Cell-Surface Marking of CD34<sup>+</sup>-Restricted Phenotypes of Human Hematopoietic Progenitor Cells by Retrovirus-Mediated Gene Transfer

Ruggieri, Luciano; Aiuti, Alessandro; Salomoni, Monica; Zappone, Elisabetta; Ferrari, Giuliana; Bordignon, Claudio

doi:10.1089/hum.1997.8.13-1611

Cited by 47 publications

(36 citation statements)

References 28 publications

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“…Subsequently, the identity of the PCR products was confirmed by sequencing. The TCRa and TCRb chains were cloned into bicistronic retroviral vectors containing the marker genes eGFP 51 and truncated nerve growth factor receptor (DNGF-R), 52 respectively. The Moloney murine leukemia virus-based retroviral vector LZRS and packaging cells j-NX-A were used.…”

Section: Construction Of the Retroviral Vectors And Production Of Thementioning

confidence: 99%

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

et al. 2005

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Both cytotoxic T cells and helper T cells are important in immune responses against pathogens and malignant cells.In hematological malignancies which express HLA class II molecules, immunotherapy may be directed to HLA class II restricted antigens. We investigated whether it is possible to engineer HLA class II restricted T cells with both antigenspecific cytolytic activity and the capacity to produce high amounts of cytokines. CD4 + and CD8 + peripheral-bloodderived T cells were retrovirally transduced with the HLA class II restricted minor histocompatibility antigen dead box RNA helicase Y (DBY)-specific TCR. The TCR-transduced CD4 + T cells exerted DBY-specific cytolytic activity, produced Th0, Th1, or Th2 cytokines, and proliferated upon DBY-specific stimulation. TCR-transduced CD8 + T cells exerted cytolytic activity which equaled the level of cytolytic activity of the TCR-transferred CD4 + T cells. Cotransfer of CD4 enhanced the cytolytic activity of the TCR-transduced CD8 + T cells, but introduction of CD4 was not sufficient to generate DBY-specific CD8 + T cells with the capacity to produce high amounts of cytokines. In this study, we demonstrated the feasibility to engineer T cells with antigen-specific cytolytic activity, as well as the ability to produce significant amounts of cytokines, by TCR transfer to CD4 + T cells. Gene Therapy (2005) IntroductionPatients relapsing from leukemia after allogeneic stem cell transplantation can successfully be treated by donor lymphocyte infusions (DLI), due to the graft-versusleukemia (GVL) response of the donor-derived T cells. [1][2][3][4] However, DLI is also associated with graft-versus-hostdisease (GVHD). Several studies have illustrated that depletion of CD8 + T cells from the DLI may preserve the beneficial GVL reactivity without the induction of GVHD, indicating that the CD4 + T lymphocytes may play an essential role in the antileukemic reactivity. [5][6][7][8][9][10] The mechanism by which the CD4 + T cells contribute to the GVL response is, however, not known. CD4 + T cells have been suggested to elicit the antileukemic response via the induction of minor histocompatibility antigen (mHag)-specific CD8 + T cells. 5 In addition, mHag-specific CD4 + T-helper cells have been reported to mature dendritic cells and enhance the expansion of mHag-specific cytotoxic T lymphocytes in vitro. 11 Alternatively, we have demonstrated that CD4 + T cells are capable of exerting direct cytolytic activity against leukemic cells. [12][13][14] Cellular immunotherapeutic approaches based on the adoptive transfer of T lymphocytes may require large cell numbers. Large numbers of T cells with a defined antigen specificity can be acquired by retroviral transfer of the T-cell receptor to peripheral-blood-derived T lymphocytes. Until now, the application of retroviral transfer of TCRs has mainly been limited to the transfer of HLA class I restricted TCRs. [15][16][17][18][19][20] However, the specificity of HLA class II restricted T lymphocytes can also be transferred to other T c...

