The Experts below are selected from a list of 14376 Experts worldwide ranked by ideXlab platform
Herman Waldmann - One of the best experts on this subject based on the ideXlab platform.
-
tgf β in Transplantation Tolerance
Current Opinion in Immunology, 2011Co-Authors: Frederico S Regateiro, Stephen P. Cobbold, Duncan Howie, Herman WaldmannAbstract:TGF-β is a cytokine required for the induction and maintenance of Transplantation Tolerance in animal models. TGF-β mediates anti-inflammatory effects by acting on many immune cell-types. Central for Transplantation Tolerance is the role for TGF-β in the induction of Foxp3 and regulatory capacity in CD4+ T cells. Recently, however, the general anti-inflammatory role of TGF-β in CD4+ T cell polarization was questioned by the discovery that, in the presence of inflammatory cytokines such as IL-6 or IL-1, TGF-β drives the differentiation of Th17 cells associated with transplant rejection. A better understanding of the factors determining TGF-β production and activation, Foxp3 induction and Treg stability is vital for the development of tolerogenic strategies in Transplantation.
-
immune privilege induced by regulatory t cells in Transplantation Tolerance
Immunological Reviews, 2006Co-Authors: Stephen Cobbold, Elizabeth Adams, Luis Graca, Stephen R Daley, Stephen F Yates, Alison M Paterson, Nathan J Robertson, Paul J. Fairchild, Kathleen F. Nolan, Herman WaldmannAbstract:Immune privilege was originally believed to be associated with particular organs, such as the testes, brain, the anterior chamber of the eye, and the placenta, which need to be protected from any excessive inflammatory activity. It is now becoming clear, however, that immune privilege can be acquired locally in many different tissues in response to inflammation, but particularly due to the action of regulatory T cells (Tregs) induced by the deliberate therapeutic manipulation of the immune system toward Tolerance. In this review, we consider the interplay between Tregs, dendritic cells, and the graft itself and the resulting local protective mechanisms that are coordinated to maintain the tolerant state. We discuss how both anti-inflammatory cytokines and negative costimulatory interactions can elicit a number of interrelated mechanisms to regulate both T-cell and antigen-presenting cell activity, for example, by catabolism of the amino acids tryptophan and arginine and the induction of hemoxygenase and carbon monoxide. The induction of local immune privilege has implications for the design of therapeutic regimens and the monitoring of the tolerant status of patients being weaned off immunosuppression.
-
induction of dominant Transplantation Tolerance by an altered peptide ligand of the male antigen dby
Journal of Clinical Investigation, 2004Co-Authors: Tseching Chen, Herman Waldmann, Paul J. FairchildAbstract:T cell reactivity to minor histocompatibility (mH) antigens is responsible for rejection of HLA-matched allografts, limiting the effectiveness of Transplantation for the treatment of end-stage organ failure. The deadbox gene Dby is located on the Y chromosome and encodes an mH antigen that prompts rejection of male tissues by female mice. Establishing a network of regulatory T (T(reg)) cells that is capable of coercing naive cells to adopt a tolerant phenotype offers an attractive strategy for immune intervention in such deleterious immune responses. While various approaches have successfully induced a dominant form of Transplantation Tolerance, they share the propensity to provoke chronic, incomplete activation of T cells. By identifying the T cell receptor (TCR) contact sites of the dominant epitope of the Dby gene product, we have designed an altered peptide ligand (APL) that delivers incomplete signals to naive T cells from A1 infinity RAG1(-/-) mice that are transgenic for a complementary TCR. Administration of this APL to female transgenic mice polarizes T cells toward a regulatory phenotype, securing a form of dominant Tolerance to male skin grafts that is capable of resisting rejection by naive lymphocytes. Our results demonstrate that incomplete signaling through the TCR may establish a network of T(reg) cells that may be harnessed in the service of Transplantation Tolerance.
