Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region

Heemskerk, Mirjam H.M.; Hoogeboom, Manja; Paus, Roelof A. de; Kester, Michel G.D.; Hoorn, Menno A.W.G. van der; Goulmy, Els; Willemze, R.; Falkenburg, J.H. Frederik

doi:10.1182/blood-2003-05-1524

Cited by 202 publications

(172 citation statements)

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“…[33][34][35] Previously, we showed that HA-2-specific T cells isolated by tetramer during a strong GVL response produced large amounts of IFNg and no or low amounts of IL-4. 18 Furthermore, we recently demonstrated that T cells contributing to the GVL reactivity of DLI can be isolated based on their production of IFNg. 36 Thus, Th1 cytokines play a very important role in antitumor reactivity.…”

Section: Discussionmentioning

confidence: 99%

“…The previously isolated functional mHag-specific T cells that may have contributed to the on going GVL response, all produced more than 800 pg/ml of IFNg. 18 Since the large amounts of cytokines produced by DBY-TCR-transduced CD4 + T cells were not equaled by the TCR-transduced CD8 + T cells, TCR-transduced CD4 + T cells may be preferred for cellular immunotherapy. Furthermore, selection of effector cells with the desired cytokine profile might be possible, since TCR transfer to the CD4 + T cells generated T cells with all different Th phenotypes (Th0, Th1, and Th2).…”

Section: Discussionmentioning

confidence: 99%

“…54 As control vectors, retroviral vectors were used containing only eGFP or DNGF-R. Functionality of the retroviral constructs encoding the TCRa and TCRb chains was confirmed by transduction of the TCRa and TCRb chain-deficient Jurkat clone 76 and subsequent analysis of TCRab cell surface expression as reported previously. 18 Production of DBY-transduced EBV-LCL Donor-derived EBV-LCL were transduced with retroviral supernatants containing the DBY gene, or the Ii-DBY epitope or the DNGF-R control vector. The transduction was performed using recombinant human fibronectin fragments CH-296 55 (Bio Whittaker, Verviers, Belgium) as described.…”

Section: Construction Of the Retroviral Vectors And Production Of Thementioning

confidence: 99%

“…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 cells. [21][22][23] Previously, we demonstrated the retroviral transfer of a dual-specific TCR recognizing both an antigenic peptide in the context of HLA class I and an antigenic peptide in the context of HLA class II.…”

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confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Construction Of the Retroviral Vectors And Production Of Thementioning

confidence: 99%

mentioning

confidence: 99%

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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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“…TCR-␤ chain variable gene segment usage of the clones was established by FACS using the IOTest ␤ Mark TCR kit (Beckman Coulter), TCR-␣ chain variable gene segment usage was determined by RT-PCR using TCR-␣ chain variable gene segment family specific primers (26). The CDR3 regions of the TCRs of selected clones were amplified by PCR, cloned into the pCR2.1 vector using TA cloning kit (Invitrogen Life Technologies), and then sequenced.…”

Section: Tcr Repertoire Analysismentioning

confidence: 99%

Phenotypic and Functional Characterization of CD4 T Cells Expressing Killer Ig-Like Receptors

Bergen

Thompson

Slik

et al. 2004

The Journal of Immunology

110

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Killer Ig-like receptors (KIR) are commonly found on human NK cells, γδ T cells, and CD8 T cells. Although KIR+ CD4 T cells are found in certain patients, their prevalence in healthy donors is controversial. We now provide definitive proof that such cells are present in most individuals, and report on their frequency, surface phenotype, cytokine profile, and Ag specificity. The number of KIR+ CD4 T cells detected in peripheral blood increased with age. In contrast with regular KIR− CD4 T cells, the majority of KIR+ CD4 T cells lacked surface expression of CD27, CD28, CCR4, and CCR7, but did express CD57 and 2B4. In addition, KIR were detected on approximately one-tenth of CD28− and CD57+ memory CD4 T cells. In line with the absence of the Th2 marker CCR4, the KIR+ CD4 cells produced mainly IFN-γ and little IL-4, IL-10, or IL-17 upon TCR triggering. Furthermore, the KIR+ population contained cells that responded to recall Ags in an HLA class II-restricted fashion. Together, our data indicate that KIR-expressing CD4 T cells are predominantly HLA class II-restricted effector memory Th1 cells, and that a significant, previously unrecognized fraction of effector memory Th1 cells expresses KIR.

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Adoptive T‐Cell Transfer in Cancer Treatment

Moosmann¹,

Krackhardt

2009

Tumor‐Associated Antigens

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Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region

Cited by 202 publications

References 43 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

Phenotypic and Functional Characterization of CD4 T Cells Expressing Killer Ig-Like Receptors

Adoptive T‐Cell Transfer in Cancer Treatment

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