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Clonal Deletion (clonal + deletion)
Selected AbstractsWeak agonist self-peptides promote selection and tuning of virus-specific T cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2003Samuel Abstract Recent progress has begun to define the interactions and signaling pathways that are triggered during positive selection. To identify and further examine self-peptides that can mediate positive selection, we searched a protein-database to find peptides that have minimal homology with the viral peptide (p33) that activates a defined P14 transgenic TCR. We identified four peptides that could bind the restriction element H-2Db and induce proliferation of P14 transgenic splenocytes at high concentration. Two of the four peptides (DBM and RPP) were able to positively select thevirus-specific TCR in fetal thymic organ culture but were unable to induce clonal deletion. Reverse-phase HPLC and mass spectrometry demonstrated that these peptides were presented by H-2Db molecules on thymic epithelial cell lines. We also examined whether the selecting ligands altered T cell responsiveness in vitro. DBM-selected T cells lost their ability to respond to the positively selecting ligand DBM, whereas RPP-selected T cells only retainrd their ability to respond to high concentrations of RPP. These results demonstrate that self-peptides that mediate positiveselection can differentially "tune" the activation threshold of T cells and alter the functional repertoire of T cells. [source] Molecular mechanisms of portal vein toleranceHEPATOLOGY RESEARCH, Issue 5 2008Tomohiro Watanabe The liver has been considered as a tolerogenic organ in the sense that favors the induction of peripheral tolerance. The administration of antigens (Ags) via the portal vein causes tolerance, which is termed portal vein tolerance and can explain the occurrence of tolerogenic responses in the liver. Here we discuss the fundamental mechanisms accounting for portal vein tolerance. Antigen-presenting cells (APCs) in the liver, especially dendritic cells and sinusoidal endothelial cells, have limited the ability to produce pro-inflammatory cytokines upon stimulation with endotoxin, an effect that could be due to the continuous exposure to bacterial Ags derived from intestinal microflora. Ag presentation by liver APCs results in T cell tolerance through clonal deletion and selection of regulatory T cells. Thus, APCs with immunosuppressive functions are associated with the achievement of portal vein tolerance via the induction of clonal deletion and generation of regulatory T cells. [source] The Role of Non-Deletional Tolerance Mechanisms in a Murine Model of Mixed Chimerism with Costimulation BlockadeAMERICAN JOURNAL OF TRANSPLANTATION, Issue 6 2005Sinda Bigenzahn Peripheral and central clonal deletion are important tolerance mechanisms in models using bone marrow transplantation (BMT) with costimulation blockade (CB). However, since tolerance can be found before peripheral deletion is complete and since elimination of recipient CD4+ cells at the time of BMT prevents tolerance induction, we investigated the potential roles of regulation and anergy in such a murine model. We found that transient elimination of CD25+ cells or neutralization of IL2 immediately after BMT and CB prevented the induction of skin graft tolerance. Cotransfer into SCID mice of CD4+ cells taken from chimeras early after BMT, together with naïve recipient-type CD4+ cells significantly prolonged donor skin graft survival. In contrast, cotransfer of CD4+ cells harvested from chimeras late after BMT did not prolong donor skin graft survival. Besides, depletion of CD25+ cells in established chimeras several months post-BMT did not break tolerance. In vivo administration of recombinant IL2 inhibited chimerism and tolerance neither early nor late post-BMT, arguing against a decisive role for classical anergy. Thus, CD4 cell-mediated regulation contributes significantly to tolerance induction early after BMT, but appears to have no critical role in the maintenance of tolerance. [source] Evaluation of T-Cell Receptor Repertoires in Patients with Long-Term Renal Allograft SurvivalAMERICAN JOURNAL OF TRANSPLANTATION, Issue 4 2005Cristiam M. Alvarez The mechanisms underlying long-term acceptance of kidney allografts in humans under minimal or no maintenance immunosuppression are poorly understood. We analyzed the T-cell receptor (TCR) repertoires in circulating T cells of patients with long-term (,9 years) renal allograft survival with (LTS-IS) and without immunosuppression (LTS-NoIS). T cells of LTS patients exhibited strongly altered TCR Vß usage, including an increased frequency of oligoclonality and a decreased frequency of polyclonality. All 3 LTS-NoIS and 12 of 16 LTS-IS patients demonstrated oligoclonality in at least three or more TCR Vß families, and the frequency