Alloantigen persistence in induction and maintenance of transplantation tolerance.

Morecki, Shoshana; Leshem, B.; Eid, Ahmed; Slavin, Shimon

doi:10.1084/jem.165.6.1468

Cited by 58 publications

(30 citation statements)

References 24 publications

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“…These results show that persistence of the antigen is essential to maintain the unresponsive state. Similar observations have been made by others, studying neonatally induced tolerance to transplantation antigens (25)(26)(27). Our study has gone further, showing that tolerance is not permanent even when induced in utero-a situation that more closely mimics the natural sequence of events involved in the development of tolerance to self.…”

Section: Discussionsupporting

confidence: 68%

T-cell tolerance: exposure to virus in utero does not cause a permanent deletion of specific T cells.

Jamieson

Ahmed

1988

Proc. Natl. Acad. Sci. U.S.A.

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This study documents the curing of a congenitally acquired chronic viral infection and the acquisition of T-cell competence by a previously tolerant host. Infection of mice with lymphocytic choriomeningitis virus (LCMV) is a classic model of viral persistence and antigen-specific T-celi unresponsiveness. Mice infected at birth or in utero become lifelong carriers with no detectable virus-specific cytotoxic T lymphocyte (CTL) responses. This chronic infection can be eliminated by adoptive transfer of Lyt-2+ T cells from LCMVimmune mice. To determine whether these cured carriers were capable of generating their own LCMV-specific CTL response, mice congenic at the Thy-i locus (Thy-1.1 and Thy-1.2) were used in the adoptive transfer experiments. Hostderived T-cell responses were checked after treating the cured carriers with a monoclonal antibody to deplete the immune donor T cells. Such cured carrier mice were able to generate a host-derived virus-specific CTL response and resisted a second LCMV challenge in the absence of any donor T cells. In addition, bone marrow cells from these cured carriers could functionally reconstitute irradiated mice. Thus this report demonstrates the acquisition of LCMV-specific T-cell competence by previously unresponsive carrier mice infected in utero. These results show that exposure to a virus even during embryonic life does not cause a permanent deletion of specific T cells. These findings are of significance to the understanding of tolerance mechanisms and have implications for the treatment of chronic viral infections.Congenitally acquired chronic infection of mice with lymphocytic choriomeningitis virus (LCMV) is a classic model of immunological tolerance and viral persistence. The prediction of Burnet and Fenner (1) that an antigen introduced into the body during embryonic life would be mistaken for self, and Burnet's (2) theory of clonal deletion of self-reactive clones, were partly based on Traub's (3) studies on congenital infection of mice with LCMV. The other finding that led Burnet and Fenner to postulate the concept of immunological tolerance to antigens encountered during ontogeny was Owen's (4) observations that dizygotic cattle twins sharing vascular supplies in utero developed into erythrocyte chimeras.Mice infected with LCMV at birth or in utero become lifelong carriers, with high levels of infectious virus in most of their organs. Although such persistently infected mice make virus-specific antibody responses (5), attempts by several investigators to demonstrate virus-specific T cells have been mostly unsuccessful (6-11). These carrier mice show minimal or no detectable cytotoxic-T-lymphocyte (CTL) or delayedtype-hypersensitivity (DTH) responses against LCMV, and they also show either a paucity or a lack of T cells that will proliferate when stimulated with the virus. In this study, we demonstrate the acquisition of T-cell competence in mice cured of congenitally acquired chronic LCMV infection. The cured carrier mice can generate a host-derived-virus-spec...

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Section: Discussionsupporting

confidence: 68%

T-cell tolerance: exposure to virus in utero does not cause a permanent deletion of specific T cells.

Jamieson

Ahmed

1988

Proc. Natl. Acad. Sci. U.S.A.

