesis of COPD exacerbation is still being investigated and represents an area of active research. Many drugs targeting autoimmune responses are already available and the results of controlled clinical trials are awaited with great interest. The potential for measuring specific serum autoantibodies as biomarkers to predict clinical phenotypes or progression of stable COPD is promising

TGF-β inhibitor Smad7 regulates dendritic cell-induced autoimmunity

TGF-β is an anti-inflammatory cytokine whose signaling is negatively controlled by Smad7. Previously, we established a role for Smad7 in the generation of autoreactive T cells; however, the function of Smad7 in dendritic cells (DCs) remains elusive. Here, we demonstrate that DC-specific Smad7 deficiency resulted in elevated expression of the transcription factors Batf3 and IRF8, leading to increased frequencies of CD8(+)CD103(+) DCs in the spleen. Furthermore, Smad7-deficient DCs expressed higher levels of indoleamine 2,3-dioxygenase (IDO), an enzyme associated with tolerance induction. Mice devoid of Smad7 specifically in DCs are resistant to the development of experimental autoimmune encephalomyelitis (EAE) as a result of an increase of protective regulatory T cells (Tregs) and reduction of encephalitogenic effector T cells in the central nervous system. In agreement, inhibition of IDO activity or depletion of Tregs restored disease susceptibility. Intriguingly, when Smad7-deficient DCs also lacked the IFN-γ receptor, the mice regained susceptibility to EAE, demonstrating that IFN-γ signaling in DCs mediates their tolerogenic function. Our data indicate that Smad7 expression governs splenic DC subset differentiation and is critical for the promotion of their efficient function in immunity

Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response

This is the publisher's version, also available electronically from http://www.jci.org/articles/view/18704While the initiation of the adaptive and innate immune response is well understood, less is known about cellular mechanisms propagating inflammation. The receptor for advanced glycation end products (RAGE), a transmembrane receptor of the immunoglobulin superfamily, leads to perpetuated cell activation. Using novel animal models with defective or tissue-specific RAGE expression, we show that in these animal models RAGE does not play a role in the adaptive immune response. However, deletion of RAGE provides protection from the lethal effects of septic shock caused by cecal ligation and puncture. Such protection is reversed by reconstitution of RAGE in endothelial and hematopoietic cells. These results indicate that the innate immune response is controlled by pattern-recognition receptors not only at the initiating steps but also at the phase of perpetuation

A Simple and Sensitive Method for Measuring Tumor-Specific T Cell Cytotoxicity

A simple and sensitive method to quantitatively measure the cytolytic effect of tumor-specific T killer cells is highly desirable for basic and clinical studies. Chromium (51Cr) release assay has been the “gold standard” for quantifying cytolytic activities of cytotoxic T lymphocytes (CTLs) against target cells and this method is still being used in many laboratories. However, a major drawback of this method is the use of radioactive materials, which is inconvenient to handle because of environmental safety concerns and expensive due to the short half-life of the isotope. Consequently, several nonradioactive methods have been reported recently. Here we report a new method that we recently developed for quantifying antigen-specific cytolytic activity of CTLs. This method fully exploits the high sensitivity and the relative simplicity of luciferase quantitative assay. We initially expected the released luciferase in the supernatant to be the adequate source for monitoring cell death. However, to our total surprise, incubation of these killer T cells with the tumor cell targets did not result in significant release of luciferase in the culture medium. Instead, we found that the remaining luciferase inside the cells could accurately reflect the overall cell viability