scholarly journals T-cell ontogeny after autologous bone marrow transplantation: failure to synthesize interleukin-2 (IL-2) and lack of CD2- and CD3-mediated proliferation by both CD4- and CD8+ cells even in the presence of exogeneous IL-2

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2270-2277 ◽  
Author(s):  
S Cayeux ◽  
S Meuer ◽  
A Pezzutto ◽  
M Korbling ◽  
R Haas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Autologous Bone Marrow Transplantation ◽  
Interleukin 2 ◽  
Autologous Bone Marrow ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Autologous Bone ◽  
Cell Ontogeny

T cells generated during a second round of ontogeny after autologous bone marrow transplantation (ABMT) represent a unique model of early T- cell ontogeny in an autologous situation. Since grafted bone marrows were pretreated in vitro with the cyclophosphamide derivative ASTA Z 7557, circulating T cells had to be regenerated from reinfused hematopoietic progenitor cells. The T-cell population derived from 25 patients post-ABMT was phenotypically characterized: an increase in CD8+ cells, a low percentage of CD4+ cells, and a median of 12% CD56+ (NKH1+) cells were found. When the T cells were stimulated with phytohemagglutinin (PHA) and phorbol myristate acetate (PMA), defective interleukin-2 (IL-2) secretion was observed. In addition, proliferative responses of the T cells after activation through the antigen-receptor- dependent CD3 pathway, through the CD2 dependent alternative T-cell pathway, and by the lectin PHA were investigated. Despite the presence of CD2, CD3, alpha/beta chains of the T-cell receptor, and CD25+ IL-2 surface receptors, abnormal proliferative responses were obtained even in the presence of exogeneous IL-2. In experiments where the T-cell population was separated into CD4+ cells and CD8+ cells, both the CD4- and CD8+ subsets were unable to respond to activating and proliferating signals. Thus, T cells at early stages of ontogeny not only possess an intrinsic defect in IL-2 synthesis but, in addition, were unable to express functional IL-2 receptors in response to mitogenic stimuli.

scholarly journals T-cell ontogeny after autologous bone marrow transplantation: failure to synthesize interleukin-2 (IL-2) and lack of CD2- and CD3-mediated proliferation by both CD4- and CD8+ cells even in the presence of exogeneous IL-2

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2270-2277 ◽  
Author(s):  
S Cayeux ◽  
S Meuer ◽  
A Pezzutto ◽  
M Korbling ◽  
R Haas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Autologous Bone Marrow Transplantation ◽  
Interleukin 2 ◽  
Autologous Bone Marrow ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Autologous Bone ◽  
Cell Ontogeny

Abstract T cells generated during a second round of ontogeny after autologous bone marrow transplantation (ABMT) represent a unique model of early T- cell ontogeny in an autologous situation. Since grafted bone marrows were pretreated in vitro with the cyclophosphamide derivative ASTA Z 7557, circulating T cells had to be regenerated from reinfused hematopoietic progenitor cells. The T-cell population derived from 25 patients post-ABMT was phenotypically characterized: an increase in CD8+ cells, a low percentage of CD4+ cells, and a median of 12% CD56+ (NKH1+) cells were found. When the T cells were stimulated with phytohemagglutinin (PHA) and phorbol myristate acetate (PMA), defective interleukin-2 (IL-2) secretion was observed. In addition, proliferative responses of the T cells after activation through the antigen-receptor- dependent CD3 pathway, through the CD2 dependent alternative T-cell pathway, and by the lectin PHA were investigated. Despite the presence of CD2, CD3, alpha/beta chains of the T-cell receptor, and CD25+ IL-2 surface receptors, abnormal proliferative responses were obtained even in the presence of exogeneous IL-2. In experiments where the T-cell population was separated into CD4+ cells and CD8+ cells, both the CD4- and CD8+ subsets were unable to respond to activating and proliferating signals. Thus, T cells at early stages of ontogeny not only possess an intrinsic defect in IL-2 synthesis but, in addition, were unable to express functional IL-2 receptors in response to mitogenic stimuli.

scholarly journals Allogeneic mixed lymphocyte reactions during a second round of ontogeny: normal accessory cells did not restore defective interleukin- 2 (IL-2) synthesis in T cells but induced responsiveness to exogeneous IL-2

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2278-2284 ◽  
Author(s):  
S Cayeux ◽  
S Meuer ◽  
A Pezzutto ◽  
M Korbling ◽  
R Haas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Autologous Bone Marrow Transplantation ◽  
Interleukin 2 ◽  
Autologous Bone Marrow ◽  
Intrinsic Defect ◽  
Accessory Cell ◽  
Accessory Cells ◽  
Autologous Bone ◽  
Mixed Lymphocyte Reactions

