Nonmyeloablative conditioning is sufficient to allow engraftment of EGFP-expressing bone marrow and subsequent acceptance of EGFP-transgenic skin grafts in mice

Andersson, Göran; Illigens, Ben Min-Woo; Johnson, Kevin; Calderhead, David M.; LeGuern, Christian; Bénichou, Gilles; White‐Scharf, Mary E.; Down, Julian D.

doi:10.1182/blood-2002-06-1649

Cited by 50 publications

(43 citation statements)

References 39 publications

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“…4 In a murine transplantation model, repeated doseregimens of treosulphan proved to be at least as effective as busulphan or total body irradiation (TBI), and further allowed the development of stable donor chimerism in recipient animals. [5][6][7][8][9] Beside its potent haematopoietic stem cell toxicity, treosulphan also demonstrated in vitro activity against a variety of haematological malignancies including acute leukaemias, chronic myelogenous leukaemia, and multiple myeloma. [10][11][12] The antileukaemic efficacy of treosulphan in human acute lymphoblastic leukaemia (ALL) xenograft models was superior compared to equitoxic doses of cyclophosphamide (Cy) or busulphan.…”

Section: Discussionmentioning

confidence: 99%

Dose-escalated treosulphan in combination with cyclophosphamide as a new preparative regimen for allogeneic haematopoietic stem cell transplantation in patients with an increased risk for regimen-related complications

Beelen

Trenschel

Casper

et al. 2004

Bone Marrow Transplant

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Summary:Treosulphan has recently demonstrated antileukaemic activity and potent haematopoietic stem cell toxicity. Dose-escalated treosulphan (3 Â 12 or 3 Â 14 g/m 2 ) combined with cyclophosphamide (Cy) was chosen for a new preparative regimen before allogeneic haematopoietic stem cell transplantation in 18 patients (median age 44, range 19-64 years) with haematological malignancies, considered ineligible for other myeloablative preparative regimens. Pharmacokinetic studies demonstrated rapid treosulphan plasma clearance and a dose-dependent increase of its maximum plasma concentrations and area under the concentration-time curves. Rapid and sustained white blood cell and platelet recovery and full donor chimerism was attained in all evaluable patients. Nonhaematological regimen-related CTC grades 3-4 adverse events were transient and predominantly consisted of cardiac (28%), gastrointestinal (39%), and hepatic (39%) toxicities. The 1-year nonrelapse mortality was 22%. Principal causes of transplant-related lethal events were infections in three of four affected patients. Only one patient died from regimen-related cardiac toxicity. The 1-year relapse estimate is 22%, overall and progressionfree survival estimates are 67 and 56%, respectively. In conclusion, this new treosulphan and Cy combination is an effective, comparatively well-tolerated myeloablative preparative regimen even in patients with an increased risk for regimen-related toxic complications. Treosulphan (L-treitol-1,4-bis-methanesulphonate) is a water-soluble bifunctional alkylating agent registered in several European countries for the treatment of ovarian cancer. In conventionally dosed chemotherapy, haematotoxicity is limiting at an intravenous (i.v.) dose of 10 g/m 2 . 1 If combined with autologous haematological stem cell rescue, a substantial dose escalation in the range of five times of the conventional maximum tolerated dose is feasible. At this escalated dose, mucositis, diarrhoea, skin toxicity, and metabolic acidosis have been found to be dose-limiting at doses of 47 and 49 g/m 2 , respectively. 2,3 Pharmacokinetic studies demonstrated linear pharmacokinetic characteristics of treosulphan up to single doses of 47 g/m 2 with a comparably low intra-and interindividual variability. 2 Recently, preclinical evaluation of the agent revealed further evidence for its feasibility as a component of preparative regimens for allogeneic haematopoietic stem cell transplantation (HSCT) in that treosulphan demonstrated pronounced haematopoietic stem cell toxicity in vitro. 4 In a murine transplantation model, repeated doseregimens of treosulphan proved to be at least as effective as busulphan or total body irradiation (TBI), and further allowed the development of stable donor chimerism in recipient animals. [5][6][7][8][9] Beside its potent haematopoietic stem cell toxicity, treosulphan also demonstrated in vitro activity against a variety of haematological malignancies including acute leukaemias, chronic myelogenous leukaemia, and multiple myeloma. [10...