-
induction of foxp3 regulatory t cells in the periphery of t cell receptor transgenic mice tolerized to transplants
Journal of Immunology, 2004Co-Authors: Stephen P. Cobbold, Elizabeth Adams, Luis Graca, Raquel Castejon, Susan Humm, Diana Zelenika, Herman WaldmannAbstract:Transplantation Tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This Tolerance is donor Ag specific and depends on a population of CD4+ regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2Ek, to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-β. The nondepleting anti-CD4 mAb was also able to induce Tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-β. As in conventional mice, acquired Tolerance was dominant, such that naive monospecific T cells were not able to override Tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-γ and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)+ CD25+ T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining Transplantation Tolerance after CD4 Ab blockade can be induced de novo through a TGF-β-dependent mechanism, and come to accumulate in tolerated grafts.
-
induction of foxp3 regulatory t cells in the periphery of t cell receptor transgenic mice tolerized to transplants
Journal of Immunology, 2004Co-Authors: Stephen P. Cobbold, Elizabeth Adams, Luis Graca, Raquel Castejon, Susan Humm, Diana Zelenika, Herman WaldmannAbstract:Transplantation Tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This Tolerance is donor Ag specific and depends on a population of CD4(+) regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2E(k), to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-beta. The nondepleting anti-CD4 mAb was also able to induce Tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-beta. As in conventional mice, acquired Tolerance was dominant, such that naive monospecific T cells were not able to override Tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-gamma and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)(+) CD25(+) T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining Transplantation Tolerance after CD4 Ab blockade can be induced de novo through a TGF-beta-dependent mechanism, and come to accumulate in tolerated grafts.
Stephen P. Cobbold - One of the best experts on this subject based on the ideXlab platform.
-
tgf β in Transplantation Tolerance
Current Opinion in Immunology, 2011Co-Authors: Frederico S Regateiro, Stephen P. Cobbold, Duncan Howie, Herman WaldmannAbstract:TGF-β is a cytokine required for the induction and maintenance of Transplantation Tolerance in animal models. TGF-β mediates anti-inflammatory effects by acting on many immune cell-types. Central for Transplantation Tolerance is the role for TGF-β in the induction of Foxp3 and regulatory capacity in CD4+ T cells. Recently, however, the general anti-inflammatory role of TGF-β in CD4+ T cell polarization was questioned by the discovery that, in the presence of inflammatory cytokines such as IL-6 or IL-1, TGF-β drives the differentiation of Th17 cells associated with transplant rejection. A better understanding of the factors determining TGF-β production and activation, Foxp3 induction and Treg stability is vital for the development of tolerogenic strategies in Transplantation.
-
induction of foxp3 regulatory t cells in the periphery of t cell receptor transgenic mice tolerized to transplants
Journal of Immunology, 2004Co-Authors: Stephen P. Cobbold, Elizabeth Adams, Luis Graca, Raquel Castejon, Susan Humm, Diana Zelenika, Herman WaldmannAbstract:Transplantation Tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This Tolerance is donor Ag specific and depends on a population of CD4+ regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2Ek, to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-β. The nondepleting anti-CD4 mAb was also able to induce Tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-β. As in conventional mice, acquired Tolerance was dominant, such that naive monospecific T cells were not able to override Tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-γ and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)+ CD25+ T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining Transplantation Tolerance after CD4 Ab blockade can be induced de novo through a TGF-β-dependent mechanism, and come to accumulate in tolerated grafts.
-
induction of foxp3 regulatory t cells in the periphery of t cell receptor transgenic mice tolerized to transplants
Journal of Immunology, 2004Co-Authors: Stephen P. Cobbold, Elizabeth Adams, Luis Graca, Raquel Castejon, Susan Humm, Diana Zelenika, Herman WaldmannAbstract:Transplantation Tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This Tolerance is donor Ag specific and depends on a population of CD4(+) regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2E(k), to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-beta. The nondepleting anti-CD4 mAb was also able to induce Tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-beta. As in conventional mice, acquired Tolerance was dominant, such that naive monospecific T cells were not able to override Tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-gamma and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)(+) CD25(+) T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining Transplantation Tolerance after CD4 Ab blockade can be induced de novo through a TGF-beta-dependent mechanism, and come to accumulate in tolerated grafts.
