CD8+ T CELL TOLERANCE AFTER BONE MARROW TRANSPLANTATION USING NON-MYELOABLATIVE CONDITIONING WITH TBI AND ANTI-CD154 MAB: IMPORTANCE OF SIGNAL 1, CD4+ T CELLS AND CTLA4, BUT NO EVIDENCE FOR LONG-TERM REGULATION

2004 ◽  
Vol 78 ◽  
pp. 41
Author(s):  
T Fehr ◽  
Y Takeuchi ◽  
J Kurtz ◽  
M Sykes
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Cd8 T Cell ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Myeloablative Conditioning

scholarly journals Extrathymic T Cell Deletion and Allogeneic Stem Cell Engraftment Induced with Costimulatory Blockade Is Followed by Central T Cell Tolerance

1998 ◽  
Vol 187 (12) ◽  
pp. 2037-2044 ◽  
Author(s):  
Thomas Wekerle ◽  
Mohamed H. Sayegh ◽  
Joshua Hill ◽  
Yong Zhao ◽  
Anil Chandraker ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Costimulatory Blockade ◽  
Cell Engraftment

A reliable, nontoxic method of inducing transplantation tolerance is needed to overcome the problems of chronic organ graft rejection and immunosuppression-related toxicity. Treatment of mice with single injections of an anti-CD40 ligand antibody and CTLA4Ig, a low dose (3 Gy) of whole body irradiation, plus fully major histocompatibility complex–mismatched allogeneic bone marrow transplantation (BMT) reliably induced high levels (>40%) of stable (>8 mo) multilineage donor hematopoiesis. Chimeric mice permanently accepted donor skin grafts (>100 d), and rapidly rejected third party grafts. Progressive deletion of donor-reactive host T cells occurred among peripheral CD4+ lymphocytes, beginning as early as 1 wk after bone marrow transplantation. Early deletion of peripheral donor-reactive host CD4 cells also occurred in thymectomized, similarly treated marrow recipients, demonstrating a role for peripheral clonal deletion of donor-reactive T cells after allogeneic BMT in the presence of costimulatory blockade. Central intrathymic deletion of newly developing T cells ensued after donor stem cell engraftment had occurred. Thus, we have shown that high levels of chimerism and systemic T cell tolerance can be reliably achieved without myeloablation or T cell depletion of the host. Chronic immunosuppression and rejection are avoided with this powerful, nontoxic approach to inducing tolerance.

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

Blood ◽  
2004 ◽  
Vol 103 (11) ◽  
pp. 4336-4343 ◽  
Author(s):  
Josef Kurtz ◽  
Juanita Shaffer ◽  
Ariadne Lie ◽  
Natalie Anosova ◽  
Gilles Benichou ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Cd4 T Cells ◽  
Marrow Transplantation ◽  
Cd4 T Cell ◽  
T Cell Tolerance ◽  
Cell Tolerance

Abstract Anti-CD154 (CD40L) monoclonal antibody (mAb) plus bone marrow transplantation (BMT) in mice receiving CD8 cell-depleting 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 donor-reactive 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 donor-reactive peripheral CD4+ T cells; the rapid deletion of these cells obviates the need for a regulatory cell population to suppress CD4 cell-mediated alloreactivity. (Blood. 2004;103:4336-4343)

scholarly journals A CD8 T cell–intrinsic role for the calcineurin-NFAT pathway for tolerance induction in vivo

Blood ◽  
2010 ◽  
Vol 115 (6) ◽  
pp. 1280-1287 ◽  
Author(s):  
Thomas Fehr ◽  
Carrie L. Lucas ◽  
Josef Kurtz ◽  
Takashi Onoe ◽  
Guiling Zhao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Tolerance Induction ◽  
Cd8 T Cell ◽  
Regulatory Function ◽  
Cd4 Cells

Abstract Previous studies have indicated that blockade of signaling through the T-cell receptor (TCR)/calcineurin/nuclear factor of activated T cells (NFAT) pathway impairs transplantation tolerance induced with anti-CD154 antibody. By using an allogeneic bone marrow transplantation model, we examined the role of the TCR/calcineurin/NFAT pathway for tolerance induction with anti-CD154. Calcineurin blockade by cyclosporine A led to a failure of CD8 but not CD4 tolerance, and experiments in NFAT1−/− mice replicated this effect. Studies in thymectomized mice demonstrated that blockade of the calcineurin/NFAT pathway after bone marrow transplantation led to a failure of peripheral CD8 tolerance. Moreover, CD8 adoptive transfer studies demonstrated that NFAT1 is cell-intrinsically required for peripheral CD8 tolerance. NFAT1 deficiency did not impair CD8 T-cell up-regulation of PD1, which is required for CD8 tolerance in this model. NFAT1 has previously been shown to have a role in CD4 cells for anergy induction and for programming CD4 cells to become regulatory cells. By generating mice lacking NFAT1 in CD4 but not CD8 cells, we demonstrate that NFAT1 is neither required for CD4 tolerance induction nor for their regulatory function on CD8 T cells. Thus, our study reveals a CD8 T cell–intrinsic NFAT1 requirement for CD8 tolerance in vivo.

scholarly journals Immunotherapy of Cancer by Active Vaccination: Does Allogeneic Bone Marrow Transplantation after Non-Myeloablative Conditioning Provide a New Option?