Abstract The T-cell-accessory-cell interaction in mixed lymphocyte cultures was investigated in 25 patients following autologous bone marrow transplantation (ABMT) using autologous bone marrow treated in vitro with the cyclophosphamide derivative ASTA Z 7557. In a previous study using the same group of patients, T cells failed to synthesize interleukin-2 (IL-2) and proliferate in response to CD3- and CD2- mediated stimuli even in the presence of exogenous IL-2. To investigate whether this defect in IL-2 synthesis and proliferation was caused by defective cell-to-cell interactions, we analyzed mixed lymphocyte reactions (MLR) using T cells and irradiated non-T cells. When normal T cells from 10 different healthy subjects were challenged with allogeneic normal non-T cells, IL-2 production and proliferation were observed. In contrast, when normal T cells were cultured with non-T cells derived from patients found between 20 and 330 days after ABMT, no IL-2 secretion and no proliferative responses could be seen. The addition of lymphokines such as interleukin-1 (IL-1), interleukin-3 (IL- 3), tumor necrosis factor (TNF), granulocyte-macrophage colony stimulating factor (GM-CSF), and interferon-gamma (IFN-y) did not improve the reactions. Furthermore, when patients' T cells were incubated with normal, irradiated non-T cells, defective IL-2 synthesis or proliferative response was obtained. However, when IL-2 was added to these cultures, an improvement in proliferative reactions was observed. Taken together, these new data provide additional evidence that T cells early in ontogeny possessed an intrinsic defect in IL-2 synthesis and that physical cell-to-cell contact between patients' T cells and allogeneic accessory cells induced functional responsiveness to exogeneous IL-2.

scholarly journals Recovery of T cell subsets after autologous bone marrow transplantation is mainly due to proliferation of mature T cells in the graft

Blood ◽  
1985 ◽  
Vol 66 (2) ◽  
pp. 428-431 ◽  
Author(s):  
GC de Gast ◽  
LF Verdonck ◽  
JM Middeldorp ◽  
TH The ◽  
A Hekker ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Marrow Transplantation ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
T Cell Subsets ◽  
Autologous Bone

Abstract In 22 patients with malignancies, treated with high-dose chemoradiotherapy and autologous bone marrow transplantation (BMT), peripheral blood T cell subsets and functions were studied. In ten cytomegalovirus (CMV)-negative patients, CD4+ and CD8+ T cells (representing T cells of the helper/inducer phenotype and T cells of the suppressor/cytotoxic phenotype, respectively), recovered slowly and simultaneously. In 12 CMV-positive patients, however, CD8+ T cells recovered more rapidly than CD4+ T cells and rose to increased counts. No T cells with an immature phenotype (CD1+, OKT6+) were observed. Lymphocyte stimulation by herpes simplex virus infected fibroblasts (and by CMV-infected fibroblasts in CMV-positive patients) in contrast remained high and even increased after BMT in both groups. These data indicate that T cell recovery after autologous BMT is mainly due to proliferation of mature T cells present in the BM graft and not to generation of new T cells from T cell precursors.

scholarly journals Recovery of T cell subsets after autologous bone marrow transplantation is mainly due to proliferation of mature T cells in the graft

Blood ◽  
1985 ◽  
Vol 66 (2) ◽  
pp. 428-431 ◽  
Author(s):  
GC de Gast ◽  
LF Verdonck ◽  
JM Middeldorp ◽  
TH The ◽  
A Hekker ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Bone Marrow Transplantation ◽  
T Cell ◽  
Cd8 T Cells ◽  
Marrow Transplantation ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
T Cell Subsets ◽  
Autologous Bone

In 22 patients with malignancies, treated with high-dose chemoradiotherapy and autologous bone marrow transplantation (BMT), peripheral blood T cell subsets and functions were studied. In ten cytomegalovirus (CMV)-negative patients, CD4+ and CD8+ T cells (representing T cells of the helper/inducer phenotype and T cells of the suppressor/cytotoxic phenotype, respectively), recovered slowly and simultaneously. In 12 CMV-positive patients, however, CD8+ T cells recovered more rapidly than CD4+ T cells and rose to increased counts. No T cells with an immature phenotype (CD1+, OKT6+) were observed. Lymphocyte stimulation by herpes simplex virus infected fibroblasts (and by CMV-infected fibroblasts in CMV-positive patients) in contrast remained high and even increased after BMT in both groups. These data indicate that T cell recovery after autologous BMT is mainly due to proliferation of mature T cells present in the BM graft and not to generation of new T cells from T cell precursors.