-
regulatory t cells and dendritic cells in Transplantation Tolerance molecular markers and mechanisms
Immunological Reviews, 2003Co-Authors: Stephen P. Cobbold, Elizabeth Adams, Luis Graca, Kathleen F. Nolan, Raquel Castejon, Alain Le Moine, Mark Frewin, Susan Humm, Sara A J Thompson, Diana ZelenikaAbstract:Transplantation Tolerance can be induced in adult rodents using monoclonal antibodies against coreceptor or costimulation molecules on the surface of T cells. There are currently two well-characterized populations of T cells, demonstrating regulatory capacity: the "natural" CD4+CD25+ T cells and the interleukin (IL)-10-producing Tr1 cells. Although both types of regulatory T cells can induce Transplantation Tolerance under appropriate conditions, it is not clear whether either one plays any role in drug-induced dominant Tolerance, primarily due to a lack of clear-cut molecular or functional markers. Similarly, although dendritic cells (DCs) can be pharmacologically manipulated to promote Tolerance, the phenotype of such populations remains poorly defined. We have used serial analysis of gene expression (SAGE) with 29 different T-cell and antigen-presenting cell libraries to identify gene-expression signatures associated with immune regulation. We found that independently derived, regulatory Tr1-like clones were highly concordant in their patterns of gene expression but were quite distinct from CD4+CD25+ regulatory T cells from the spleen. DCs that were treated with the Tolerance-enhancing agents IL-10 or vitamin D3 expressed a gene signature reflecting a functional specification in common with the most immature DCs derived from embryonic stem cells.
-
dominant Transplantation Tolerance impairs cd8 t cell function but not expansion
Nature Immunology, 2002Co-Authors: Chunyen Lin, Luis Graca, Stephen P. Cobbold, Herman WaldmannAbstract:Alloreactive CD8+ T cells may persist in animals made tolerant of transplanted tissues; their function is controlled through continuous censorship by regulatory CD4+ T cells. We sought to establish the stage at which such censorship operates. We found that monospecific CD8+ T cells introduced into tolerant animals responded to the tolerated tissue antigen as if they had received CD4+ T cell “help”: they proliferated and accumulated normally. However, they did show compromised graft rejection, interferon-γ production and cell-mediated cytotoxicity. These findings suggest that Tolerance mediated by regulatory T cells acts by censoring immune effector functions rather than by limiting the induction of T cell responses.
Luis Graca - One of the best experts on this subject based on the ideXlab platform.
-
immune privilege induced by regulatory t cells in Transplantation Tolerance
Immunological Reviews, 2006Co-Authors: Stephen Cobbold, Elizabeth Adams, Luis Graca, Stephen R Daley, Stephen F Yates, Alison M Paterson, Nathan J Robertson, Paul J. Fairchild, Kathleen F. Nolan, Herman WaldmannAbstract:Immune privilege was originally believed to be associated with particular organs, such as the testes, brain, the anterior chamber of the eye, and the placenta, which need to be protected from any excessive inflammatory activity. It is now becoming clear, however, that immune privilege can be acquired locally in many different tissues in response to inflammation, but particularly due to the action of regulatory T cells (Tregs) induced by the deliberate therapeutic manipulation of the immune system toward Tolerance. In this review, we consider the interplay between Tregs, dendritic cells, and the graft itself and the resulting local protective mechanisms that are coordinated to maintain the tolerant state. We discuss how both anti-inflammatory cytokines and negative costimulatory interactions can elicit a number of interrelated mechanisms to regulate both T-cell and antigen-presenting cell activity, for example, by catabolism of the amino acids tryptophan and arginine and the induction of hemoxygenase and carbon monoxide. The induction of local immune privilege has implications for the design of therapeutic regimens and the monitoring of the tolerant status of patients being weaned off immunosuppression.