2003 ◽  
Vol 2 (3) ◽  
pp. 237-260
Author(s):  
Margot Zöller
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Cancer Immunotherapy ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
Myeloablative Conditioning

The critical role of antigen-specific T cells in cancer immunotherapy has been amply demonstrated in many model systems. Though success of clinical trials still remains far behind expectation, the continuous improvement in our understanding of the biology of the immune response will provide the basis of optimized cancer vaccines and allow for new modalities of cancer treatment. This review focuses on the current status of active therapeutic vaccination and future prospects. The latter will mainly be concerned with allogeneic bone marrow cell transplantation after non-myeloablative conditioning, because it is my belief that this approach could provide a major breakthrough in cancer immunotherapy. Concerning active vaccination protocols the following aspects will be addressed: i) the targets of immunotherapeutic approaches; ii) the response elements needed for raising a therapeutically successful immune reaction; iii) ways to achieve an optimal confrontation of the immune system with the tumor and iv) supportive regimen of immunomodulation. Hazards which one is most frequently confronted with in trials to attack tumors with the inherent weapon of immune defense will only be briefly mentioned. Many question remain to be answered in the field of allogeneic bone marrow transplantation after non-myeloablative conditioning to optimize the therapeutic setting for this likely very powerful tool of cancer therapy. Current considerations to improve engraftment and to reduce graft versus host disease while strengthening graft versus tumor reactivity will be briefly reviewed. Finally, I will discuss whether tumor-reactive T cells can be “naturally” maintained during the process of T cell maturation in the allogeneic host. Provided this hypothesis can be substantiated, a T cell vaccine will meet a pool of virgin T cells in the allogeneically reconstituted host, which are tolerant towards the host, but not anergised towards tumor antigens presented by MHC molecules of the host.

scholarly journals Cytolytic function of clonable T cells after human bone marrow transplantation

Blood ◽  
1990 ◽  
Vol 75 (6) ◽  
pp. 1364-1369 ◽  
Author(s):  
A Velardi ◽  
P Varese ◽  
CE Grossi ◽  
N Albi ◽  
C Dembech ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
T Cell Clones ◽  
Cell Clones

Abstract We evaluated T-cell mediated lymphokine activated killer (LAK) function during the late (greater than 5 months) reconstitution phase after T cell-depleted allogeneic bone marrow transplantation (BMT) for hematologic malignancy. Since LAK cells are sustained by interleukin-2 (IL-2), we also investigated the ability of post-BMT T cells to produce IL-2. These functions were investigated at the clonal level. More than 200 T-cell clones from six long-term BMT recipients were generated and compared with 60 T-cell clones derived from two normal controls. Almost all the CD8+ clonal cultures from BMT recipients expressed cytolytic activity in a lectin-dependent cellular cytoxicity assay. Interestingly, a higher proportion of BMT recipient-derived cytolytic clones were able to mediate LAK activity in comparison with control clones (28% versus 4%, P less than .05). However, T-cell clones from BMT recipients, as opposed to control clones, were largely incapable of producing IL-2. Given the high proportions of post-BMT circulating CD8+ T cells, it appears that, in long-term BMT recipients, the precursors of nonspecific LAK effectors are present at above normal levels. However, their function may be defective in vivo due to poor IL-2 production.

scholarly journals Cytolytic function of clonable T cells after human bone marrow transplantation

Blood ◽  
1990 ◽  
Vol 75 (6) ◽  
pp. 1364-1369
Author(s):  
A Velardi ◽  
P Varese ◽  
CE Grossi ◽  
N Albi ◽  
C Dembech ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
T Cell Clones ◽  
Cell Clones

We evaluated T-cell mediated lymphokine activated killer (LAK) function during the late (greater than 5 months) reconstitution phase after T cell-depleted allogeneic bone marrow transplantation (BMT) for hematologic malignancy. Since LAK cells are sustained by interleukin-2 (IL-2), we also investigated the ability of post-BMT T cells to produce IL-2. These functions were investigated at the clonal level. More than 200 T-cell clones from six long-term BMT recipients were generated and compared with 60 T-cell clones derived from two normal controls. Almost all the CD8+ clonal cultures from BMT recipients expressed cytolytic activity in a lectin-dependent cellular cytoxicity assay. Interestingly, a higher proportion of BMT recipient-derived cytolytic clones were able to mediate LAK activity in comparison with control clones (28% versus 4%, P less than .05). However, T-cell clones from BMT recipients, as opposed to control clones, were largely incapable of producing IL-2. Given the high proportions of post-BMT circulating CD8+ T cells, it appears that, in long-term BMT recipients, the precursors of nonspecific LAK effectors are present at above normal levels. However, their function may be defective in vivo due to poor IL-2 production.

Sign in / Sign up

Export Citation Format

Share Document