Reconstitution of Cellular Immunity against Cytomegalovirus in Recipients of Allogeneic Bone Marrow by Transfer of T-Cell Clones from the Donor

Walter, Elizabeth; Greenberg, Philip D.; Gilbert, Mark J.; Finch, Rosalynde J.; Watanabe, Kazue; Thomas, E. D.; Riddell, Stanley R.

doi:10.1056/nejm199510193331603

Cited by 1,693 publications

(1,203 citation statements)

References 34 publications

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“…Data from both mouse and human allogeneic studies have shown that donor T cells exhibit decreased allo-reactivity and GVHD potential following ex vivo activation and expansion [2][3][4][5][6]. This loss of allo-reactivity is extremely undesirable because both the conversion to full donor chimerism and the anti-leukemia effect after allogeneic HSCT are mediated, at least in part, by alloreactive donor T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Many of the therapeutic strategies that are being developed to control GVHD while maintaining the beneficial graft-versus-leukemia and/or graft-versus-infection effects provided by donor lymphocyte infusion after allogeneic HSCT require ex vivo T cell stimulation and expansion. Unfortunately, multiple preclinical and clinical studies have demonstrated that these ex vivo expanded T cells exhibit decreased survival and function in vivo, including reduced alloreactivity and GVHD potential [2][3][4][5][6]. Recently, others and we described an ex vivo method for expansion of human T (huT) cells, using anti-CD3 and anti-CD28 monoclonal antibodies that are covalently attached to superparamagnetic microbeads (CD3/CD28 beads) [7,8].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Nervi

Rettig

Ritchey

et al. 2007

Experimental Hematology

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Objective-Graft-versus-host disease (GVHD) is the major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Models of immunodeficient mice that consistently and efficiently reconstitute with xenoreactive human T cells would be a valuable tool for the in vivo study of GVHD, as well as other human immune responses.Materials and Methods-We developed a consistent and sensitive model of human GVHD by retro-orbitally injecting purified human T cells into sublethally irradiated NOD/SCID-β2m null recipients. In addition, we characterized for the first time the trafficking patterns and expansion profiles of xenoreactive human T cells in NOD/SCID-β2m null recipients using in vivo bioluminescence imaging.Results-All NOD/SCID-β2m null mice conditioned with 300 cGy of total body irradiation and injected with 1 × 10 7 human T cells exhibited human T cell engraftment, activation, and expansion, with infiltration of multiple target tissues and a subsequent greater than 20% loss of pretransplant body weight. Importantly, histological examination of the GVHD target tissues revealed changes consistent with human GVHD. Furthermore, we also showed by in vivo bioluminescence imaging that the development of lethal GVHD in the NOD/SCID-β2m null recipients was dependent upon the initial retention and early expansion of human T cells in the retroorbital sinus cavity.Conclusion-Our NOD/SCID-β2m null mouse model provides a system to study the pathophysiology of acute GVHD induced by human T cells and aids in the development of more effective therapies for human GVHD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Nervi

Rettig

Ritchey

et al. 2007

Experimental Hematology

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“…Antivirals also favor late-onset CMV disease [4], and the occurrence of resistant CMV strains [5]. In search of therapeutic alternatives, the reconstitution of protective T cell immunity by adoptive transfer of CMV-specific T cells has been successfully performed [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…However, clinical studies on CMV indicated that the acquisition of both CD8 + and CD4 + antigen-specific T cells was necessary for long-term maintenance of specific T cell immunity and therapeutic efficacy [5,7,8]. CD4 + T cells have an important role in the establishment of a functional CD8 + T cell memory [15,16].…”

Section: Introductionmentioning

confidence: 99%

Selection of CMV-specific CD8+ and CD4+ T cells by mini-EBV-transformed B cell lines

et al. 2005

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Efficient protocols to generate cytomegalovirus (CMV)-specific T cells are required for adoptive immunotherapy. Recombinant Epstein-Barr virus (EBV) vectors called mini-EBV can be used to establish permanent B cell lines in a single step, which present the CMV antigen pp65 in a constitutive manner. These B cell lines, coined pp65 mini-LCL, were successfully used to reactivate and expand CMV-specific cytotoxic T cells. Here we evaluate this pp65 mini-EBV system in closer detail, focusing on (1) the quantification of T cells with specific effector function and (2) the identification of CMV-specific CD4 + helper T cells. The co-expansion of various functional CMV epitope specificities was demonstrated by IFN-c enzyme-linked immunospot assay (ELISPOT) assays and HLApeptide tetramer staining. Single-cell cloning resulted in both CD4 + and CD8 + T cell clones, the majority of which was CMV specific. Thus, mini-LCL present the pp65 antigen on HLA class I and II, mobilizing both arms of the T cell response. Using a peptide library covering the pp65 sequence for further analysis of T cell clones, we identified new pp65 CD8 + and CD4 + T cell epitopes.

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“…It is clear that there is generally a similar requirement to help the CTL response [4,5]. This applies also to adoptive transfer of CTL to attack viruses such as CMV, where the transferred CTL only survive and function efficiently with co-transferred Th cells [6].…”

Section: Importance Of T-cell Helpmentioning

confidence: 99%

Optimizing cancer immunotherapy trials: Back to basics

Stevenson¹,

Rice²

2006

Eur J Immunol

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Attempts to raise effective immunity against cancer are benefiting from information on the nature of the immunity involved and its regulation and, perhaps, now it is time to step back and define our approach in molecular terms prior to clinical testing. Although there are immunological differences between mice and patients, results from murine studies are encouraging early 'translation' of concepts to the clinic and it is vital to take immunological principles emerging from mice into clinical vaccine design. One is the requirement to break tolerance against over-expressed self-antigens, a potentially risky procedure but necessary for several cancer targets. A study in this issue of the European Journal of Immunology attempts to do this by using xenogeneic antigens, albeit with variable outcome. The unstated goal is to activate T-cell help but this can be achieved more effectively by harnessing a predictable anti-microbial repertoire. The second issue lies in the delivery of antigen. One strategy is "prime/boost" using DNA priming and boosting with a viral vector; however, this induces blocking immunity against viral proteins, and must be used judiciously. There are other physical methods to increase immunity such as electroporation, which can itself be used in 'prime/boost' sequence. These twin problems of engagement of T-cell help and delivery of adequate antigen can now be addressed by applying immunological logic to cancer vaccines.See accompanying article http://dx

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Reconstitution of Cellular Immunity against Cytomegalovirus in Recipients of Allogeneic Bone Marrow by Transfer of T-Cell Clones from the Donor

Abstract: The transfer of CMV-specific clones of CD8+ T cells derived from the bone marrow donor is a safe and effective way to reconstitute cellular immunity against CMV after allogeneic marrow transplantation.

Cited by 1,693 publications

References 34 publications

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Factors affecting human T cell engraftment, trafficking, and associated xenogeneic graft-vs-host disease in NOD/SCID β2mnull mice

Selection of CMV-specific CD8+ and CD4+ T cells by mini-EBV-transformed B cell lines

Optimizing cancer immunotherapy trials: Back to basics

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