-
induction of foxp3 regulatory t cells in the periphery of t cell receptor transgenic mice tolerized to transplants
Journal of Immunology, 2004Co-Authors: Stephen P. Cobbold, Elizabeth Adams, Luis Graca, Raquel Castejon, Susan Humm, Diana Zelenika, Herman WaldmannAbstract:Transplantation Tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This Tolerance is donor Ag specific and depends on a population of CD4+ regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2Ek, to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-β. The nondepleting anti-CD4 mAb was also able to induce Tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-β. As in conventional mice, acquired Tolerance was dominant, such that naive monospecific T cells were not able to override Tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-γ and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)+ CD25+ T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining Transplantation Tolerance after CD4 Ab blockade can be induced de novo through a TGF-β-dependent mechanism, and come to accumulate in tolerated grafts.
-
induction of foxp3 regulatory t cells in the periphery of t cell receptor transgenic mice tolerized to transplants
Journal of Immunology, 2004Co-Authors: Stephen P. Cobbold, Elizabeth Adams, Luis Graca, Raquel Castejon, Susan Humm, Diana Zelenika, Herman WaldmannAbstract:Transplantation Tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This Tolerance is donor Ag specific and depends on a population of CD4(+) regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2E(k), to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-beta. The nondepleting anti-CD4 mAb was also able to induce Tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-beta. As in conventional mice, acquired Tolerance was dominant, such that naive monospecific T cells were not able to override Tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-gamma and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)(+) CD25(+) T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining Transplantation Tolerance after CD4 Ab blockade can be induced de novo through a TGF-beta-dependent mechanism, and come to accumulate in tolerated grafts.
-
regulatory t cells and dendritic cells in Transplantation Tolerance molecular markers and mechanisms
Immunological Reviews, 2003Co-Authors: Stephen P. Cobbold, Elizabeth Adams, Luis Graca, Kathleen F. Nolan, Raquel Castejon, Alain Le Moine, Mark Frewin, Susan Humm, Sara A J Thompson, Diana ZelenikaAbstract:Transplantation Tolerance can be induced in adult rodents using monoclonal antibodies against coreceptor or costimulation molecules on the surface of T cells. There are currently two well-characterized populations of T cells, demonstrating regulatory capacity: the "natural" CD4+CD25+ T cells and the interleukin (IL)-10-producing Tr1 cells. Although both types of regulatory T cells can induce Transplantation Tolerance under appropriate conditions, it is not clear whether either one plays any role in drug-induced dominant Tolerance, primarily due to a lack of clear-cut molecular or functional markers. Similarly, although dendritic cells (DCs) can be pharmacologically manipulated to promote Tolerance, the phenotype of such populations remains poorly defined. We have used serial analysis of gene expression (SAGE) with 29 different T-cell and antigen-presenting cell libraries to identify gene-expression signatures associated with immune regulation. We found that independently derived, regulatory Tr1-like clones were highly concordant in their patterns of gene expression but were quite distinct from CD4+CD25+ regulatory T cells from the spleen. DCs that were treated with the Tolerance-enhancing agents IL-10 or vitamin D3 expressed a gene signature reflecting a functional specification in common with the most immature DCs derived from embryonic stem cells.
