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  • The American Association of Immunologists  (4)
  • 1
    Online Resource
    Online Resource
    Characterization of Latent Membrane Protein 2 Specificity in CTL Lines from Patients with EBV-Positive Nasopharyngeal Carcinoma and Lymphoma
    The American Association of Immunologists ; 2005
    In:  The Journal of Immunology Vol. 175, No. 6 ( 2005-09-15), p. 4137-4147
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 175, No. 6 ( 2005-09-15), p. 4137-4147
    Abstract: Viral proteins expressed by EBV-associated tumors provide target Ags for immunotherapy. Adoptive T cell therapy has proven effective for posttransplant EBV-associated lymphoma in which all EBV latent Ags are expressed (type III latency). Application of immunotherapeutic strategies to tumors such as nasopharyngeal carcinoma and Hodgkin’s lymphoma that have a restricted pattern of EBV Ag expression (type II latency) is under investigation. Potential EBV Ag targets for T cell therapy expressed by these tumors include latent membrane proteins (LMP) 1 and 2. A broad panel of epitopes must be identified from these target Ags to optimize vaccination strategies and facilitate monitoring of tumor-specific T cell populations after immunotherapeutic interventions. To date, LMP2 epitopes have been identified for only a limited number of HLA alleles. Using a peptide library spanning the entire LMP2 sequence, 25 CTL lines from patients with EBV-positive malignancies expressing type II latency were screened for the presence of LMP2-specific T cell populations. In 21 of 25 lines, T cell responses against one to five LMP2 epitopes were identified. These included responses to previously described epitopes as well as to newly identified HLA-A*0206-, A*0204/17-, A29-, A68-, B*1402-, B27-, B*3501-, B53-, and HLA-DR-restricted epitopes. Seven of the nine newly identified epitopes were antigenically conserved among virus isolates from nasopharyngeal carcinoma tumors. These new LMP2 epitopes broaden the diversity of HLA alleles with available epitopes, and, in particular, those epitopes conserved between EBV strains provide valuable tools for immunotherapy and immune monitoring.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.175.6.4137
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2005
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
    Online Resource
    Generation of EBV-Specific CD4+ Cytotoxic T Cells from Virus Naive Individuals
    The American Association of Immunologists ; 2002
    In:  The Journal of Immunology Vol. 168, No. 2 ( 2002-01-15), p. 909-918
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 168, No. 2 ( 2002-01-15), p. 909-918
    Abstract: Adoptive immunotherapy with EBV-specific CTL (EBV-CTL) effectively prevents and treats EBV-driven lymphoproliferation in immunocompromised hosts. EBV-seronegative solid organ transplant recipients are at high risk of EBV-driven lymphoproliferation because they lack EBV-specific memory T cells. For the same reason, standard techniques for generating EBV-CTL in vitro from EBV-naive individuals are unsuccessful. To overcome this problem, we compared several methods of expanding EBV-CTL from seronegative adults and children. First, the standard protocol, using EBV-transformed lymphoblastoid B cell lines (LCL) as the source of APC, was compared with protocols using EBV-Ag-loaded dendritic cells as APC. Surprisingly, the standard protocol effectively generated CTL from all seronegative adults. The additional finding of EBV-DNA in the peripheral blood of three of these four adults suggested that some individuals may develop cellular, but not humoral, immune responses to EBV. By contrast, LCL failed to reactivate EBV-CTL from any of the six EBV-seronegative children. EBV-Ag-loaded dendritic cells could expand EBV-CTL, but only in a minority of children. However, the selective expansion of CD25-expressing T cells, 9–11 days after activation with LCL alone, proved to be a simple and reliable method for generating EBV-CTL from all seronegative children. The majority of these CTL were CD4+ (71 ± 26%) and demonstrated HLA class II-restricted, EBV-specific killing. Our results suggest that a negative EBV serology does not accurately identify EBV-negative individuals. In addition, our method for selecting EBV-specific CTL from naive individuals by precursor cell enrichment may be applicable to the immunotherapy of cancer patients with a low frequency of tumor- or virus-specific CTL.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.168.2.909
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2002
