Biomedical subjects

Ana M C Faria

Publications and source records attributed to Ana M C Faria.

5 recordsLinked to original sources

PubMed2006

The nucleoporin Nup96 is required for proper expression of interferon-regulated proteins and functions.

Nup98 and Nup96 are components of the nuclear transport machinery and are induced by interferons (IFN). Nup98 is a constituent of an mRNA export pathway that is targeted by viruses and regulated by IFN. However, the role of Nup96 in IFN-related mechanisms has not been established. To investigate the function of Nup96 in vivo, we generated Nup96(+/-) mice that express low levels of Nup96, as Nup96(-/-) mice are lethal. The Nup96(+/-) mice presented selective alterations of the immune system, which resulted in downregulation and impaired IFN alpha- and gamma-mediated induction of MHC I and IFNgamma induction of MHC II, ICAM-1, and other proteins. Frequency of TCRalphabeta+ and CD4+ T cells, which depends on MHC function, is reduced in NUP96(+/-) mice. Upon immunization, Nup96(+/-) mice showed impaired antigen presentation and T cell proliferation. Nup96(+/-) cells and mice were highly susceptible to viral infection, demonstrating a role for Nup96 in innate and adaptive immunity.

Animals↗

PubMed2006

Oral tolerance and TGF-beta-producing cells.

Multiple mechanisms have been proposed to explain the immune hyporesponsiveness to fed antigens, a phenomenon named oral tolerance. Low doses of orally administered antigen are reported to favor active suppression with the generation of regulatory cells, whereas high doses would favor clonal anergy/deletion. A major conceptual advance in oral tolerance has been the demonstration that TGF-beta plays a central role in oral tolerance as a mediator secreted by Th3 cells. In addition, recent pieces of evidence suggest that TGF-beta may be a primary link between distinct populations of regulatory T cells that are induced by feeding. Conversion of CD4+CD25- into CD4+CD25+ T cells by the expression of FoxP3 involves TGF-beta. A membrane-bound form of TGF-beta (containing latency-associated peptide - LAP) has also been described and LAP+ CD4+ T cells mediate suppression in the gut by a TGF-beta-dependent mechanism. Most of these regulatory T cells are anergic cells indicating that anergy may be also related to Treg induction. Moreover, deletional events taking place in the gut mucosa induce TGF-beta production by either macrophages that phagocyte apoptotic cells or by the dying T cells. Thus, it appears that TGF-beta-producing cells are not only crucial for oral tolerance, but they may be master regulators of most of the mechanisms triggered by antigen feeding.

Administration, Oral↗

PubMed2005

Oral tolerance.

Multiple mechanisms of tolerance are induced by oral antigen. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral antigen induces T-helper 2 [interleukin (IL)-4/IL-10] and Th3 [transforming growth factor (TGF)-beta] T cells plus CD4+CD25+ regulatory cells and latency-associated peptide+ T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit, Flt-3 ligand, and anti-CD40 ligand. Oral (and nasal) antigen administration suppresses animal models of autoimmune diseases including experimental autoimmune encephalitis, uveitis, thyroiditis, myasthenia, arthritis, and diabetes in the non-obese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, graft rejection, allergy, colitis, stroke, and models of Alzheimer's disease. Oral tolerance has been tested in human autoimmune diseases including multiple sclerosis (MS), arthritis, uveitis, and diabetes and in allergy, contact sensitivity to dinitrochlorobenzene (DNCB), and nickel allergy. Although positive results have been observed in phase II trials, no effect was observed in phase III trials of CII in rheumatoid arthritis or oral myelin and glatiramer acetate (GA) in MS. Large placebo effects were observed, and new trials of oral GA are underway. Oral insulin has recently been shown to delay onset of diabetes in at-risk populations, and confirmatory trials of oral insulin are being planned. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time, and antigen-specific mechanisms of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy, and early therapy.

Animals↗

PubMed2003

Oral tolerance induced by continuous feeding: enhanced up-regulation of transforming growth factor-beta/interleukin-10 and suppression of experimental autoimmune encephalomyelitis.

Oral administration of antigen leads to specific immune hyporesponsiveness termed as oral tolerance. Different doses and feeding regimens have been demonstrated to induce different types of tolerance and degrees of immune suppression. Herein, we compare distinct different regimens of feeding using equivalent final doses of antigen in order to investigate the role of frequency of antigen uptake in the induction of oral tolerance. We demonstrate that continuous feeding of antigen in the drinking water, as compared to a single feeding or feeding once per day over several days enhances suppression to both Th1 and Th2 type responses in B6D2F1 and BALB/c mice. Continuous feeding suppresses antibody responses in aged B6D2F1 mice, which are otherwise refractory to oral tolerance induction. Continuous feeding of ovalbumin (OVA) in high or low doses, as compared to control or single daily feeding over several days, up-regulates interleukin-10 (IL-10) and transforming growth factor-beta (TGF-beta) production in both OVA TCR transgenic and BALB/c mice. In all regimens tested in wild type mice, low doses were more efficacious than high doses in inducing IL-10 and TGF-beta. Serial feeding (multiple low dose daily gavages) using OVA or myelin basic protein (MBP), also led to up-regulation of TGF-beta and IL-10 production in OVA TCR and MBP TCR transgenic mice, as well as enhanced inhibition of MBP-induced experimental autoimmune encephalomyelitis (EAE) in (PLxSJL) F1 mice. We did not find differences in the cytokine profile between serial (multiple low dose daily gavages) and continuous feeding regimens, suggesting that repetitive discrete delivery of oral antigen provides a sustained signal for the induction of oral tolerance. Thus, using different regimens of feeding that resemble natural feeding with equivalent final doses of antigen, we found enhancement of oral tolerance utilizing regimens that resemble natural feeding. Such feeding regimens may be advantageous in the application of oral tolerance for clinical purposes in the treatment of autoimmune and other inflammatory conditions.

Adjuvants, Immunologic↗

PubMedDate not supplied

Oral tolerance: therapeutic implications for autoimmune diseases.

Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-beta) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy.

Administration, Oral↗