PubMed Health⌕ Search

Biomedical subjects

Maria Rescigno

Publications and source records attributed to Maria Rescigno.

16 recordsLinked to original sources
PubMed2026

Intestinal blood vessel-associated macrophages and gut-vascular barrier dysfunction in cirrhosis.

BACKGROUND: Bacterial translocation in cirrhosis can trigger infection and hepatic decompensation, leading to systemic inflammation, organ failure and increased mortality. These infections often originate from the gastrointestinal tract after bacteria breach the intestinal barrier and disseminate to systemic sites. OBJECTIVE: In this study, we explore the mechanisms underlying intestinal barrier dysfunction in cirrhosis using an experimental cirrhosis model and patient-derived intestinal biopsies. DESIGN: We developed a murine model of cirrhosis through chronic administration of carbon tetrachloride for up to 20 weeks. We investigated both the intestinal epithelial and vascular compartments and performed single-cell transcriptomic profiling of myeloid cells isolated from cirrhotic mice and from individuals with compensated and decompensated cirrhosis. RESULTS: Our findings indicate that bacterial translocation in cirrhosis is the result of failure at multiple checkpoints, including aberrant epithelial cell death, vascular barrier damage and dysfunction of gut-vascular macrophages. In a preclinical model of cirrhosis, macrophages exhibited increased levels of monocyte-attracting chemokines, reduced bacterial clearance and impaired interactions with blood vessels. Importantly, depleting vascular-lining macrophages resulted in bacterial translocation to systemic sites, even in the absence of experimental liver disease. Transcriptional profiling of macrophages from duodenal biopsies of patients with cirrhosis indicated similar dysregulation of pathways supporting blood vessels and elevated expression of chemokines. CONCLUSIONS: This study emphasises the critical role of intestinal macrophages in preventing the dissemination of luminal bacteria and highlights the multifaceted breakdown of the intestinal barrier in cirrhosis and the importance of the gut-vascular barrier.

Animals↗
PubMed2005

Accelerated dendritic-cell migration and T-cell priming in SPARC-deficient mice.

On their path to draining lymph nodes, epidermal Langerhans cells traverse collagen-dense connective tissue before reaching lymphatic vessels. The matricellular protein SPARC (secreted protein, acidic and rich in cysteine), which is induced during inflammation and tissue repair, organizes collagen deposition in tissue stroma. We analyzed Langerhans cell and dendritic-cell migration and its impact on T-cell priming in SPARC-null (SPARC(-/-)) and SPARC-sufficient (SPARC(+/+)) mice. Although the same number of Langerhans cells populate the ear skin of SPARC(-/-) and SPARC(+/+) mice, more Langerhans cells were found in the lymph nodes draining antigen-sensitized ears of SPARC(-/-) mice and significantly more Langerhans cells migrated from null-mice-derived ear skin explants. Such favored Langerhans cell migration is due to the host environment, as demonstrated by SPARC(+/+)>SPARC(-/-) and reciprocal chimeras, and have a profound influence on T-cell priming. Contact-, delayed type-hypersensitivity and naive T-cell receptor-transgenic T-cell priming, together indicate that the lack of SPARC in the environment accelerates the onset of T-cell priming by hastening Langerhans cell/dendritic-cell migration.

Animals↗
PubMed2005

Monocyte-derived dendritic cells activated by bacteria or by bacteria-stimulated epithelial cells are functionally different.

Dendritic cells (DCs) are able to open the tight junctions between adjacent epithelial cells (ECs) and to take up both invasive and noninvasive bacteria directly from the intestinal lumen. In this study, we describe a tight cross talk between ECs and human monocyte-derived DCs (MoDCs) in bacterial handling across epithelial monolayers. We show that the release of proinflammatory mediators by ECs in response to bacteria is dependent on bacterial invasiveness and on the presence of flagella. This correlates with the capacity of EC-derived factors to modulate MoDC function. MoDCs incubated with supernatants of bacteria-treated ECs are "noninflammatory" as they release interleukin-10 (IL-10) but not IL-12 and can drive only T helper (Th)-2 type T cells. Moreover, noninflammatory MoDCs release chemokines aimed at recruiting Th2 and T-regulatory cells. In contrast, when MoDCs are incubated with ECs and bacteria in a transwell coculture system, and can contact directly the bacteria across stimulated EC monolayers, they are more inflammatory as they release IL-12 and IL-10 and induce both Th1 and Th2 responses. These results suggest that ECs are not simply a barrier to bacteria entering via the oral route, but they actively influence the activating properties of DCs.

Animals↗
PubMed2005

Cancer immunotherapy based on killing of Salmonella-infected tumor cells.