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“…A requirement for persisting chimerism to maintain tolerance in this pre-existing CD4 cell population is consistent with anergy as a mechanism of tolerance before deletion occurs, as other studies have shown dependence on antigen persistence for the maintenance of anergy. [47][48][49] In a minor histocompatibility antigen-mismatched skin graft model, anti-CD154 can induce a state of linked suppression, in which tolerized CD4 ϩ T cells induce tolerance to other antigens expressed on skin grafts sharing the same antigens to which the CD4 ϩ T cells were tolerized. 12 Our studies involving early and later grafting of third-party skin expressing both donor and third-party alloantigens on the same cells provides no evidence for linked suppression in this model.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of early peripheral CD4 T-cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: evidence for anergy and deletion but not regulatory cells

Kurtz

Shaffer

Lie

et al. 2004

Blood

103

116

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Anti-CD154 (CD40L) monoclonal antibody (mAb) plus bone marrow transplantation (BMT) in mice receiving CD8 celldepleting mAb leads to long-term mixed hematopoietic chimerism and systemic donor-specific tolerance through peripheral and central deletional mechanisms. However, CD4 ؉ T-cell tolerance is demonstrable in vitro and in vivo rapidly following BMT, before deletion of donorreactive CD4 cells is complete, suggesting the involvement of other mechanisms. We examined these mechanisms in more detail. Spot enzyme-linked immunosorbent (ELISPOT) analysis revealed specific tolerization (within 4 to 15 days) of both T helper 1 (Th1) and Th2 cytokine responses to the donor, with no evidence for cytokine deviation. Tolerant lymphocytes did not significantly down-regulate rejection by naive donor-reactive T cells in adoptive transfer experiments. No evidence for linked suppression was obtained when skin expressing donor alloantigens in association with third-party alloantigens was grafted. T-cell receptor (TCR) transgenic mixing studies revealed that specific peripheral deletion of alloreactive CD4 T cells occurs over the first 4 weeks following BMT with anti-CD154. In contrast to models involving anti-CD154 without BMT, BMT with anti-CD154 leads to the rapid induction of anergy, followed by deletion of pre-existing donorreactive peripheral CD4 ؉ T cells; the rapid deletion of these cells obviates the need for a regulatory cell population to suppress CD4 cell-mediated alloreactivity.

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“…However, because CD8 þ T cells are thought to require several days to recover their activity from an anergic state (19,20), the clonal deletion of donor-reactive T cells cannot be assumed based on short-term in vitro assays. Therefore, we evaluated donor reactivity of CD8 þ T cells of chimeras in vivo.…”

Section: Cd8mentioning

confidence: 99%

Clonal Deletion Established via Invariant NKT Cell Activation and Costimulatory Blockade Requires In Vivo Expansion of Regulatory T Cells

Hirai

Ishii

Miyairi

et al. 2016

American Journal of Transplantation

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Recently, the immune-regulating potential of invariant natural killer T (iNKT) cells has attracted considerable attention. We previously reported that a combination treatment with a liposomal ligand for iNKT cells and an anti-CD154 antibody in a sublethally irradiated murine bone marrow transplant (BMT) model resulted in the establishment of mixed hematopoietic chimerism through in vivo expansion of regulatory T cells (Tregs). Herein, we show the lack of alloreactivity of CD8 þ T cells in chimeras and an early expansion of donor-derived dendritic cells (DCs) in the recipient thymi accompanied by a sequential reduction in the donor-reactive Vb-T cell receptor repertoire, suggesting a contribution of clonal deletion in this model. Since thymic expansion of donor DCs and the reduction in the donorreactive T cell repertoire were precluded with Treg depletion, we presumed that Tregs should preform before the establishment of clonal deletion. In contrast, the mice thymectomized before BMT failed to increase the number of Tregs and to establish CD8 þ T cell tolerance, suggesting the presence of mutual dependence between the thymic donor-DCs and Tregs. These results provide new insights into the regulatory mechanisms that actively promote clonal deletion.

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Alloantigen persistence in induction and maintenance of transplantation tolerance.

Cited by 58 publications

References 24 publications

T-cell tolerance: exposure to virus in utero does not cause a permanent deletion of specific T cells.

T-cell tolerance: exposure to virus in utero does not cause a permanent deletion of specific T cells.

Mechanisms of early peripheral CD4 T-cell tolerance induction by anti-CD154 monoclonal antibody and allogeneic bone marrow transplantation: evidence for anergy and deletion but not regulatory cells

Clonal Deletion Established via Invariant NKT Cell Activation and Costimulatory Blockade Requires In Vivo Expansion of Regulatory T Cells

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