CD4+ TCRαβ+ T-cell clones derived shortly after allogeneic bone marrow transplantation: Theophyllamine and verapamil inhibit proliferation of functionally heterogeneous T-cells

1992 ◽  
Vol 14 (5) ◽  
pp. 783-789 ◽  
Author(s):  
Øystein Bruserud ◽  
Wilfried Hamann ◽  
Sarita Patel ◽  
Graham Pawelec
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
T Cell Clones ◽  
Cell Clones

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.

scholarly journals Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 4080-4088 ◽  
Author(s):  
Mathias M. Hauri-Hohl ◽  
Marcel P. Keller ◽  
Jason Gill ◽  
Katrin Hafen ◽  
Esther Pachlatko ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Thymic Epithelial Cells ◽  
Allogeneic Bone ◽  
Donor T Cells

Abstract Acute graft-versus-host disease (aGVHD) impairs thymus-dependent T-cell regeneration in recipients of allogeneic bone marrow transplants through yet to be defined mechanisms. Here, we demonstrate in mice that MHC-mismatched donor T cells home into the thymus of unconditioned recipients. There, activated donor T cells secrete IFN-γ, which in turn stimulates the programmed cell death of thymic epithelial cells (TECs). Because TECs themselves are competent and sufficient to prime naive allospecific T cells and to elicit their effector function, the elimination of host-type professional antigen-presenting cells (APCs) does not prevent donor T-cell activation and TEC apoptosis, thus precluding normal thymopoiesis in transplant recipients. Hence, strategies that protect TECs may be necessary to improve immune reconstitution following allogeneic bone marrow transplantation.

scholarly journals Differential effects of donor T-cell cytokines on outcome with continuous bortezomib administration after allogeneic bone marrow transplantation

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1522-1529 ◽  
Author(s):  
Kai Sun ◽  
Minghui Li ◽  
Thomas J. Sayers ◽  
Lisbeth A. Welniak ◽  
William J. Murphy
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
T Cell Subsets ◽  
Allogeneic Bone

Abstract Dissociating graft-versus-tumor (GVT) effect from acute graft-versus-host disease (GVHD) still remains a great challenge in allogeneic bone marrow transplantation (allo-BMT). Bortezomib, a proteasome inhibitor, has shown impressive efficacy as a single agent in patients with hematologic malignancies but can result in toxicity when administered late after allogeneic transplantation in murine models of GVHD. In the current study, the effects of T-cell subsets and their associated cytokines on the efficacy of bortezomib in murine allogeneic BMT were investigated. Increased levels of serum tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ) were observed after allo-BMT and continuous bortezomib administration. Bortezomib-induced GVHD-dependent mortality was preventable by depletion of CD4+ but not CD8+ T cells from the donor graft. The improved survival correlated with markedly reduced serum TNFα but not IFNγ levels. Transfer of Tnf−/− T cells also protected recipients from bortezomib-induced GVHD-dependent toxicity. Importantly, prolonged administration of bortezomib after transplantation of purified CD8+ T cells resulted in enhanced GVT response, which was dependent on donor CD8+ T cell–derived IFNγ. These results indicate that decreased toxicity and increased efficacy of bortezomib in murine allo-BMT can be achieved by removal of CD4+ T cells from the graft or by inhibiting TNFα.

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 A fixed low number of T cells in HLA-identical allogeneic bone marrow transplantation

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 776-780 ◽  
Author(s):  
LF Verdonck ◽  
GC de Gast ◽  
HG van Heugten ◽  
AW Dekker
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Graft Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone

Abstract Allogeneic bone marrow transplantation (BMT) in humans is hampered mainly by graft-versus-host disease (GVHD). Ex vivo T-cell depletion of the marrow graft has decreased the incidence and severity of GVHD, but has resulted in a higher incidence of graft failure and of relapse of the disease. In order to find an optimal T-cell number that avoids the extreme risks on both sides, we performed BMTs with a fixed low number of T cells. Thirty-one patients received marrow grafts, containing 1 x 10(5) T cells per kilogram body weight, from their HLA-identical sibs. All patients, except one, received cyclosporin A. Engraftment of donor marrow cells occurred in all patients and (late) graft rejections are not observed to date. Eighteen of 30 (60%) evaluable patients had acute GVHD, grade I (10 patients) or grade II (8 patients), limited to the skin in all patients. Chronic GVHD, also limited to the skin, was found in 9 of 27 (33%) evaluable patients. Incidence but not severity of GVHD in our study seems similar to that observed in non-T-cell depleted marrow grafting. Relapse was observed in 1 of 13 leukemic patients transplanted in first (or second) remission or first chronic phase with a follow-up of at least 6 months. These results suggest that with a fixed low number of T cells severe GVHD and failure to engraft can be avoided. More patients and longer follow-up are necessary for conclusions regarding relapse rate and late graft failure.

Donor-derived TNF-α regulates pulmonary chemokine expression and the development of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation

Blood ◽  
2004 ◽  
Vol 104 (2) ◽  
pp. 586-593 ◽  
Author(s):  
Gerhard C. Hildebrandt ◽  
Krystyna M. Olkiewicz ◽  
Leigh A. Corrion ◽  
Yayi Chang ◽  
Shawn G. Clouthier ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Marrow Transplantation ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Allogeneic Bone ◽  
Idiopathic Pneumonia Syndrome ◽  
Tnf Α

Abstract Idiopathic pneumonia syndrome (IPS) is a significant cause of mortality after allogeneic bone marrow transplantation (allo-BMT), and tumor necrosis factor-α (TNF-α) is a significant effector molecule in this process. However, the relative contribution of donor-versus host-derived TNF-α to the development of IPS has not been elucidated. Using a lethally irradiated parent → F1 mouse IPS model, we showed that 5 weeks after transplantation allo-BMT recipients developed significant lung injury compared with syngeneic controls, which was associated with increased bronchoalveolar lavage (BAL) fluid levels of TNF-α, elevated numbers of donor-derived TNF-α-secreting T cells, and increased pulmonary macrophage production of TNF-α to lipopolysaccharide (LPS) stimulation. Allo-BMT with TNF-α-/- donor cells resulted in significantly reduced IPS severity, whereas utilization of TNF-α-deficient mice as BMT recipients had no effect on IPS. We next determined that TNF-α secretion from both donor accessory cells (monocytes/macrophages) and T cells significantly contributed to the development of IPS. Importantly, the absence of donor T-cell-derived TNF-α resulted in a significant decrease in inflammatory chemokine production in the lung and near complete abrogation of IPS. Collectively, these data demonstrate that donor TNF-α is critical to the development of IPS and reveal a heretofore unknown mechanism for T-cell-derived TNF-α in the evolution of this process. (Blood. 2004;104:586-593)

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