Use of Anti-T-Cell Monoclonal Antibody Okt3 to Prevent Acute Graft-Versus-Host Disease in Allogeneic Bone-Marrow Transplantation for Acute Leukaemia

Prentice, HG; Jánossy, G.; Skeggs, D.; Blacklock, Hilary; Bradstock, K. F.; Goldstein, Gideon; Hoffbrand, A. V.

doi:10.1016/s0140-6736(82)92619-8

Cited by 207 publications

(50 citation statements)

References 23 publications

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“…The addition of cytokines, by amplifying minor antigenic differences might be sufficient to trigger a CD69 response, almost equivalent to a third-party response in some instances. What is clear though is that both CD69 expression and proliferation detected by 3 HTdR uptake do serve as markers for a specific alloreactive response.…”

Section: Discussionmentioning

confidence: 99%

“…The other controls present were irradiated stimulators alone. Cultures were incubated at 37°C/5% CO 2 for 5 days, and pulsed for the last 18 h with 1 Ci/well of 3 HTdR. Cells were harvested and tritiated thymidine incorporation measured in a Wallac 1205 Betaplate (Wallac, Turku, Finland).…”

Section: Identification and Selection Of Alloreactive T Cellsmentioning

confidence: 99%

“…The specificity of depletion was assessed by comparing the proliferation assays of the depleted fraction against the pre-sorted cells. The 3 HTdR incorporation of the unsorted cells against either patient (first-party stimulator) or third party was nor-malized to 100%, and the degree of depletion achieved established from the following formula:…”

Section: Identification and Selection Of Alloreactive T Cellsmentioning

confidence: 99%

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Selective removal of alloreactive cells from haematopoietic stem cell grafts: graft engineering for GVHD prophylaxis

Koh

Lowdell

1999

Bone Marrow Transplant

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Summary:One of the main goals in allogeneic bone marrow transplantation is the abrogation of graft-versus-host disease with the preservation of antileukaemia and antiviral activity. We have established a novel system for the selective removal of alloreactive lymphocytes from donor grafts while retaining an effective allogeneic response to third-party stimulator cells. Initial feasibility studies were done with unrelated HLA-mismatched pairs and then extended into the matched setting. Mononuclear cells from HLA-matched donors were cocultured with irradiated recipient cells prestimulated with cytokines (␥-IFN and TNF-␣) in a modified mixed lymphocyte culture (MLC). Alloreactive donor lymphocytes were identified by expression of CD69, an early activation marker and selectively removed by paramagnetic bead sorting. The remaining 'non-alloreactive' lymphocytes were tested in proliferative assays against the original matched recipient and to a third-party donor. A mean depletion of proliferative capacity to 11.5 ؎ 9.9% of the original matched recipient response was achieved while the residual third-party response was largely preserved at 77.8 ؎ 20.9% which should translate into improved immune reconstitution and preservation of antiviral activity. The non-alloreactive lymphocytes could also possess functional antileukaemia activity. Moreover, the alloreactive cells are easily recoverable in this selective T cell depletion strategy for cryopreservation and ready for immediate access as therapeutic donor lymphocyte infusions in cases of frank relapse post transplant.

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Section: Discussionmentioning

confidence: 99%

Section: Identification and Selection Of Alloreactive T Cellsmentioning

confidence: 99%

Section: Identification and Selection Of Alloreactive T Cellsmentioning

confidence: 99%

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Selective removal of alloreactive cells from haematopoietic stem cell grafts: graft engineering for GVHD prophylaxis

Koh

Lowdell

1999

Bone Marrow Transplant

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“…The host-reactive T cells play a major role in the pathogenesis of GVHD, proven not only by studies of experimental murine BMT models but also by several clinical studies. 1,2 However, the precise mechanism of the development of tissue damage associated with aGVHD has not been clarified.…”

mentioning

confidence: 99%

Increased soluble Fas-ligand in sera of bone marrow transplant recipients with acute graft-versus-host disease

