T CELL-DEPLETED ALLOGENEIC BONE MARROW TRANSPLANTATION (BMT) INDUCES MIXED CHIMERISM AND DONOR - SPECIFIC TOLERANCE AND PREVENTS DIABETES IN NOD MICE RECEIVING LOW-DOSE (4 GY) TOTAL BODY IRRADIATION (TBI), CD8 T CELL DEPLETION, AND ANTI-CD40LMAB.

2004 ◽  
Vol 78 ◽  
pp. 432
Author(s):  
Y Takeuchi ◽  
B Nikolic ◽  
M Sykes
Keyword(s):  
T Cell ◽  
Low Dose ◽  
Allogeneic Bone Marrow Transplantation ◽  
Nod Mice ◽  
Cd8 T Cell ◽  
Mixed Chimerism ◽  
Allogeneic Bone ◽  
Total Body ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

scholarly journals Transient antibody targeting of CD45RC inhibits the development of graft-versus-host disease

2020 ◽  
Vol 4 (11) ◽  
pp. 2501-2515 ◽  
Author(s):  
Laetitia Boucault ◽  
Maria-Dolores Lopez Robles ◽  
Allan Thiolat ◽  
Séverine Bézie ◽  
Michael Schmueck-Henneresse ◽  
...  
Keyword(s):  
T Cells ◽  
Graft Versus Host Disease ◽  
Rat Model ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Nsg Mice ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Abstract Allogeneic bone marrow transplantation (BMT) is a widely spread treatment of many hematological diseases, but its most important side effect is graft-versus-host disease (GVHD). Despite the development of new therapies, acute GVHD (aGVHD) occurs in 30% to 50% of allogeneic BMT and is characterized by the generation of effector T (Teff) cells with production of inflammatory cytokines. We previously demonstrated that a short anti-CD45RC monoclonal antibody (mAb) treatment in a heart allograft rat model transiently decreased CD45RChigh Teff cells and increased regulatory T cell (Treg) number and function allowing long-term donor-specific tolerance. Here, we demonstrated in rat and mouse allogeneic GVHD, as well as in xenogeneic GVHD mediated by human T cells in NSG mice, that both ex vivo depletion of CD45RChigh T cells and in vivo treatment with short-course anti-CD45RC mAbs inhibited aGVHD. In the rat model, we demonstrated that long surviving animals treated with anti-CD45RC mAbs were fully engrafted with donor cells and developed a donor-specific tolerance. Finally, we validated the rejection of a human tumor in NSG mice infused with human cells and treated with anti-CD45RC mAbs. The anti-human CD45RC mAbs showed a favorable safety profile because it did not abolish human memory antiviral immune responses, nor trigger cytokine release in in vitro assays. Altogether, our results show the potential of a prophylactic treatment with anti-human CD45RC mAbs in combination with rapamycin as a new therapy to treat aGVHD without abolishing the antitumor effect.

NK Cells Efficiently Prevent Engraftment of Donor Stem Cells after Tolerigenic Bone Marrow Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3025-3025 ◽  
Author(s):  
Leslie Kean ◽  
Kelly Hamby ◽  
Thomas Pearson ◽  
Christian Larsen
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Nk Cells ◽  
Mixed Chimerism ◽  
Low Doses ◽  
Donor Bone Marrow ◽  
Donor Specific Tolerance ◽  
Specific Tolerance

Abstract Introduction: Immunologic tolerance remains an elusive goal of transplantation. In mice, mixed-chimerism and donor-specific tolerance can be induced by blocking the CD28/CD40L T-cell costimulatory pathways after bone marrow transplant (BMT). However, large doses of marrow (~1x109 cells/kg) are required, and these regimens have not yet been successfully translated to clinical practice. There is a growing body of evidence that NK cells may play a central role in the failure of low doses of donor bone marrow to engraft, but the mechanisms underlying NK alloreactivity remain to be determined. Methods: (1) BMT in the presence of CD28/CD40L T cell costimulation blockade was performed using C57BL/6 (B6) recipients and Balb/C donor bone marrow. The role of host-anti-donor NK alloreactivity in preventing engraftment was determined by specifically depleting B6 NK cells. The contribution of the NK cell-surface receptor, LFA1 to NK alloreactivity was determined with the anti-LFA1 blocking antibody M17/5.2. (2) An in vivo NK alloreactivity assay was developed that should allow the investigation of the mechanism of NK alloreactivity and the molecular mediators of this process. In this assay, CFSE-labeled B6 splenocytes were adoptively transferred into B6xBalbC F1 progeny. As such, alloreactivity was specifically mediated by NK cells. NK alloreactivity was measured flow-cytometrically by the disappearance of the CFSE-labeled B6 population. Results: Transient depletion of recipient NK cells resulted in increased donor stem cell survival and the induction of stable mixed-chimerism and tolerance despite BMT with low doses (≤2x106 cells) of donor bone marrow. This effect was specific to allogeneic donor cells: depletion of NK cells did not increase engraftment of syngeneic bone marrow. Blocking the adhesion molecule, LFA-1 recapitulated the effects of whole-scale NK depletion. Newly emergent NK cells exhibited significantly lower expression of the donor-specific activating receptor, Ly49D, and these NK cells did not exhibit in vivo alloreactivity. These results suggest that the NK repertoire in the mixed-chimeric setting exhibited donor-specific tolerance. Using the in vivo hybrid resistance NK alloreactivity assay, we measured 80% NK-specific target killing 8 days after adoptive transfer. Significantly less killing occurred at 2, 4, and 6 days. Pre-sensitizing the recipient for 4 days increased the efficiency of killing—from 50% to 80%, suggesting a potent activation phenomenon required for efficient NK allorecognition and/or cytotoxicity. Implications: These results reveal the importance of NK alloreactivity in the acquisition of mixed-chimerism after BMT at limiting stem cell doses, and suggest that clinical approaches to tolerance-induction transplantation may require mechanisms to control NK alloreactivity.