of oligoclonality in these patients was significantly higher as compared to patients with well-functioning grafts at 3 years (p < 0.005 both), an uncomplicated course during the first year (p < 0.0001, both), acute rejection (p < 0.0001, both), chronic allograft nephropathy at 7 (p < 0.0001, both) or 13 years (p < 0.0001, both), dialysis patients (p < 0.0001, both) or healthy controls (p < 0.0001, both). In contrast to LTS patients, all other studied patient groups exhibited a polyclonal TCR repertoire. Our data indicate that TCR alteration is a common feature of long-term allograft outcome, which might be explained by clonal deletion, exhaustion of alloreactive T cells or predominant expression of particular T-cell subpopulations, such as regulatory T cells. [source] Prolactin alters the mechanisms of B cell tolerance inductionARTHRITIS & RHEUMATISM, Issue 6 2009Subhrajit Saha Objective Autoimmune diseases predominantly affect women, suggesting that female sex hormones may play a role in the pathogenesis of such diseases. We have previously shown that persistent mild-to-moderate elevations in serum prolactin levels induce a break in self tolerance in mice with a BALB/c genetic background. The aim of this study was to evaluate the effects of hyperprolactinemia on the mechanisms of B cell tolerance induction. Methods Effects of prolactin on splenic B cell subsets were studied in female BALB/c mice. B cell receptor (BCR),mediated apoptosis and proliferation of transitional B cells were analyzed by flow cytometry. Expression of apoptotic genes was examined by microarrays and real-time polymerase chain reaction analysis. B cells coexpressing ,/, light chains were assessed by flow cytometry and immunohistochemistry. Activation status of transitional type 3 (T3) B cells was evaluated by BCR-induced calcium influx studies. Results BCR-mediated apoptosis of the T1 B cell subset, a major checkpoint for negative selection of autoreactive specificities, was decreased in prolactin-treated mice. Microarray studies indicated that this event may be mediated by the prolactin-induced up-regulation of the antiapoptotic gene interferon-, receptor type II and down-regulation of the proapoptotic gene Trp63. Prolactin treatment also altered the amount of receptor editing, as indicated by the increased number of transitional B cells coexpressing ,/, light chains. Additionally, hyperprolactinemia modified the level of B cell anergy by increasing the degree of BCR-induced calcium influx in the T3 B cells. Conclusion Persistently elevated serum prolactin levels interfere with B cell tolerance induction by impairing BCR-mediated clonal deletion, deregulating receptor editing, and decreasing the threshold for activation of anergic B cells, thereby promoting autoreactivity. [source] Strategy and mechanism for the prevention of hepatocellular carcinoma: Phosphorylated retinoid X receptor , is a critical target for hepatocellular carcinoma chemopreventionCANCER SCIENCE, Issue 3 2009Masahito Shimizu Hepatocellular carcinoma (HCC) is a major health care problem worldwide. The prognosis of patients with HCC is poor because even in the early stages when surgical treatment might be expected to be curative, the incidence of recurrence in patients with underlying cirrhosis is very high due to multicentric carcinogenesis. Therefore, strategies to prevent recurrence and second primary HCC are required to improve the prognosis. One of the most practical approaches to prevent the multicentric development of HCC is ,clonal deletion' therapy, which is defined as the removal of latent (i.e. invisible) (pre)malignant clones from the liver in a hypercarcinogenic state. Retinoids, a group of structural and functional analogs of vitamin A, exert their biological function primarily through two distinct nuclear receptors, retinoic acid receptors and retinoid X receptors (RXR), and abnormalities in the expression and function of these receptors are highly associated with the development of various cancers, including HCC. In particular, a malfunction of RXR, due to phosphorylation by the Ras,mitogen-activated protein kinase signaling pathway is profoundly associated with the development of HCC and thus may be a critical target for HCC chemoprevention. Acyclic retinoid, which has been clinically shown to reduce the incidence of a post-therapeutic recurrence of HCC, can inhibit Ras activity and phosphorylation of the extracellular signal-regulated kinase and RXR, proteins. In conclusion, the inhibition of RXR, phosphorylation and the restoration of its physiological function as a master regulator for nuclear receptors may be a potentially effective strategy for HCC chemoprevention and clonal deletion. Acyclic retinoid, which targets phosphorylated RXR,, may thus play a critical role in preventing the development of multicentric HCC. (Cancer Sci 2009; 100: 369,374) [source] | ||||||||||