-
dominant Transplantation Tolerance impairs cd8 t cell function but not expansion
Nature Immunology, 2002Co-Authors: Chunyen Lin, Luis Graca, Stephen P. Cobbold, Herman WaldmannAbstract:Alloreactive CD8+ T cells may persist in animals made tolerant of transplanted tissues; their function is controlled through continuous censorship by regulatory CD4+ T cells. We sought to establish the stage at which such censorship operates. We found that monospecific CD8+ T cells introduced into tolerant animals responded to the tolerated tissue antigen as if they had received CD4+ T cell “help”: they proliferated and accumulated normally. However, they did show compromised graft rejection, interferon-γ production and cell-mediated cytotoxicity. These findings suggest that Tolerance mediated by regulatory T cells acts by censoring immune effector functions rather than by limiting the induction of T cell responses.
Elizabeth Adams - One of the best experts on this subject based on the ideXlab platform.
-
immune privilege induced by regulatory t cells in Transplantation Tolerance
Immunological Reviews, 2006Co-Authors: Stephen Cobbold, Elizabeth Adams, Luis Graca, Stephen R Daley, Stephen F Yates, Alison M Paterson, Nathan J Robertson, Paul J. Fairchild, Kathleen F. Nolan, Herman WaldmannAbstract:Immune privilege was originally believed to be associated with particular organs, such as the testes, brain, the anterior chamber of the eye, and the placenta, which need to be protected from any excessive inflammatory activity. It is now becoming clear, however, that immune privilege can be acquired locally in many different tissues in response to inflammation, but particularly due to the action of regulatory T cells (Tregs) induced by the deliberate therapeutic manipulation of the immune system toward Tolerance. In this review, we consider the interplay between Tregs, dendritic cells, and the graft itself and the resulting local protective mechanisms that are coordinated to maintain the tolerant state. We discuss how both anti-inflammatory cytokines and negative costimulatory interactions can elicit a number of interrelated mechanisms to regulate both T-cell and antigen-presenting cell activity, for example, by catabolism of the amino acids tryptophan and arginine and the induction of hemoxygenase and carbon monoxide. The induction of local immune privilege has implications for the design of therapeutic regimens and the monitoring of the tolerant status of patients being weaned off immunosuppression.
-
induction of foxp3 regulatory t cells in the periphery of t cell receptor transgenic mice tolerized to transplants
Journal of Immunology, 2004Co-Authors: Stephen P. Cobbold, Elizabeth Adams, Luis Graca, Raquel Castejon, Susan Humm, Diana Zelenika, Herman WaldmannAbstract:Transplantation Tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This Tolerance is donor Ag specific and depends on a population of CD4+ regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2Ek, to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-β. The nondepleting anti-CD4 mAb was also able to induce Tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-β. As in conventional mice, acquired Tolerance was dominant, such that naive monospecific T cells were not able to override Tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-γ and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)+ CD25+ T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining Transplantation Tolerance after CD4 Ab blockade can be induced de novo through a TGF-β-dependent mechanism, and come to accumulate in tolerated grafts.
-
induction of foxp3 regulatory t cells in the periphery of t cell receptor transgenic mice tolerized to transplants
Journal of Immunology, 2004Co-Authors: Stephen P. Cobbold, Elizabeth Adams, Luis Graca, Raquel Castejon, Susan Humm, Diana Zelenika, Herman WaldmannAbstract:Transplantation Tolerance can be induced in mice by grafting under the cover of nondepleting CD4 plus CD8 or CD154 mAbs. This Tolerance is donor Ag specific and depends on a population of CD4(+) regulatory T cells that, as yet, remain poorly defined in terms of their specificity, origin, and phenotype. Blocking of the Ag-specific response in vitro with an anti-CD4 mAb allowed T cells from monospecific female TCR-transgenic mice against the male Ag Dby, presented by H-2E(k), to express high levels of foxP3 mRNA. foxP3 induction was dependent on TGF-beta. The nondepleting anti-CD4 mAb was also able to induce Tolerance in vivo in such monospecific TCR-transgenic mice, and this too was dependent on TGF-beta. As in conventional mice, acquired Tolerance was dominant, such that naive monospecific T cells were not able to override Tolerance. Splenic T cells from tolerant mice proliferated normally in response to Ag, and secreted IFN-gamma and some IL-4, similar to control mice undergoing primary or secondary graft rejection. High levels of foxP3 mRNA, and glucocorticoid-induced TNFR superfamily member 18 (GITR)(+) CD25(+) T cells were found within the tolerated skin grafts of long-term tolerant recipients. These data suggest that regulatory T cells maintaining Transplantation Tolerance after CD4 Ab blockade can be induced de novo through a TGF-beta-dependent mechanism, and come to accumulate in tolerated grafts.