scholarly journals Peripheral deletional tolerance of alloreactive CD8 but not CD4 T cells is dependent on the PD-1/PD-L1 pathway

Blood ◽  
2008 ◽  
Vol 112 (5) ◽  
pp. 2149-2155 ◽  
Author(s):  
Fabienne Haspot ◽  
Thomas Fehr ◽  
Carrie Gibbons ◽  
Guiling Zhao ◽  
Timothy Hogan ◽  
...  
Keyword(s):  
T Cell ◽  
Allogeneic Bone Marrow Transplantation ◽  
Cell Receptor ◽  
Allogeneic Bone ◽  
Cd4 Cells ◽  
Activation Markers ◽  
Cd8 Cells ◽  
Cd8 Cell ◽  
Cd4 Help ◽  
Total Body

Abstract Although interaction between programmed death-1 (PD-1) and the ligand PD-L1 has been shown to mediate CD8 cell exhaustion in the setting of chronic infection or the absence of CD4 help, a role for this pathway in attenuating early alloreactive CD8 cell responses has not been identified. We demonstrate that the PD-1/PD-L1 pathway is needed to rapidly tolerize alloreactive CD8 cells in a model that requires CD4 cells and culminates in CD8 cell deletion. This protocol involves allogeneic bone marrow transplantation (BMT) following conditioning with low-dose total body irradiation and anti-CD154 antibody. Tolerized donor-reactive T-cell receptor transgenic CD8 cells are shown to be in an abortive activation state prior to their deletion, showing early and prolonged expression of activation markers (compared with rejecting CD8 cells) while being functionally silenced by day 4 after transplantation. Although both tolerized and rejecting alloreactive CD8 cells up-regulate PD-1, CD8 cell tolerance is dependent on the PD-1/PD-L1 pathway. In contrast, CD4 cells are tolerized independently of this pathway following BMT with anti-CD154. These studies demonstrate a dichotomy between the requirements for CD4 and CD8 tolerance and identify a role for PD-1 in the rapid tolerization of an alloreactive T-cell population via a deletional mechanism.

Partial chimerism after T-cell-depleted allogeneic bone marrow transplantation in leukemic HLA-matched patients: a cytogenetic documentation

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 89-93
Author(s):  
MF Bertheas ◽  
D Maraninchi ◽  
M Lafage ◽  
J Fraisse ◽  
D Blaise ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
High Frequency ◽  
Alkylating Agents ◽  
Allogeneic Bone Marrow Transplantation ◽  
Control Group ◽  
Allogeneic Bone ◽  
High Doses ◽  
Total Body ◽  
Mixed Chimeras

We evaluated serially by cytogenetics the blood and marrow chimerism of 38 leukemic recipients of HLA-matched bone marrow transplants (BMT) who were prepared by high doses of alkylating agents and fractionated total- body irradiation (2.2 Gy X 5). Donor or host mitoses were identified by examination of sex chromosomes in 32 patients or by evaluation of the polymorphism of other chromosomes after specific banding in six patients. Twenty-four patients were recipients of untreated BMT, and 14 were recipients of T-cell-depleted BMT. In the 24 patients who received untreated BMT, all showed successful engraftment, and only three had a transient mixed chimera. In the 14 recipients of T-cell-depleted BMTs, four rejected their grafts, and seven had mixed chimeras; these mixed chimeras were more frequent in blood lymphocytes than in marrow cells and could be detected up to 26 months after BMT. This high frequency of partial chimerism after T-cell-depleted BMT by comparison with a control group suggests that the donor's T cells play an important role in the eradication of host residual hematopoiesis after allogeneic BMT.

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