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Section: Discussionmentioning

confidence: 99%

Dose-escalated treosulphan in combination with cyclophosphamide as a new preparative regimen for allogeneic haematopoietic stem cell transplantation in patients with an increased risk for regimen-related complications

Beelen

Trenschel

Casper

et al. 2004

Bone Marrow Transplant

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“…[2][3][4]7,8 In several studies using tumor-rejection models, minimal or no immunogenicity of EGFP was reported in C57BL/6 mice, 7,8 whereas in other studies, reduced tumor growth of EGFP-transgenic tumor cells or enhanced rejection of EGFP-transgenic skin grafts was observed. 2,3 Similar as in BALB/c mice, engrafting EGFP-transduced hematopoietic cells in C57BL/6 mice results in tolerance to EGFP-transgenic skin grafts. 3,5 Thus, although EGFP is clearly less immunogenic in C57BL/6 mice as compared with BALB/c mice, significant immune responses and tolerance to EGFP can be induced in C57BL/6 mice.…”

mentioning

confidence: 99%

“…2,3 Similar as in BALB/c mice, engrafting EGFP-transduced hematopoietic cells in C57BL/6 mice results in tolerance to EGFP-transgenic skin grafts. 3,5 Thus, although EGFP is clearly less immunogenic in C57BL/6 mice as compared with BALB/c mice, significant immune responses and tolerance to EGFP can be induced in C57BL/6 mice. This offers unique possibilities to study immunomodulatory strategies to less immunogenic transgene products in well-defined model systems.…”

mentioning

confidence: 99%

“…Enhanced green fluorescent protein (EGFP) is frequently used as a marker/model transgene in experimental genetherapy (bone marrow), transplantation and tumor models, and indeed, immune responses against EGFP can interfere in these models by clearing EGFP-expressing cells. [1][2][3][4] Conversely, the immunogenic potential of a transgene such as EGFP can be exploited to establish immunological tolerance or to induce deletion of EGFPspecific cytotoxic T cells by using EGFP-transduced hematopoietic cells 3,5 or splenic B cells, 4 thereby preventing rejection of gene-transduced cells/tissues. The immunogenicity of a transgene product is influenced by numerous factors such as the nature of the product, the vector, the target cell, the local microenvironment as well as the genetic and immunologic background of the host.…”

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confidence: 99%

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Identification of the immunodominant CTL epitope of EGFP in C57BL/6 mice

2008

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“…While the skin tissue of GFP-expressing B6 mice will be immune rejected when transplanted into GFP-negative B6 mice due to the expression of the immunogenic GFP minor antigen, 12,13 it is quite surprising that B6 iPSC-derived GFPexpressing skin tissue is completely immune tolerated by the GFP-negative B6 mice in this study. 11 Therefore, if using this chimeric mouse transplantation system, the B6 iPSC-derived skin cells will be immune tolerated by B6 mice even if they express minor antigens, making it an inappropriate assay to evaluate the immunogenicity of iPSC-derived cells.…”

Section: The Immunogenicity Of Ipsc-derived Tissues From Chimeric Micementioning

confidence: 91%

The immunogenicity of cells derived from induced pluripotent stem cells

2013

Cell Mol Immunol

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With their ability to undergo unlimited self-renewal in culture and to differentiate into all cell types in the body, human embryonic stem cells (hESCs) hold great potential for the treatment of currently incurable diseases. Two hESC-based cell therapies for spinal cord injury and macular degeneration have been advanced into human clinical trials. Despite this rapid progress, one key challenge of hESC-based cell therapy is the allogeneic immune rejection of hESC-derived cells by recipients. This problem could be mitigated by a recent breakthrough in the technology of induced pluripotent stem cells (iPSCs) by nuclear reprogramming of patient-specific somatic cells with defined factors, which could become a renewable source of autologous cells for cell therapy. However, recent studies revealing the abnormal epigenetics, genomic stability and immunogenicity of iPSCs have raised safety concerns over iPSC-based therapy. Recent findings related to the immunogenicity of iPSC derivatives will be summarized in this review.

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Nonmyeloablative conditioning is sufficient to allow engraftment of EGFP-expressing bone marrow and subsequent acceptance of EGFP-transgenic skin grafts in mice

Cited by 50 publications

References 39 publications

Dose-escalated treosulphan in combination with cyclophosphamide as a new preparative regimen for allogeneic haematopoietic stem cell transplantation in patients with an increased risk for regimen-related complications

Dose-escalated treosulphan in combination with cyclophosphamide as a new preparative regimen for allogeneic haematopoietic stem cell transplantation in patients with an increased risk for regimen-related complications

Identification of the immunodominant CTL epitope of EGFP in C57BL/6 mice

The immunogenicity of cells derived from induced pluripotent stem cells

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