CD1-restricted adaptive immune responses to Mycobacteria in human group 1 CD1 transgenic mice

Group 1 CD1 (CD1a, CD1b, and CD1c)–restricted T cells recognize mycobacterial lipid antigens and are found at higher frequencies in Mycobacterium tuberculosis (Mtb)–infected individuals. However, their role and dynamics during infection remain unknown because of the lack of a suitable small animal model. We have generated human group 1 CD1 transgenic (hCD1Tg) mice that express all three human group 1 CD1 isoforms and support the development of group 1 CD1–restricted T cells with diverse T cell receptor usage. Both mycobacterial infection and immunization with Mtb lipids elicit group 1 CD1–restricted Mtb lipid–specific T cell responses in hCD1Tg mice. In contrast to CD1d-restricted NKT cells, which rapidly respond to initial stimulation but exhibit anergy upon reexposure, group 1 CD1–restricted T cells exhibit delayed primary responses and more rapid secondary responses, similar to conventional T cells. Collectively, our data demonstrate that group 1 CD1–restricted T cells participate in adaptive immune responses upon mycobacterial infection and could serve as targets for the development of novel Mtb vaccines

Direct In Vivo Evidence for Tumor Propagation by Glioblastoma Cancer Stem Cells

High-grade gliomas (World Health Organization grade III anaplastic astrocytoma and grade IV glioblastoma multiforme), the most prevalent primary malignant brain tumors, display a cellular hierarchy with self-renewing, tumorigenic cancer stem cells (CSCs) at the apex. While the CSC hypothesis has been an attractive model to describe many aspects of tumor behavior, it remains controversial due to unresolved issues including the use of ex vivo analyses with differential growth conditions. A CSC population has been confirmed in malignant gliomas by preferential tumor formation from cells directly isolated from patient biopsy specimens. However, direct comparison of multiple tumor cell populations with analysis of the resulting phenotypes of each population within a representative tumor environment has not been clearly described. To directly test the relative tumorigenic potential of CSCs and non-stem tumor cells in the same microenvironment, we interrogated matched tumor populations purified from a primary human tumor transplanted into a xenograft mouse model and monitored competitive in vivo tumor growth studies using serial in vivo intravital microscopy. While CSCs were a small minority of the initial transplanted cancer cell population, the CSCs, not the non-stem tumor cells, drove tumor formation and yielded tumors displaying a cellular hierarchy. In the resulting tumors, a fraction of the initial transplanted CSCs maintained expression of stem cell and proliferation markers, which were significantly higher compared to the non-stem tumor cell population and demonstrated that CSCs generated cellular heterogeneity within the tumor. These head-to-head comparisons between matched CSCs and non-stem tumor cells provide the first functional evidence using live imaging that in the same microenvironment, CSCs more than non-stem tumor cells are responsible for tumor propagation, confirming the functional definition of a CSC

High-throughput analysis and functional interpretation of extracellular vesicle content in hematological malignancies

Extracellular vesicles (EVs) are membrane-coated particles secreted by virtually all cell types in response to different stimuli, both in physiological and pathological conditions. Their content generally reflects their biological functions and includes a variety of molecules, such as nucleic acids, proteins and cellular components. The role of EVs as signaling vehicles has been widely demonstrated. In particular, they are actively involved in the pathogenesis of several hematological malignancies (HM), mainly interacting with a number of target cells and inducing functional and epigenetic changes. In this regard, by releasing their cargo, EVs play a pivotal role in the bilateral cross-talk between tumor microenvironment and cancer cells, thus facilitating mechanisms of immune escape and supporting tumor growth and progression. Recent advances in high-throughput technologies have allowed the deep characterization and functional interpretation of EV content. In this review, the current knowledge on the high-throughput technology-based characterization of EV cargo in HM is summarized

Contribution of an Aged Microenvironment to Aging-Associated Myeloproliferative Disease

The molecular and cellular mechanisms of the age-associated increase in the incidence of acute myeloid leukemia (AML) remain poorly understood. Multiple studies support that the bone marrow (BM) microenvironment has an important influence on leukemia progression. Given that the BM niche itself undergoes extensive functional changes during lifetime, we hypothesized that one mechanism for the age-associated increase in leukemia incidence might be that an aged niche promotes leukemia progression. The most frequent genetic alteration in AML is the t(8;21) translocation, resulting in the expression of the AML1-ETO fusion protein. Expression of the fusion protein in hematopoietic cells results in mice in a myeloproliferative disorder. Testing the role of the age of the niche on leukemia progression, we performed both transplantation and in vitro co-culture experiments. Aged animals transplanted with AML1-ETO positive HSCs presented with a significant increase in the frequency of AML-ETO positive early progenitor cells in BM as well as an increased immature myeloid cell load in blood compared to young recipients. These findings suggest that an aged BM microenvironment allows a relative better expansion of pre-leukemic stem and immature myeloid cells and thus imply that the aged microenvironment plays a role in the elevated incidence of age-associated leukemia

Increased Vascular Permeability in the Bone Marrow Microenvironment Contributes to Disease Progression and Drug Response in Acute Myeloid Leukemia