-
regulatory t cells and dendritic cells in Transplantation Tolerance molecular markers and mechanisms
Immunological Reviews, 2003Co-Authors: Stephen P. Cobbold, Elizabeth Adams, Luis Graca, Kathleen F. Nolan, Raquel Castejon, Alain Le Moine, Mark Frewin, Susan Humm, Sara A J Thompson, Diana ZelenikaAbstract:Transplantation Tolerance can be induced in adult rodents using monoclonal antibodies against coreceptor or costimulation molecules on the surface of T cells. There are currently two well-characterized populations of T cells, demonstrating regulatory capacity: the "natural" CD4+CD25+ T cells and the interleukin (IL)-10-producing Tr1 cells. Although both types of regulatory T cells can induce Transplantation Tolerance under appropriate conditions, it is not clear whether either one plays any role in drug-induced dominant Tolerance, primarily due to a lack of clear-cut molecular or functional markers. Similarly, although dendritic cells (DCs) can be pharmacologically manipulated to promote Tolerance, the phenotype of such populations remains poorly defined. We have used serial analysis of gene expression (SAGE) with 29 different T-cell and antigen-presenting cell libraries to identify gene-expression signatures associated with immune regulation. We found that independently derived, regulatory Tr1-like clones were highly concordant in their patterns of gene expression but were quite distinct from CD4+CD25+ regulatory T cells from the spleen. DCs that were treated with the Tolerance-enhancing agents IL-10 or vitamin D3 expressed a gene signature reflecting a functional specification in common with the most immature DCs derived from embryonic stem cells.
-
cutting edge anti cd154 therapeutic antibodies induce infectious Transplantation Tolerance
Journal of Immunology, 2000Co-Authors: Luis Graca, Elizabeth Adams, Stephen P. Cobbold, Karen Honey, Herman WaldmannAbstract:Nondepleting anti-CD154 (CD40 ligand) mAbs have proven effective in inducing Transplantation Tolerance in rodents and primates. In the induction phase, anti-CD154 Ab therapy is known to enhance apoptosis of Ag reactive T cells. However, this may not be the sole explanation for Tolerance, as we show in this study that Tolerance is maintained through a dominant regulatory mechanism which, like Tolerance induced with CD4 Abs, manifests as infectious Tolerance. Therefore, Tolerance induced with anti-CD154 Abs involves not only the deletion of potentially aggressive T cells, but also a contagious spread of Tolerance to new cohorts of graft-reactive T cells as they arise.
Shimon Sakaguchi - One of the best experts on this subject based on the ideXlab platform.
