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P Musiani

Publications and source records attributed to P Musiani.

151 records · Page 9Linked to original sources
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The expression of LEC/CCL16, a powerful inflammatory chemokine, is upregulated in ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory disease of unknown aetiology and pathogenesis. The presence in the colonic mucosa of reactive cells expressing proinflammatory cytokines and chemokines is associated with high levels of IL-10, an anti-inflammatory cytokine. Our aim was to investigate the role of IL-10 and the beta chemokine LEC/CCL16 selectively up-regulated by IL-10 in inflammatory cell recruitment and cytokine and chemokine production during UC. We studied histologically, immunohistochemically and ultrastructurally colonic biopsies from 20 active UC patients and 10 control specimens taken far from any macroscopically detectable lesion in age and sex-matched patients with noninflammatory bowel disease. In active UC, immature dendritic cells (DCs) in the LP are associated with IL-10 in the T cell rich area. Furthermore, most of the LP-infiltrating macrophages strongly expressed LEC/CCL16, a chemokine upregulated by IL-10. To evaluate if LEC/CCL16 plays a role in the inflammatory reaction present in UC, we performed morphological studies in mice injected s.c. with syngeneic tumor cells engineered to produce LEC/CCL16. We found that the LEC protein locally released by LEC-gene-transfected tumor cells is a potent proinflammatory chemokine that induces the recruitment of a reactive infiltrate, and an angiogenic process mirroring that in human UC.

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A limited autoimmunity to p185neu elicited by DNA and allogeneic cell vaccine hampers the progression of preneoplastic lesions in HER-2/NEU transgenic mice.

Prevention of the progression of precancerous lesions by vaccines is virtually uncharted territory. Their potential, however, is being assessed in transgenic mice which develop autochthonous tumors with defined stages of progression. In this paper we show that the DNA micro-array technology significantly helps assessment of the preventive efficacy of a combined DNA and cell vaccine. All female rat Her-2/neu transgenic BALB/c (BALB-neuT) mice develop an invasive carcinoma in each of their mammary glands within 25 weeks of age. This is elicited by the activated transforming rat Her-2/neu oncogene embedded in their genome. We have previously shown that vaccination of mice bearing multiple in situ carcinomas with DNA plasmids which code for the extracellular and transmembrane domain of rat p185neu, the product of the rat Her-2/neu oncogene, followed by a boost with rat p185neu+ allogeneic cells engineered to secrete interferon-gamma, keeps 48% of mice tumor free until week 32. We have now extended our follow-up until mice reach one year of age and show that protection vanishes as time progresses. This observation suggests that the accuracy of the results studying immunotherapy against life-threatening tumors is a function of the length of the follow-up. The application of microarrays, and the concordance of morphologic and gene expression data led us to identify antibody as the main mechanism induced by vaccination. Protection is associated with a break of tolerance and a limited autoimmunity against the endogenous mouse p185neu.

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Xenotransplantation rejection is antibody-mediated in both sensitized and nonsensitized recipients.

This study analyzes the mechanisms involved in xenotransplantation rejection between closely related species. Hamster hearts were transplanted heterotopically into both normal rats and rats previously sensitized by the transfusion of donor blood. Sequential ultrastructural and immunohistochemical analyses were performed on the grafts, spleens, and sera. The data obtained support the view that induced antibodies directed against the xenograft endothelium play a very important role in producing graft damage. Moreover, the demonstration of antibodies against myocyte determinants suggests that it is possible, in this particular model, that the antiendothelial antibodies are not the only ones involved in the injury process.

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Prevention by delay: nonspecific immunity elicited by IL-12 hinders Her-2/neu mammary carcinogenesis in transgenic mice.

As a natural consequence of the expression of the activated transforming rat Her-2/neu oncogene all mammary glands of female transgenic BALB/c (BALB-neuT) mice develop atypical epithelial hyperplasia which progresses to invasive carcinoma. A lobular carcinoma is palpable in all mammary glands of 33-week-old BALB-neuT mice. This progression is markedly delayed by systemic administration of IL-12. In a series of studies the best administration schedule, the lowest dose and the most effective administration time have been defined. The cellular and molecular mechanisms resulting in the delay of carcinogenesis have been established. By means of a series of downstream mediators IL-12 inhibits the angiogenic burst that goes along with the passage from preneoplastic to neoplastic and invasive lesions; it also recruits lymphoid cells in the mammary pad and activates their cytotoxicity towards neoplastic cells and newly formed vessels; and furthermore, it induces lymphoid cells to trigger antiangiogenic activities in neoplastic epithelial cells. Effective, low-dose and non-toxic IL-12 treatments may thus be envisaged as a possible option in the management of preneoplastic mammary lesions and in mammary cancer prevention.

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Nature and potential of the reactive response to mouse mammary adenocarcinoma cells engineered with interleukin-2, interleukin-4 or interferon-gamma genes.

A spontaneous mammary adenocarcinoma of BALB/c mice was transduced with the murine interleukin (IL)-2, IL-4, and interferon (IFN)-gamma genes. The ability of clones releasing IL-2, IL-4 or IFN-gamma to form tumors after s.c. challenge was compared to the TS/A parental cells (TS/A-pc) and to cells transduced with the neomycin resistance gene alone. Cytokine-gene-transduced clones activated a strong inflammatory reaction. The elicited by IL-2 and IL-4-gene-transduced cells efficiently led to tumor rejection. This reaction depended on the activation of several cell mechanisms, those classed as nonspecific being predominant. The repertoire of reactive leukocytes recruited in the reaction varies as a function of the secreted cytokine. The growth of a secondary contralateral TS/A-pc challenge after clone rejection was significantly impaired.

Adenocarcinoma↗
PubMedDate not supplied

Characterization and tumorigenicity of human neuroblastoma cells transfected with the IL-2 gene.

Immunization of cancer patients with cytokine-engineered tumor cells is being currently tested in several trials. To test the feasibility of this approach in neuroblastoma (NB) patients we investigated the functional consequences of interleukin-2 (IL-2) gene transfer into NB cell lines. Two human NB cell lines were transfected with the plasmid expression vector RSV.5neo containing the human IL-2 cDNA, and their tumorigenicity was evaluated in a nude mice xenograft model after characterization of the growth patterns and phenotypic features in vitro. The combination of IL-2 gene transfection and the xenograft model in nude mice was chosen on the basis of the low or absent expression of HLA class I antigen in human NB tumors. Our aim was to evaluate the effectiveness of an immunization protocol that could elicit a nonspecific antitumor response. The IL-2 stable transfectants were morphologically identical to parental or vector-transfected cells but completely lost tumorigenicity and inhibited, through a bystander effect, the growth of parental cells injected simultaneously at the same site. Histologic and immunohistochemical analysis of the nodules showed extensive necrosis with severe endothelial damage. The infiltrating cells were mainly macrophages, while natural killer (NK) cells were scarce. However, depletion of NK cells by anti-CD122 monoclonal antibody indicated that the rejection process required NK cell activity. The relevance of these data for the development of therapeutic approaches using cytokine-engineered NB cell lines is discussed.

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