A major obstacle for the development of effective immunotherapy is the ability of tumors to escape the immune system. The possibility to kill tumor cells because they are recognized as infected rather than as malignant could help overcome immune escape mechanisms. Here we report a conceptually new approach of cancer immunotherapy based on in vivo infection of tumors and killing of infected tumor cells. Attenuated but still invasive, Salmonella typhimurium can be successfully exploited to invade melanoma cells that can present antigenic determinants of bacterial origin and become targets for anti-Salmonella-specific T cells. However, to fully appreciate the anticancer therapeutic properties of S. typhimurium, tumor-bearing mice need to be vaccinated against S. typhimurium before intratumoral Salmonella injection. Tumor infection when coupled to anti-Salmonella vaccination leads to 50% to 100% tumor-free mice with a better outcome on larger tumors. Invasive Salmonella also exert an indirect toxic effect on tumor cells through the recruitment of inflammatory cells and the cross-presentation of tumor antigens, which allow induction of tumor-specific immune response. This is effective in retarding the growth of untreated established distant tumors and in protecting the mice from subsequent tumor challenges.

Animals↗
PubMed2005

Intestinal immune homeostasis is regulated by the crosstalk between epithelial cells and dendritic cells.

The control of damaging inflammation by the mucosal immune system in response to commensal and harmful ingested bacteria is unknown. Here we show epithelial cells conditioned mucosal dendritic cells through the constitutive release of thymic stromal lymphopoietin and other mediators, resulting in the induction of 'noninflammatory' dendritic cells. Epithelial cell-conditioned dendritic cells released interleukins 10 and 6 but not interleukin 12, and they promoted the polarization of T cells toward a 'classical' noninflammatory T helper type 2 response, even after exposure to a T helper type 1-inducing pathogen. This control of immune responses seemed to be lost in patients with Crohn disease. Thus, the intimate interplay between intestinal epithelial cells and dendritic cells may help to maintain gut immune homeostasis.

Cell Differentiation↗
PubMed2005

Uptake and presentation of orally administered antigens.

The mucosae of the gastrointestinal tract are continuously exposed to a myriad of antigens and microorganisms that the immune system has to discriminate between dangerous and harmless. Entry of pathogenic microorganisms occurs mainly via M cells that are concentrated in the follicle-associated epithelium overlying the Peyer's Patches (PPs). M cells are very selective and do not allow entry of all microorganisms. We have recently described an additional mechanism by which dendritic cells (DCs) can monitor the contents of the intestinal lumen. DCs send dendrites outside the epithelium, like periscopes. It is not clear whether this mechanism is constitutively active or is induced in response to signals from epithelial cells that have been in contact with pathogens or high numbers of non pathogenic bacteria in the lumen. Therefore, deciphering the signals that are released by epithelial cells after the encounter with mucosal antigens is of paramount importance to understand the ability of the DCs to respond to the different antigens and to mount immune or tolerogenic responses.

Administration, Oral↗
PubMed2004

What is new in melanoma research? Vaccines, Basic and Translational Research in 2003: report of a workshop at the Third Research Meeting on Melanoma, Milan, Italy, May 2003.

During the session on Vaccines, Basic and Translational Research at the Third Research Meeting on Melanoma, Milan, Italy, held in May 2003, many questions regarding the development of new immunotherapeutical strategies for the treatment of melanoma and more basic research on tumorigenesis, as well as new prognostic markers for disease progression, were addressed. This report briefly summarizes some of the highlights and themes of this session.

Biomarkers, Tumor↗
PubMed2004

Intestinal epithelial cells control dendritic cell function.

Dendritic cells (DCs) comprise a family of cells specializing in antigen capture and presentation to T cells. We have recently shown that DC play an active role in bacterial uptake across mucosal surfaces. Indeed, DC are able to open tight junctions and to sample antigens directly across epithelia, both in vitro and in vivo. Because DC express tight junction proteins, the integrity of the epithelial barrier is preserved. In this study we have analyzed the possible involvement of epithelial cells in controlling DC function. We developed an in vitro model in our laboratory consisting of a three-player system of dendritic cells, epithelial cell monolayers, and bacteria. The crosstalk between epithelial cells and dendritic cells was analyzed, and epithelial cells were tested for their capacity to release cytokines and chemokines that induce the migration and activation of DC. We show that the capacity of epithelial cells to produce cytokines and activate DC is dependent on the invasiveness of the bacteria tested. In particular, invasive bacteria stimulate epithelial cells to release proinflammatory cytokines and to induce the maturation state of DC. By contrast, noninvasive bacteria are unable to stimulate epithelial cells, but can activate DC directly when DC translocate to the apical side. In conclusion, epithelial cells are not simply a barrier to bacteria entering via the oral route, but actively influence the activating properties of bystander DC.

Animals↗
PubMed2003

Lipopolysaccharide or whole bacteria block the conversion of inflammatory monocytes into dendritic cells in vivo.

