Cellular Alloreactivity of Human Cord Blood Cells Detected by T-Cell Frequency Analysis and a Human Skin Explant Model1

Wang, Xiao N.; Sviland, Lisbet; Ademokun, Adebo J.; Dunn, J.; Cavanagh, G.; Proctor, Stephen J.; Dickinson, Anne M.

doi:10.1097/00007890-199810150-00015

Cited by 20 publications

(8 citation statements)

References 23 publications

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“…The decreased incidence of severe GVHD after pediatric UCBT may be due to a reduction in the magnitude of the cytotoxic alloresponse in neonatal T cells, [36][37][38][39] and this reduction may compromise the ability of genetically modified UCB-derived T cells to kill tumor targets. Therefore, we determined whether UCB-derived T cells expressing the CD19R transgene could specifically lyse CD19 ϩ tumor targets.…”

Section: Genetically Modified Ucb-derived T Cells Exhibit Redirected mentioning

confidence: 99%

Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy

Serrano

Pfeiffer

Olivares

et al. 2006

Blood

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Disease relapse is a barrier to achieving therapeutic success after unrelated umbilical cord-blood transplantation (UCBT) for B-lineage acute lymphoblastic leukemia (B-ALL). While adoptive transfer of donor-derived tumor-specific T cells is a conceptually attractive approach to eliminating residual disease after allogeneic hematopoietic stem cell transplantation, adoptive immunotherapy after UCBT is constrained by the difficulty of generating antigen-specific T cells from functionally naive umbilical cord-blood (UCB)-derived T cells. Therefore, to generate T cells that recognize B-ALL, we have developed a chimeric immunoreceptor to redirect the specificity of T cells for CD19, a B-lineage antigen, and expressed this transgene in UCB-derived T cells. An ex vivo process, which is compliant with current good manufacturing practice for T-cell trials, has been developed to genetically modify and numerically expand UCB-derived T cells into CD19-specific effector cells. These are capable of CD19-restricted cytokine production and cytolysis in vitro, as well as mediating regression of CD19 ؉ tumor and being selectively eliminated in vivo. Moreover, time-lapse microscopy of the genetically modified T-cell clones revealed an ability to lyse CD19 ؉ tumor cells specifically and repetitively. These data provide the rationale for infusing UCB-derived CD19-specific T cells after UCBT to reduce the incidence of CD19 ؉ B-ALL relapse. IntroductionBanked unrelated umbilical cord blood (UCB) is source of hematopoietic stem cells for patients with B-lineage acute lymphoblastic leukemia (B-ALL). 1 However, despite maximally intensive preparative regimens, disease-relapse remains a significant cause of mortality after umbilical cord-blood transplantation (UCBT).Adoptive therapy after allogeneic hematopoietic stem cell transplantation (HSCT) with ex vivo-expanded donor-derived tumor-specific T cells might be used to augment the graft-versusleukemia (GVL)-effect, thereby reducing the incidence of leukemic relapse, without exacerbating graft-versus-host disease (GVHD). 2,3 While the feasibility of isolating, expanding, and infusing antigen-specific ␣␤ T-cell receptor (TCR) ϩ T cells from peripheral blood (PB) has been validated in animals and humans, 4-10 the naive function of neonatal T cells precludes a priori identification of resident tumor-specific T cells. Redirecting the specificity of T cells through enforced expression of antigenspecific immunoreceptors and differentiating UCB-derived T cells into cytotoxic T lymphocytes (CTLs) is one approach to overcoming this lack of endogenous tumor-specific T cells specific for desired targets. 11,12 We and others are developing adoptive immunotherapy platforms using single-chain chimeric immunoreceptors to redirect the specificity of primary human T cells and NK cells for cell-surface proteins expressed on tumor targets, such as the B-lineage-specific antigen CD19, a molecule expressed on normal and neoplastic B cells. [13][14][15][16][17][18][19][20][21][22] These chimeric immunoreceptor...

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Section: Genetically Modified Ucb-derived T Cells Exhibit Redirected mentioning

confidence: 99%

Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy

Serrano

Pfeiffer

Olivares

et al. 2006

Blood

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“…24 25 The immunological mechanism underlying this phenomenon is not clear, so a study was set up to investigate the alloreactive capacity of cord blood cells in vitro using the skin explant model. 26 The results showed, for the first time, that cord blood mononuclear cells are less able to induce skin GVH type alloreactivity in vitro. Some changes typical of a GVHD reaction were still seen, but the grade of histological damage was less than that induced by peripheral blood mononuclear cells.…”

Section: The Skin Explant Model As a Research Toolmentioning

confidence: 88%

A human skin explant model for predicting graft-versus-host disease following bone marrow transplantation.

Sviland¹,

Dickinson²

1999

J Clin Pathol

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Graft-versus-host disease (GVHD) is the most serious complication following bone marrow transplantation, with an incidence of 40-60%. The disease can be fatal in 50% of cases, even in patients receiving marrow from an HLA identical sibling. Several assays have been developed to try to predict the development of GVHD, including mixed lymphocyte culture reaction, cytotoxic T lymphocyte precursor, and helper T lymphocyte precursor frequency assays. This review describes an in vitro skin explant model which has been used since 1988 for both predicting acute GVHD in HLA identical sibling bone marrow transplantation and studying the pathophysiology of the disease. The model involves sensitising donor lymphocytes in vitro in a primary mixed lymphocyte reaction and then evaluating the secondary response on patient skin biopsies by grading the graft-versus-host reactivity (grades I-IV) histopathologically. From analysis of collective data the model is a clear predictor of GVHD and superior to the other assays widely used, with a correlation of 82% with clinical outcome. The skin explant model allows the investigator to study the pathogenesis of GVHD. The cytokines TNF and IFN are shown to be important mediators of cellular damage in graft-versus-host reactions. Recent work has also involved using the model to study the alloreactivity of cord blood. The model is currently being assessed in several bone marrow transplantation centres in Europe on diVerent patient groups including those who receive marrow from haploidentical and matched unrelated donors. (J Clin Pathol 1999;52:910-913)

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“…Comparison with in vitro systems that model allograft tissue rejection (18)(19)(20) may provide an explanation for the lack of success in the present experimental design.…”

Section: Discussionmentioning

confidence: 99%

“…and organ tissues. However, these systems are generally designed to study allograft rejection and as such, differences in tissue histocompatibility are an integral feature in such models (18)(19)(20). Since differences in histocompatibility may themselves induce an immune response, the use of immunologically distinct tissues may compromise a model intended for the study of immune activation induced by tissue necrosis.…”

Section: Executive Summarymentioning

confidence: 99%

Evaluation of an In Vitro of Human Immune Activation Induced by Freeze-Thaw Tissue Damage

DuBose¹,

Rufolo²,

Morehouse³

2002

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Cellular Alloreactivity of Human Cord Blood Cells Detected by T-Cell Frequency Analysis and a Human Skin Explant Model1

Cited by 20 publications

References 23 publications

Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy

Differentiation of naive cord-blood T cells into CD19-specific cytolytic effectors for posttransplantation adoptive immunotherapy

A human skin explant model for predicting graft-versus-host disease following bone marrow transplantation.

Evaluation of an In Vitro of Human Immune Activation Induced by Freeze-Thaw Tissue Damage

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