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Biomedical subjects

Francisco Leon

Publications and source records attributed to Francisco Leon.

9 recordsLinked to original sources
PubMed2006

Antibodies to complement receptor 3 treat established inflammation in murine models of colitis and a novel model of psoriasiform dermatitis.

Prior studies indicated the ability of Abs to complement receptor 3 (CR3, CD11b/CD18) to suppress the production of IL-12 from immune cells. Therefore, we tested the ability of an anti-CR3 Ab (clone M1/70) to treat established IL-12-dependent Th1-mediated inflammation in murine models. Systemic administration of anti-CR3 significantly ameliorated established intestinal inflammation following the intrarectal administration of trinitrobenzene sulfonic acid (TNBS-colitis), as well as colitis and skin inflammation in C57BL/10 RAG-2(-/-) mice reconstituted with CD4+CD45RBhigh T cells. The hyperproliferative skin inflammation in this novel murine model demonstrated many characteristics of human psoriasis, and was prevented by the adoptive transfer of CD45RBlow T cells. In vitro and in vivo studies suggest that anti-CR3 treatment may act, at least in part, by directly inhibiting IL-12 production by APCs. Administration of anti-CR3 may be a useful therapeutic approach to consider for the treatment of inflammatory bowel disease and psoriasis in humans.

Adoptive Transfer↗
PubMed2006

Involvement of dendritic cells in the pathogenesis of inflammatory bowel disease.

In conclusion, during inflammation, DCs are likely activated by inflammatory signals and induced to migrate to T cell zones of organized lymphoid tissues where the cells induce T cell responses. In addition to their established role in T cell priming and the induction of tolerance, DCs may act to enhance (or possibly suppress) T cell responses at sites of mucosal inflammation. Determining the importance of DCs in this regard, as well as establishing a potential role for DCs in continuous activation of naive or central memory cells in lymph nodes draining inflammatory sites, will elucidate the role of DCs as a potential therapeutic target for chronic inflammatory diseases, like IBD. Resident intestinal macrophages are noninflammatory and do not efficiently present antigens to intestinal T cells, yet are avidly phagocytic and able to kill internalized organisms. During intestinal inflammation, monocytes are recruited from the blood, become inflammatory macrophages in the inflamed tissue, and are major contributors to tissue destruction and perpetuation of inflammation via their production of chemokines and pro-inflammatory cytokines. Macrophages may also contribute directly to DC activation and maturation, which would drive DCs to present antigens from the bacterial flora to T cells locally within tissue or to more efficiently traffic to T cell zones of lymphoid tissue. Thus, DCs and macrophages have evolved functional niches that promote cooperation in the prevention of untoward intestinal inflammation in the steady state and in the eradication of invasive microorganisms during infection. The balance between suppressing inflammation and promoting host defense is altered in humans with IBD allowing a persistent inflammatory response to commensal bacteria. Based on studies from animal models, the pathogenesis of IBD likely involves either the lack of appropriate regulation from T cells, or an over-production of effector T cells. The end result of these potential mechanisms is the abnormal induction and/or survival of effector T cells and the production of factors such as cytokines by inflammatory macrophages and neutrophils that result in tissue destruction. The destructive process likely involves normally tolerizing DCs, which in the microenvironment of the inflamed mucosa activate T cell responses to normal flora in both draining lymphoid tissues and at sites of inflammation, with macrophages and neutrophils contributing the bulk of inflammatory and destructive cytokines.

Animals↗
PubMed2005

Involvement of intestinal dendritic cells in oral tolerance, immunity to pathogens, and inflammatory bowel disease.

Dendritic cells (DCs) are composed of a family of cells, now recognized to be essential for innate and acquired immunity. DCs at mucosal surfaces have a particular capacity to induce the differentiation of regulatory T cells producing interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) in the steady state (non-infected, non-immunized), yet they retain the capacity to induce effector T cells in response to invasive pathogens. This decision between the induction of active immunity and tolerance will depend on the subpopulation of DC involved and the surface receptors engaged during DC activation and T-cell priming. The local microenvironment will likely play an important role both in defining the DC phenotype and in providing direct signals to responding T cells. Furthermore, DCs in organized mucosal lymphoid tissues preferentially induce the expression of CCR9 and alpha4beta7 on T cells, which results in T-cell homing to the intestinal lamina propria. Finally, DCs may play an important role in the maintenance of abnormal intestinal inflammation either by driving pathogenic T-cell responses in mesenteric lymph nodes or by acting to expand or maintain pathogenic T cells locally at sites of inflammation. In this review, a brief discussion of general issues of DC biology that are pertinent to mucosal immunity is followed by a more in-depth discussion of the phenotype and function of DC populations in the intestine.

Animals↗
PubMed2005

Men with hip fractures have poorer nutritional status and survival than women: a prospective study of 165 patients.

BACKGROUND: Many hip fracture patients have a poor nutritional status which may be one explanation for their increased mortality. PATIENTS AND METHODS: We studied nutritional status and other mortality-related factors prospectively in 165 patients with hip fractures (85 women). We concentrated on differences between death rates and survival rates at 3 months and at 1 year, and between those patients who died within 3 months and those who died later. RESULTS: In general, men had a poorer nutritional status and a larger number of comorbidities. Also, there were more smokers and alcohol abusers amongst the men. Of the patients who died during the first 3 months, most were men, and their initial nutritional status was poorer than that of women. Multivariate logistic regression analysis revealed a correlation between mortality and total serum protein, retinol binding protein and the number of comorbidities. Among patients who died after 3 months, mortality was associated with the number of comorbidities and smoking. INTERPRETATION: The higher mortality rate in men than in women after hip fracture may in part be explained by the poor nutritional status in men.

