Topic
Peripheral tolerance induction
About: Peripheral tolerance induction is a research topic. Over the lifetime, 64 publications have been published within this topic receiving 4338 citations.
Papers published on a yearly basis
Papers
TL;DR: It is found that mice with defective passive or active T-cell apoptotic pathways were resistant to induction of transplantation tolerance, and deletion of activated T cells through activation-induced cell death or growth factor withdrawal seems necessary to achieve peripheral tolerance across major histocompatibility complex barriers.
Abstract: The mechanisms of allograft tolerance have been classified as deletion, anergy, ignorance and suppression/regulation. Deletion has been implicated in central tolerance1, whereas peripheral tolerance has generally been ascribed to clonal anergy and/or active immunoregulatory states2. Here, we used two distinct systems to assess the requirement for T-cell deletion in peripheral tolerance induction. In mice transgenic for Bcl-xL, T cells were resistant to passive cell death through cytokine withdrawal, whereas T cells from interleukin-2-deficient mice did not undergo activation-induced cell death. Using either agents that block co-stimulatory pathways or the immunosuppressive drug rapamycin, which we have shown here blocks the proliferative component of interleukin-2 signaling but does not inhibit priming for activation-induced cell death, we found that mice with defective passive or active T-cell apoptotic pathways were resistant to induction of transplantation tolerance. Thus, deletion of activated T cells through activation-induced cell death or growth factor withdrawal seems necessary to achieve peripheral tolerance across major histocompatibility complex barriers.
635 citations
TL;DR: The DO11.10 TCR transgenic adoptive transfer system was used to show that cells of similar phenotype may also arise in the course of peripheral tolerance induction, and emerged within 1 wk following Ag exposure and correlated negatively with the number of initial cell divisions.
Abstract: Immunoregulatory CD25 + CD4 T cells are thought to arise from the thymus as a distinct lineage of CD4 T cells specific for self Ags. We used the DO11.10 TCR transgenic adoptive transfer system to show that cells of similar phenotype may also arise in the course of peripheral tolerance induction. Such cells emerged within 1 wk following Ag exposure and correlated negatively with the number of initial cell divisions. Limiting i.v. Ag dose or using an oral tolerance protocol yielded the greatest numbers of Ag-specific CD25 + CD4 T cells. In contrast, immunogenic Ag exposure in the presence of an adjuvant did not lead to emergence of CD25 + CD4 T cells. The profound anergic phenotype of these cells and their potential immunoregulatory properties make them an especially desirable population to induce in the course of immunotherapy in numerous clinical settings. This experimental system may be useful in future studies designed to optimize immunologic tolerance induction.
446 citations
TL;DR: It is argued that interactions between these two T-cell pools might account for the distinctive immunological role of the liver as a focus of peripheral tolerance induction.
174 citations
TL;DR: In mice surviving the acute phase, the transferred CD8+ T cells persisted at high levels in an anergic state; they were unable to generate cytolytic activity in vitro or to control LCMV infection in vivo, impinge on the understanding of the role of infectious agents in graft verus host reactions towards minor histocompatibility antigens.
Abstract: We studied the impact of various infectious and proinflammatory agents on the induction of peripheral T cell tolerance. Adoptive transfer of CD8+ T cells from lymphocytic choriomeningitis virus (LCMV) T cell receptor transgenic mice into LCMV antigen transgenic mice expressing the LCMV glycoprotein epitope (gp) 33–41 under control of a major histocompatibility complex class I promoter led to efficient induction of peripheral tolerance after a period of transient activation. If, however, the recipient mice were challenged with viral or bacterial infections or proinflammatory agents (lipopolysaccharide or Poly:IC) early after cell transfer, tolerance induction was prevented and instead, CD8+ T cell activation leading to vigorous expansion and generation of cytolytic activity ensued. This became manifest in significant immunopathology mainly involving destruction of the splenic architecture and lysis of antigen-expressing lymphocyte and macrophage populations. Important parameters involved in the activation of host-reactive T cells by nonspecific infectious agents included the presence, localization, and quantity of the specific transgene-encoded self-antigen; in contrast, CD4+ T cells were not required. In mice surviving the acute phase, the transferred CD8+ T cells persisted at high levels in an anergic state; they were unable to generate cytolytic activity in vitro or to control LCMV infection in vivo. These results impinge on our understanding of the role of infectious agents in graft verus host reactions towards minor histocompatibility antigens.
167 citations
TL;DR: It is demonstrated in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4+CD25+FoxP3+ T cells but also their homeostatic behavior in peripheral immune compartments, which has potential clinical relevance.
Abstract: Graft-versus-host-disease (GVHD) is the most common cause of poor outcome after allogeneic stem cell transplantation (SCT). Of late, exploitation of FOXP3(+) regulatory T-cell (T(REG)) function is emerging as a promising strategy in suppression of GVHD, while preserving graft-versus-leukemia (GVL). Cyclosporine and rapamycin reduce the expansion of effector T cells by blocking interleukin (IL)-2, but signaling by IL-2 is pivotal for T(REG) homeostasis. The resolution of GVHD is critically dependent on thymus-dependent reconstitution of the immunoregulatory system. Thus, there has been concern about the impact of blocking IL-2 signaling by immunosuppressive agents on T(REG) homeostasis. Here we demonstrate in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4(+)CD25(+)FoxP3(+) T cells but also their homeostatic behavior in peripheral immune compartments. Treatment with cyclosporine resulted in a sharp reduction of peripheral CD25(+)FoxP3(+) T cells in all immune compartments studied. Prolonged rapamycin treatment allowed for thymic generation of CD4(+)FoxP3(+) T cells, whereas treatment with cyclosporine led to a reduced generation of these cells. In conclusion, cyclosporine and rapamycin differentially affect homeostasis of CD4(+)FoxP3(+) T(REG) in vivo. As peripheral tolerance induction is a prerequisite for successful treatment outcome after allogeneic SCT, these findings are of potential clinical relevance.
167 citations
Related Topics (5)
Performance Metrics
| Year | Papers |
|---|---|
| 2021 | 1 |
| 2018 | 2 |
| 2017 | 4 |
| 2015 | 2 |
| 2014 | 1 |
| 2013 | 4 |