D.P. was supported by a non-clinical research fellowship from EHA. This work was supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001045), The UK Medical Research Council (FC001045), and the Welcome Trust (FC001045)

The role of microenvironment and immunity in drug response in leukemia

Leukemia is a cancer of the white blood cells, with over 54,000 new cases per year diagnosed worldwide and a 5-year survival rate below 60%. This highlights a need for research into the mechanisms behind its etiology and causes of therapy failure. The bone marrow microenvironment, in which adult stem cells are maintained in healthy individuals, has been implicated as a source of chemoresistance and disease relapse. Here the various ways that the microenvironment can contribute to the resistance and persistence of leukemia are discussed. The targeting of the microenvironment by leukemia cells to create an environment more suitable for cancer progression is described. The role of soluble factors, drug transporters, microvesicles, as well as the importance of direct cell–cell contact, in addition to the effects of inflammation and immune surveillance in microenvironment-mediated drug resistance are discussed. An overview of the clinical potential of translating research findings to patients is also provided. Understanding of and further research into the role of the bone marrow microenvironment in leukemia progression and relapse are crucial towards developing more effective treatments and reduction in patient morbidity

This Month in AJP

The following highlights summarize research articles that are published in the current issue of The American Journal of Pathology

L'immaginario medievale hugoliano: ricostruzione delle fonti e motivi d'ispirazione

Il presente lavoro nasce dall'esigenza d'indagare le tecniche di costruzione del mondo medievale hugoliano in "Notre-Dame de Paris". I primi studi hanno rivelato che l'opera viene composta mediante l'uso di uno stile ibrido, necessario ad esprimere la nascita di un'arte romantica innovativa. Il romanzo, infatti, mescola con maestria diversi stili e registri, ma anche diversi generi letterari, in particolare il gotico e lo storico. Dal paragone con il modello scottiano si sono rilevate una serie di differenze che impedirebbero tuttavia all'opera di essere categorizzata nel genere, in particolare in riferimento alla degradazione dei valori borghesi, all'inserimento di elementi di fantasia e allo spostamento dell'asse focale dalla singola figura alla società. Allo stesso tempo si sono rilevati una serie di elementi che, nonostante suggeriscano una vicinanza di "Notre-Dame de Paris" al romanzo nero, non permettono una totale identificazione con esso, specie per l'importanza data al realismo e per la necessità di umanizzare le figure mostruose. Per comprendere meglio come Hugo abbia applicato le tecniche dell'ibridismo all'interno del romanzo si è voluto guardare anche ai personaggi, indagandone le tecniche di costruzione e le funzioni. Da questa analisi si è rilevato che i soggetti hugoliani vengono rappresentati mediante l'accostamento di elementi opposti, e che non di rado costituiscono insieme ad altri soggetti delle coppie binarie fortemente stridenti. Ciascuno di essi, inoltre, è segnato da una serie di fallimenti, ansie e ossessioni che, lungi dal rappresentare i valori della società medievale, si rivelano lo specchio delle angosce del Romanticismo. Ciò avviene tanto in riferimento ai personaggi di sfondo, quanto ai secondari e ai principali, che spesso entrano in conflitto tra loro e risultano dilaniati da complessi esistenziali che talvolta li inducono alla follia e all'esasperazione. Gli spazi e i monumenti si mescolano inevitabilmente ai soggetti, sino a prenderne le sembianze e, talvolta, ad animarsi. La Cattedrale di Notre-Dame è rappresentata come una madre amorevole, con la quale il campanaro pare identificarsi sino a somigliarle, Montfaucon rispecchia l'atmosfera lugubre dei morti che la abitano, il Palazzo di Giustizia fonde bassorilievi e personaggi nella stessa caleidoscopica mescolanza. Tanto il contesto storico-antropologico quanto luoghi e personaggi vengono costruiti mediante un'abile alternanza di dati storici ed elementi di fantasia, che confermano la difficoltà di inserire l'opera nello spettro dei generi letterari. Le fonti vengono così rielaborate ed alterate, talvolta deliberatamente modificate ai fini della narrazione. Gli elementi del soprannaturale vengono filtrati mediante una serie di espedienti, quali il sogno, la superstizione e la visione. Per completare la nostra indagine si è inoltre concesso ampio spazio allo studio delle tematiche esoteriche nel romanzo, stabilendo la presenza di una serie di riferimenti al mondo alchemico e alla filosofia ermetica. Tali studi ci hanno permesso di rilevare la presenza di una serie di allegorie ed elementi simbolici che nel romanzo rinvierebbero al lavoro dell'alchimista e ai suoi plurimi e spesso fallimentari tentativi di completare la Grande Opera. I riferimenti alla storia attuale hanno inoltre permesso di rilevare una serie di messaggi a fini didattico-moraleggianti, che giustificherebbero lo scopo finale dell'opera, ossia quello di comunicare ai suoi lettori la necessità di salvaguardare i monumenti nazionali. E' questo il significato del romanzo-cattedrale, che mediante le illustrazioni prende le simboliche sembianze della facciata gotica, comunicando al lettore-osservatore la necessità dell'utilità dell'arte