Monocytes can develop into dendritic cells (DCs) that migrate to lymph nodes (LNs) and present antigens to T cells. However, we find that this differentiation is blocked when monocytes accumulate subcutaneously in response to bacteria or lipopolysaccharide (LPS). The inhibition of DC differentiation is mediated by the bacteria and in conjunction with inflammatory cells recruited at the site of injection. Inhibition of migratory DC development was reversed in Toll-like receptor (TLR)4-mutated mice when LPS, but not whole bacteria, was injected, suggesting that TLR4 is one but not the only mediator of the inhibition. The block imposed by bacteria was partly relieved by the absence of interleukin (IL)-12 p40, but not by individual absence of several cytokines involved in DC differentiation or in inflammation, i.e., IL-6, IL-10, IL-12 p35, and interferon gamma. Consistent with the inability of monocytes to yield migrating DCs, and the finding that other DCs had limited access to particulate or bacterial antigens, these antigens were weakly presented to T cells in the draining LN. These results illustrate that bacteria-associated signals can have a negative regulatory role on adaptive immunity and that local innate responses for containment of infectious bacteria can at least initially supersede development of adaptive responses.

Animals↗
PubMed2002

Toll-like receptor 4 is not required for the full maturation of dendritic cells or for the degradation of Gram-negative bacteria.

Toll-like receptor 4 (TLR4) has been recently associated with cellular responses to lipopolysaccharide (LPS), and mice mutated in tlr4, such as C57BL/10ScCr or C3H/HeJ mice, become hyporesponsive to LPS. In this study, we have analyzed the capacity of bone marrow-derived dendritic cells (BMDC) from C57BL/10ScCr (ScCr-BMDC) or C3H/HeJ (HeJ-BMDC) mice to respond to LPS or to Gram-negative bacteria. We show that ScCr- or HeJ-BMDC are insensitive to LPS, but can mature in response to live and killed Gram-negative bacteria. Interestingly, only ScCr-BMDC but not HeJ-BMDC, stimulated with bacteria, have reduced capacity to produce pro- and anti-inflammatory cytokines as compared to BMDC from control mice, probably due to genetic defects unrelated to the tlr4 mutation. Nevertheless, ScCr-BMDC and ScCr BM-macrophages (BM-Mphi) phagocytose Salmonella typhimurium similarly to control cells, indicating that TLR4 is not compulsory for bacterial uptake. Moreover, BM-Mphi, but not BM-DC from B10ScCr or C3H/HeJ mice, are impaired in their capacity to kill intracellular bacteria and to produce NO as compared to wild type controls. However, the bacteria killing property of BM-Mphi is completely restored by pretreating the cells with IFN-gamma. Hence, TLR4 plays different roles in DC versus Mphi.

Animals↗
PubMed2002

In vivo receptor-mediated delivery of a recombinant invasive bacterial toxoid to CD11c + CD8 alpha -CD11bhigh dendritic cells.

The precise contribution of mouse dendritic cells (DC) CD8 alpha +CD11blow and CD8 alpha -CD11bhigh subsets to CTL priming is not fully defined. Here we show that CyaA, the adenylate cyclase toxin of Bordetella pertussis, an invasive bacterial toxin that binds cells through CD11b/CD18 can be exploited for the targeted delivery of an exogenous peptide to the CD8 alpha -CD11bhigh subset in vivo. Antigen (Ag) genetically inserted in the N-terminal domain of mutant CyaA devoid of catalytic activity, are targeted to CD8 alpha -CD11bhigh DC by the CD11b/CD18-dependent binding of CyaA to the cell surface. Ag is then presented by MHC class I molecules of CD8 alpha -CD11bhigh DC after a TAP-dependent, cytosolic processing. As a result, CTL are primed after a single injection, bypassing requirement for adjuvant, CD4+ T cell help and CD40 signaling. Beside the interest of the CyaA vector for vaccine development, these results show that Ag presentation focused on CD8 alpha -CD11bhigh DC in vivo is sufficient for eliciting a vigorous CTL response and that CD11b/CD18 could be a suitable surface molecule for targeting Ag to DC.

Adenylate Cyclase Toxin↗
PubMed2002

Dendritic cells and the complexity of microbial infection.

Dendritic cells (DCs) can discriminate between different classes of microorganisms, present antigens to T cells and initiate innate and adaptive immune responses. DCs do not act individually, and their function can be fine-tuned by environmental and tissue factors as well as by the microorganisms themselves. Recent studies have reported DCs can integrate stimuli derived from microbial pathogens and other cells present at, or recruited to, the site of infection. These interactions can determine the success or failure of the immune response induced against pathogens.

Animals↗
PubMed2002

Novel Tn antigen-containing neoglycopeptides: synthesis and evaluation as anti tumor vaccines.

The fully unprotected alpha-C-glycosyl analogue of N-acetylgalactosamine 9 was conjugated by a non-natural oxime bond to the segment peptides (328--340)OVA and (327--339)OVA, affording neoglycopeptides 1--2 and 3, having one or two sugar units, respectively. The three neoglycopeptides were tested in vitro in an antigen presentation assay as antitumor vaccines. Neoglycopeptides 1--3 could be presented to and recognized by the T cell receptor; neoglycopeptide 3, bearing two B-epitopes, was presented to the TCR with higher efficiency, compared to neoglycopeptide 2, having only one B-epitope.

Animals↗