Aged↗
PubMed2004

Peyer's patch dendritic cells process viral antigen from apoptotic epithelial cells in the intestine of reovirus-infected mice.

We explored the role of Peyer's patch (PP) dendritic cell (DC) populations in the induction of immune responses to reovirus strain type 1 Lang (T1L). Immunofluorescence staining revealed the presence of T1L structural (sigma1) and nonstructural (sigmaNS) proteins in PPs of T1L-infected mice. Cells in the follicle-associated epithelium contained both sigma1 and sigmaNS, indicating productive viral replication. In contrast, sigma1, but not sigmaNS, was detected in the subepithelial dome (SED) in association with CD11c(+)/CD8alpha(-)/CD11b(lo) DCs, suggesting antigen uptake by these DCs in the absence of infection. Consistent with this possibility, PP DCs purified from infected mice contained sigma1, but not sigmaNS, and PP DCs from uninfected mice could not be productively infected in vitro. Furthermore, sigma1 protein in the SED was associated with fragmented DNA by terminal deoxy-UTP nick-end labeling staining, activated caspase-3, and the epithelial cell protein cytokeratin, suggesting that DCs capture T1L antigen from infected apoptotic epithelial cells. Finally, PP DCs from infected mice activated T1L-primed CD4(+) T cells in vitro. These studies show that CD8alpha(-)/CD11b(lo) DCs in the PP SED process T1L antigen from infected apoptotic epithelial cells for presentation to CD4(+) T cells, and therefore demonstrate the cross-presentation of virally infected cells by DCs in vivo during a natural viral infection.

Animals↗
PubMed2004

Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis.

While Crohn disease (CD) has been clearly identified as a Th1 inflammation, the immunopathogenesis of its counterpart inflammatory bowel disease, ulcerative colitis (UC), remains enigmatic. Here we show that lamina propria T (LPT) cells from UC patients produce significantly greater amounts of IL-13 (and IL-5) than control cells and little IFN-gamma, whereas comparable cells from CD patients produce large amounts of IFN-gamma and small amounts of IL-13. We then show that stimulation of UC LPT cells bearing an NK marker (CD161) with anti-CD2/anti-CD28 or with B cells expressing transfected CD1d induces substantial IL-13 production. While this provided firm evidence that the IL-13-producing cell is an NK T (NKT) cell, it became clear that this cell does not express invariant NKT cell receptors characteristic of most NKT cells since there was no increase in cells binding alpha-galactosylceramide-loaded tetramers, and alpha-galactosylceramide did not induce IL-13 secretion. Finally, we show that both human NKT cell lines as well as UC CD161(+) LPT cells are cytotoxic for HT-29 epithelial cells and that this cytotoxicity is augmented by IL-13. These studies show that UC is associated with an atypical Th2 response mediated by nonclassical NKT cells producing IL-13 and having cytotoxic potential for epithelial cells.

Antigens, CD1↗
PubMed2004

Involvement of dendritic cell subsets in the induction of oral tolerance and immunity.

Dendritic cells (DCs) play a central role in the generation of immune responses in the intestine. DCs induce differentiation and tolerance of T cells, and may have a direct role in B cell switching to IgA. Four distinct subsets of CD11c(+) DCs are present in murine Peyer's patches, which represent primary sites for the induction of mucosal T and B cell responses. Studies suggest that CD11b(+) DCs or plasmacytoid DCs may be specialized for the induction of regulatory T cells, and CD8alpha(+) DCs for the induction of clonal deletion in response to soluble oral antigen, while all DC subsets (including CD8alpha(-)/CD11b(-) DCs) may be involved in responses to pathogens. We are currently using reovirus type-1 Lang (TIL) to explore the role of DC populations in mucosal immunity in vivo, as oral administration of live T1L to mice induces strong mucosal and systemic antiviral immune responses, whereas oral administration of inactivated T1L results in tolerance to viral proteins. We found that primary infection with T1L occurs in epithelial cells of the PP follicle-associated epithelium, but that CD8alpha(-)/CD11b(-) DCs in the subepithelial dome region (SED) are loaded with T1L antigens in the absence of active DC infection. At least a portion of this antigen is associated with cell fragments from apoptotic epithelial cells, demonstrating that SED DCs cross-present antigens from apoptotic epithelial cells. In vitro, in contrast to exposure to several TLR-ligands or anti-CD40, exposure to T1L does not activate DCs to mature or to produce cytokines, despite clear loading of the DCs with viral antigens. These data suggest that T1L is taken up by a "silent" receptor on DCs, and that the induction of immunity to T1L is dependent on signals from non-DCs following active viral infection that induce DC maturation. Thus, the decision between tolerance and immunity to inactive and live virus, respectively, likely depends on whether there is active infection of epithelial cells by T1L, which results in the elaboration of molecules, such as cytokines, that induce DC maturation.

Animals↗