-
regulatory t cells derived from naive cd4 cd25 t cells by in vitro foxp3 gene transfer can induce Transplantation Tolerance
Transplantation, 2005Co-Authors: Jianguo Chai, Shaoan Xue, Hans J Stauss, David Coe, Caroline Addey, Istvan Bartok, Diane Scott, Elizabeth Simpson, Shohei Hori, Shimon SakaguchiAbstract:Background. Regulatory T (Treg) cells, generated in vitro by Foxp3 gene transfer into naive CD4 + 25 - T cells, have been shown to inhibit the development of inflammation and autoimmune disease, but it is not known whether they are able to prevent allograft rejection. This study investigated whether Treg cells generated from naive CD4 + T cells by Foxp3 gene transfer could induce Transplantation Tolerance. Methods. HY-specific, T-cell receptor (TCR)-transgenic CD4 + 25 - T cells were retrovirally transduced with the Foxp3 gene. The phenotype, function, and cytokine profiles of the transduced cells were examined in vitro by fluorescence-activated cell sorter, T-cell proliferation assays, enzyme-linked immunosorbent assay, and intracellular cytokine staining. Adoptive transfer and skin grafting experiments were conducted to assess whether Foxp3-transduced HY-specific T cells could prevent the rejection of syngeneic male grafts. Results. CD4 + 25 - T cells retrovirally transduced with Foxp3 express a panel of cell surface and intracellular molecules closely associated with Treg activity. This Treg phenotype was stable during in vitro culture with some further maturation. In vitro, Foxp3-transduced cells were functionally anergic and suppressive T cells. In vivo adoptive transfer of Foxp3-transduced HY-specific TCR-transgenic CD4 + T cells protected male skin grafts from rejection by syngeneic females. Retroviral transduction of the Foxp3 gene into non-TCR-transgenic CD4 + 25 - T cells, however, had no influence on male skin graft rejection. Conclusion. This study provides the first evidence that Foxp3-transduced T cells can control the rejection of an allogeneic transplant and suggests that T-cell Foxp3 gene transfer may have therapeutic value in clinical Transplantation.
-
naturally arising foxp3 expressing cd25 cd4 regulatory t cells in immunological Tolerance to self and non self
Nature Immunology, 2005Co-Authors: Shimon SakaguchiAbstract:Naturally arising CD25+CD4+ regulatory T cells actively maintain immunological self-Tolerance. Deficiency in or dysfunction of these cells can be a cause of autoimmune disease. A reduction in their number or function can also elicit tumor immunity, whereas their antigen-specific population expansion can establish Transplantation Tolerance. They are therefore a good target for designing ways to induce or abrogate immunological Tolerance to self and non-self antigens.
-
regulatory t cells in Transplantation Tolerance
Nature Reviews Immunology, 2003Co-Authors: Kathryn J. Wood, Shimon SakaguchiAbstract:The identification and characterization of regulatory T (TReg) cells that can control immune responsiveness to alloantigens have opened up exciting opportunities for new therapies in Transplantation. After exposure to alloantigens in vivo, alloantigen-specific immunoregulatory activity is enriched in a population of CD4+ T cells that express high levels of CD25. In vivo, common mechanisms seem to underpin the activity of CD4+CD25+ TReg cells in both naive and manipulated hosts. However, the origin, allorecognition properties and molecular basis for the suppressive activity of CD4+CD25+ TReg cells, as well as their relationship to other populations of regulatory cells that exist after Transplantation, remain a matter of debate.
-
immunologic Tolerance maintained by cd25 cd4 regulatory t cells their common role in controlling autoimmunity tumor immunity and Transplantation Tolerance
Immunological Reviews, 2001Co-Authors: Shimon Sakaguchi, Noriko Sakaguchi, Jun Shimizu, Sayuri Yamazaki, Toshiko Sakihama, Misako Itoh, Yuhshi Kuniyasu, Takashi Nomura, Masaaki Toda, Takeshi TakahashiAbstract:There is accumulating evidence that T-cell-mediated dominant control of self-reactive T-cells contributes to the maintenance of immunologic self-Tolerance and its alteration can cause autoimmune disease. Efforts to delineate such a regulatory T-cell population have revealed that CD25+ cells in the CD4+ population in normal naive animals bear the ability to prevent autoimmune disease in vivo and, upon antigenic stimulation, suppress the activation/proliferation of other T cells in vitro. The CD25+ CD4+ regulatory T cells, which are naturally anergic and suppressive, appear to be produced by the normal thymus as a functionally distinct subpopulation of T cells. They play critical roles not only in preventing autoimmunity but also in controlling tumor immunity and Transplantation Tolerance.