Kanda

Tanaka

Shirakawa

et al. 1998

Bone Marrow Transplant

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Summary:Acute graft-versus-host disease (aGVHD) is a major complication following allogeneic bone marrow transplantation (BMT). Recently, accumulating evidence indicates that the Fas/Fas ligand (FasL) system is implicated in the pathogenesis of aGVHD in murine models. We determined the serum levels of soluble FasL (sFasL) in BMT recipients using an enzyme-linked immunosorbent assay. The serum sFasL was suppressed during the period of myelosuppression following the preparative regimen and subsequently increased with hematopoietic reconstitution after BMT. In patients with aGVHD, the serum sFasL level was significantly higher than in those without aGVHD. In the mixed lymphocyte reaction assay, sFasL in the supernatants was increased with a significant correlation to the level of 3 H-thymidine uptake. Our findings suggest that the Fas/FasL system is activated by allogeneic stimulation and may have close correlation to the development of aGVHD in human BMT. Keywords: bone marrow transplantation; graft-versushost disease; Fas; soluble Fas ligand Allogeneic bone marrow transplantation (BMT) is a clinical treatment modality for a variety of hematologic diseases. Acute graft-versus-host disease (aGVHD) remains a main complication following BMT. The host-reactive T cells play a major role in the pathogenesis of GVHD, proven not only by studies of experimental murine BMT models but also by several clinical studies. 1,2 However, the precise mechanism of the development of tissue damage associated with aGVHD has not been clarified.Fas (Apo-1, CD95) is a member of the tumor necrosis factor (TNF) receptor family and transmits an apoptotic cell death signal upon ligation with Fas ligand (FasL). 3 Fas is expressed in target tissues of aGVHD including the skin, liver and intestine. 4 The involvement of the Fas/FasL system in the development of aGVHD has been demonstrated in murine BMT models. [5][6][7][8] Recipients transplanted from allogeneic FasL-defective mice exhibited less symptoms of aGVHD compared with those transplanted from allogeneic normal mice. 5 However, little information is available about the involvement of the Fas/FasL system in complications associated with human BMT.FasL is released from the T cell surface by metalloproteinase-mediated processing. 9 The soluble FasL (sFasL) is increased in the sera of some patients with large granular lymphocytic leukemia and natural killer cell lymphoma. 10 In the present study, we examined the serum sFasL levels in BMT recipients using the enzyme-linked immunosorbent assay (ELISA) to evaluate the implication of sFasL in clinical aGVHD. Patients and methods Patients and sera samplesWe retrospectively analyzed sera from 21 BMT recipients transplanted between June 1995 and November 1997. There were 17 males and four females with a median age of 33.0 years (range 17-47 years). Nine patients with chronic myelogenous leukemia, five with acute lymphoblastic leukemia, four with acute myeloblastic leukemia, two with myelodysplastic syndrome, and one with severe aplastic anemia were ...

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“…14 Classical interventions suppress inflammation through depletion (mono-clonal antibody [15][16][17] ) of key parts of the immune system, or universally suppress the whole immune system (cyclophosphamide 18 or steroid immuno-suppressants 19 ). With these interventions, pathogenic inflammation is surely in some degree brought under control but at the cost of impaired or retarded normal immune responses, a situation which increases the risks of infection and tumorigenesis (Fig.…”

Section: Introductionmentioning

confidence: 99%

Diabetes tolerogenic vaccines targeting antigen-specific inflammation

Geng¹,

Zhang

Zhou³

et al. 2015

Human Vaccines & Immunotherapeutics

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Use of Anti-T-Cell Monoclonal Antibody Okt3 to Prevent Acute Graft-Versus-Host Disease in Allogeneic Bone-Marrow Transplantation for Acute Leukaemia

Cited by 207 publications

References 23 publications

Selective removal of alloreactive cells from haematopoietic stem cell grafts: graft engineering for GVHD prophylaxis

Selective removal of alloreactive cells from haematopoietic stem cell grafts: graft engineering for GVHD prophylaxis

Increased soluble Fas-ligand in sera of bone marrow transplant recipients with acute graft-versus-host disease

Diabetes tolerogenic vaccines targeting antigen-specific inflammation

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