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    Engineering T cells to prevent graft-versus-host disease and leukemia relapse following allogeneic stem cell transplantation
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 208, No. 1_Supplement ( 2022-05-01), p. 175.22-175.22
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 208, No. 1_Supplement ( 2022-05-01), p. 175.22-175.22
    Abstract: Acute graft-versus-host disease (aGvHD) and leukemia relapse remain major causes of mortality after allogeneic hematopoietic stem cell transplantation (alloHSCT). Prophylaxis and treatment of aGvHD rely on generalized immunosuppression, increasing the risk of tumor relapse and opportunistic infections and emphasizing the need for more targeted therapies. Alloreactive donor CD4+ T cells play a central role in aGvHD pathogenesis, we thus hypothesized that elimination of activated CD4+ T cells with engineered T cells would mitigate aGvHD while preserving protective CD8+ T cell immunity post alloHSCT. We developed an alloimmune defense receptor (ADR) targeting OX40, a surface marker predominantly upregulated on activated CD4+ T cells. OX40 ADR-expressing T cells eliminated activated CD4+ T cells during coculture but spared the majority of activated CD8+ T cells, including virus-specific T cells, and had no discernible activity against resting lymphocytes. A single infusion of ADR T cells fully protected mice from fatal xenogeneic aGvHD induced by intravenous injection of human PBMC, minimizing signs of aGvHD and maximizing survival. To enable simultaneous activity of engineered T cells against aGvHD and leukemia relapse, we further armed ADR T cells with a CD19-directed chimeric antigen receptor (CAR). In a mouse model of residual leukemia post alloHSCT, administration of T cells co-expressing OX40 ADR and CD19 CAR mediated dual protection against tumor relapse and aGvHD. These results support the feasibility of a bi-functional CAR.ADR T cell product to improve outcomes post alloHSCT and reduce transplant-related mortality. Supported by grant from Leukemia & Lymphoma Society.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.208.Supp.175.22
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2022
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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  • 4
    Online Resource
    Online Resource
    Rejection-resistant off-the-shelf T cells for adoptive cell therapy
    The American Association of Immunologists ; 2019
    In:  The Journal of Immunology Vol. 202, No. 1_Supplement ( 2019-05-01), p. 71.8-71.8
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 202, No. 1_Supplement ( 2019-05-01), p. 71.8-71.8
    Abstract: ‘Off-the-shelf’ (OTS) chimeric antigen receptor (CAR) T cells pre-manufactured from healthy donors are a readily available and less expensive alternative to autologous products. However, immune rejection of OTS cells by host T- and NK-cells may limit their persistence and reduce therapeutic effect. Here, we engineered rejection-resistant OTS T cells that recognize and eliminate alloreactive lymphocytes while retaining desired anti-tumor activity. As T- and NK-cells transiently upregulate 4-1BB after activation, T cells expressing a 4-1BB-specific alloimmune defense receptor (ADR) selectively eliminated activated T- and NK-cells while sparing resting lymphocytes. Using this mechanism, ADR-expressing T cells suppressed alloimmune activation and resisted rejection in a mixed lymphocyte reaction (MLR) model in vitro. Further, T cells co-expressing the ADR and a CD19 CAR retained undiminished activity through both receptors in vitro and in vivo. We established a mouse model of allogeneic cell therapy in which NSG mice were engrafted with systemic CD19+ leukemia and normal human T cells. In this model, adoptively transferred unmodified CD19 CAR T cells from an HLA mismatched donor produced only transient anti-tumor activity and were rapidly rejected by pre-engrafted alloreactive T cells within 7 days, leading to fatal leukemia relapse. In contrast, T cells co-expressing both CAR and ADR were protected from immune rejection, resulting in long-term persistence ( & gt;9 weeks) and durable leukemia eradication in most animals. These data support the feasibility of using ADR to generate highly potent OTS CAR T cell products that suppress immune rejection to produce long-term therapeutic benefit even in immunocompetent patients.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.202.Supp.71.8
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2019
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
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