scholarly journals Allogeneic mixed lymphocyte reactions during a second round of ontogeny: normal accessory cells did not restore defective interleukin- 2 (IL-2) synthesis in T cells but induced responsiveness to exogeneous IL-2

Blood ◽  
1989 ◽  
Vol 74 (6) ◽  
pp. 2278-2284 ◽  
Author(s):  
S Cayeux ◽  
S Meuer ◽  
A Pezzutto ◽  
M Korbling ◽  
R Haas ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Autologous Bone Marrow Transplantation ◽  
Interleukin 2 ◽  
Autologous Bone Marrow ◽  
Intrinsic Defect ◽  
Accessory Cell ◽  
Accessory Cells ◽  
Autologous Bone ◽  
Mixed Lymphocyte Reactions

The T-cell-accessory-cell interaction in mixed lymphocyte cultures was investigated in 25 patients following autologous bone marrow transplantation (ABMT) using autologous bone marrow treated in vitro with the cyclophosphamide derivative ASTA Z 7557. In a previous study using the same group of patients, T cells failed to synthesize interleukin-2 (IL-2) and proliferate in response to CD3- and CD2- mediated stimuli even in the presence of exogenous IL-2. To investigate whether this defect in IL-2 synthesis and proliferation was caused by defective cell-to-cell interactions, we analyzed mixed lymphocyte reactions (MLR) using T cells and irradiated non-T cells. When normal T cells from 10 different healthy subjects were challenged with allogeneic normal non-T cells, IL-2 production and proliferation were observed. In contrast, when normal T cells were cultured with non-T cells derived from patients found between 20 and 330 days after ABMT, no IL-2 secretion and no proliferative responses could be seen. The addition of lymphokines such as interleukin-1 (IL-1), interleukin-3 (IL- 3), tumor necrosis factor (TNF), granulocyte-macrophage colony stimulating factor (GM-CSF), and interferon-gamma (IFN-y) did not improve the reactions. Furthermore, when patients' T cells were incubated with normal, irradiated non-T cells, defective IL-2 synthesis or proliferative response was obtained. However, when IL-2 was added to these cultures, an improvement in proliferative reactions was observed. Taken together, these new data provide additional evidence that T cells early in ontogeny possessed an intrinsic defect in IL-2 synthesis and that physical cell-to-cell contact between patients' T cells and allogeneic accessory cells induced functional responsiveness to exogeneous IL-2.

Requirements for the promotion of allogeneic engraftment by anti-CD154 (anti-CD40L) monoclonal antibody under nonmyeloablative conditions

Blood ◽  
2001 ◽  
Vol 98 (2) ◽  
pp. 467-474 ◽  
Author(s):  
Patricia A. Taylor ◽  
Christopher J. Lees ◽  
Herman Waldmann ◽  
Randolph J. Noelle ◽  
Bruce R. Blazar
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Suppression ◽  
Regulatory T Cell ◽  
Cd4 Cells ◽  
Major Goal ◽  
Cd8 Cells

The promotion of alloengraftment in the absence of global immune suppression and multiorgan toxicity is a major goal of transplantation. It is demonstrated that the infusion of a single modest bone marrow dosage in 200 cGy-irradiated recipients treated with anti-CD154 (anti-CD40L) monoclonal antibody (mAb) resulted in chimerism levels of 48%. Reducing irradiation to 100 or 50 cGy permitted 24% and 10% chimerism, respectively. In contrast, pan–T-cell depletion resulted in only transient engraftment in 200 cGy-irradiated recipients. Host CD4+ cells were essential for alloengraftment as depletion of CD4+ cells abrogated engraftment in anti-CD154–treated recipients. Strikingly, the depletion of CD8+ cells did not further enhance engraftment in anti-CD154 mAb–treated recipients in a model in which rejection is mediated by both CD4+ and CD8+ T cells. However, anti-CD154 mAb did facilitate engraftment in a model in which only CD8+ T cells mediate rejection. Furthermore, CD154 deletional mice irradiated with 200 cGy irradiation were not tolerant of grafts, suggesting that engraftment promotion by anti-CD154 mAb may not simply be the result of CD154:CD40 blockade. Together, these data suggest that a CD4+regulatory T cell may be induced by anti-CD154 mAb. In contrast to anti-CD154 mAb, anti-B7 mAb did not promote donor engraftment. Additionally, the administration of either anti-CD28 mAb or anti-CD152 (anti–CTLA-4) mAb or the use of CD28 deletional recipients abrogated engraftment in anti-CD154 mAb–treated mice, suggesting that balanced CD28/CD152:B7 interactions are required for the engraftment-promoting capacity of anti-CD154 mAb. These data have important ramifications for the design of clinical nonmyeloablative regimens based on anti-CD154 mAb administration.

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