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Section: Construction Of the Retroviral Vectors And Production Of Thementioning

confidence: 99%

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

et al. 2005

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“…LNGFR transduction tag stably expressing cell lines As a prototype gene transfer monitoring transduction tag system, a C-terminal-deleted LNGFR lacking the coding sequence for the intracellular receptor domain (p75mut or ⌬LNGFR 16 ) and its natural ligand NGF were used. A commercially available p75-specific mAb (anti-p75 mAb) was also tested.…”

Section: Resultsmentioning

confidence: 99%

“…The retroviral vector pL⌬NSN 16 was kindly provided by Dr. R. Rüger (Boehringer Mannheim, Penzberg, Germany). Recombinant pL⌬NSN-transducing retroviral particles were generated by standard techniques.…”

Section: Cell Culture Transfections and Generation Of Recombinant Rmentioning

confidence: 99%

“…20 Moreover, these transduced lymphocytes were not found to elicit an immune response to ⌬LNGFR when transplanted into the recipient host. 16 Taken together, all of these properties identify ⌬LNGFR as an ideal transduction tag receptor molecule.…”

mentioning

confidence: 99%

“…14 -19 The presence of ⌬LNGFR ϩ CD34 ϩ cells after long-term culture suggested that ⌬LNGFR is stably integrated and stably expressed in retroviral vectortransduced CD34 ϩ cells grown ex vivo. 16,18 Recent data indicated that ex vivo-transduced human lymphocytes expressing ⌬LNGFR can be safely transplanted into neoplastic patients. 20 Moreover, these transduced lymphocytes were not found to elicit an immune response to ⌬LNGFR when transplanted into the recipient host.…”

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A prototype transduction tag system (ΔLNGFR/NGF) for noninvasive clinical gene therapy monitoring

et al. 2000

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Expression of CXCR4, the receptor for stromal cell-derived factor-1 on fetal and adult human lymphohematopoietic progenitors

et al. 1999

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Stromal cell-derived factor-1 (SDF-1) is a CXC chemokine produced by stromal cells that acts as a chemoattractant for human CD34 + progenitor cells. We investigated the expression of CXCR4, the receptor for SDF-1, on CD34 + cells from different hematopoietic sites and developmental stages. CXCR4 was detected by flow cytometry on 37 % of fetal bone marrow (BM) [gestation weeks (gw) 14-23] and 40 % of adult BM CD34 + cells. Interestingly, in fetal liver CD34 + cells, CXCR4 was expressed at lower levels at later stages (9 %, gw 20-23) compared to early stages of development (39 %, gw 7.5-18), suggesting a development-related change in the migratory capacity of progenitors. CXCR4 was detected at similar levels on both phenotypically primitive and committed progenitors from fetal and adult sites. However, B cell lineage progenitor and precursor cells expressed CXCR4 at the highest density (80 % of BM CD34 + /CD10 + pro-B cells are CXCR4 +). CXCR4 was also expressed in the fetal thymus in early T cell precursors and found to be down-regulated during T cell matura-tion. Finally, we found that stem cell factor, alone or in combination with other cytokines, can up-modulate CXCR4 expression on CD34 + cells by three-to fourfold. In conclusion, our results suggest that CXCR4 may play an important role in the local and systemic trafficking of human CD34 + cells as well as in human B lymphopoiesis and that its expression can be modulated by cytokines.

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Cell-Surface Marking of CD34⁺-Restricted Phenotypes of Human Hematopoietic Progenitor Cells by Retrovirus-Mediated Gene Transfer

Cited by 47 publications

References 28 publications

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

A prototype transduction tag system (ΔLNGFR/NGF) for noninvasive clinical gene therapy monitoring

Expression of CXCR4, the receptor for stromal cell-derived factor-1 on fetal and adult human lymphohematopoietic progenitors

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Cell-Surface Marking of CD34+-Restricted Phenotypes of Human Hematopoietic Progenitor Cells by Retrovirus-Mediated Gene Transfer

Cited by 47 publications

References 28 publications

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

HLA class II restricted T-cell receptor gene transfer generates CD4+ T cells with helper activity as well as cytotoxic capacity

A prototype transduction tag system (ΔLNGFR/NGF) for noninvasive clinical gene therapy monitoring

Expression of CXCR4, the receptor for stromal cell-derived factor-1 on fetal and adult human lymphohematopoietic progenitors

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Cell-Surface Marking of CD34⁺-Restricted Phenotypes of Human Hematopoietic Progenitor Cells by Retrovirus-Mediated Gene Transfer