Effect of interleukin‐15 on anti‐CD3/anti‐CD28 induced apoptosis of umbilical cord blood CD4<sup>+</sup> T cells

Lin, Syh‐Jae; Yu, Jung-Chuan; Cheng, Po‐Jen; Hsiao, Shiu-Shan; Kuo, Ming‐Ling

doi:10.1046/j.0902-4441.2003.00162.x

Cited by 12 publications

(12 citation statements)

References 31 publications

(31 reference statements)

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“…CD3/TCR signaling activates STAT5 and when this signaling leads to apoptosis, it is dependant on Fas/FasL interactions [48,49]. IL-15 exacerbates apoptosis in CD4+ T cells activated with anti-CD3 and anti-CD28, potentially by recruiting more blasts capable to die [50]. AgICD requires Fas/FasL interactions, does not require perforin or granzymes, and TNF-α is thought to play a late role in the process [51].…”

Section: Discussionmentioning

confidence: 99%

Tumor-derived macrophage migration inhibitory factor (MIF) inhibits T lymphocyte activation

2006

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Macrophage migration inhibitory factor (MIF) is a multi-functional cytokine that is considered a proinflammatory cytokine. However, our studies show that MIF, when produced in super-physiological levels by a murine neuroblastoma cell line (Neuro-2a) exceeding those normally seen during an immune response, inhibits cytokine-, CD3-, and allo-induced T-cell activation. MIF is also able to inhibit T cells that have already received an activation signal. The T-cell inhibitory effects of culture supernatants from neuroblastoma cells were reversed when the cells were transfected with dicergenerated si-RNA to MIF. When T cells were activated in vitro by co-culture with interleukin (IL)-2 and IL-15 and analyzed for cytokine production in the presence or absence of MIF-containing culture supernatant, inhibition of T-cell proliferation and induced cell death were observed even as the treated T cells produced high levels of interferon-gamma (IFN-γ). The inhibitory effects of MIF were partially reversed when lymphocytes from IFN-γ knockout mice were tested. We propose that the high levels of MIF produced by neuroblastoma cause activation induced T-cell death through an IFN-γ pathway and may eliminate activated T cells from the tumor microenvironment and thus contribute to escape from immune surveillance.

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Section: Discussionmentioning

confidence: 99%

Tumor-derived macrophage migration inhibitory factor (MIF) inhibits T lymphocyte activation

2006

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“…We also showed that survival of CB T cells post-activation can be improved to a greater degree by IL-15 than their adult counterparts. The timing of IL-15 administration is important, as IL-15 promotes AICD of CB CD4 + T cells when used with TCR cross-linking [18] while serving as a survival factor when PHA-activated CB MNCs were washed before culture with IL-15.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous reports have addressed the deficient CB T and NK function compared to adults and their enhancement with IL-15 [18,27], suggesting that IL-15 immunotherapy may alleviate the problems of delayed engraftment and infection susceptibility following CB transplantation. In addition to its IL-2-like activities, we demonstrated in the present study the unique effect of IL-15 on the survival enhancement and apoptosis protection of PHA activated CB T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Unlike IL-2, IL-15 also promotes the survival of CD8 memory phenotype T cells [14] and greatly enhances HIV-specific cytotoxic T lymphocyte (CTL) function [15]. Our previous work demonstrated the differential effects of IL-15 on CB and APB T-cell activation and apoptosis in several in vitro experimental settings and showed that CB T cells readily responded to IL-15 [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Differential effect of IL‐15 and IL‐2 on survival of phytohemagglutinin‐activated umbilical cord blood T cells

et al. 2005

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Cytokine immunotherapy using interleukin (IL)-2 and IL-15 may be beneficial for patients receiving umbilical cord blood (CB) transplantation by ameliorating post-transplant T-cell apoptosis. The present study compares the differential effect of IL-15 and IL-2 on survival of phytohemagglutinin (PHA)-activated CB and adult peripheral blood (APB) T lymphocytes. In comparison with IL-2, IL-15 preferentially enhanced the survival of CB PHA-activated T cells by decreasing the caspase-3 + population and by increasing the Bcl-2 + population. Activated CB T cells were more susceptible to TNF-a-induced apoptosis compared to their adult counterparts. However, the susceptibility could be abrogated by IL-15 but not by IL-2. IL-15 but not IL-2 down-regulated CD28 expression on both activated CB and APB CD8 + T cells, with a much greater effect seen with CB. Westernblot analysis shows that IL-15 Ra is deficient in CB compared to APB immediately after PHA stimulation, while culturing with IL-15 significantly enhanced CB IL-15 Ra expression to levels comparable to that of adults. Thus, IL-15 may provide a better therapeutic choice for immune reconstitution than IL-2 post-CB transplantation due to its preferential survival enhancing effect on CB T cells. Am.

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“…While UCB-derived T cells can be propagated ex vivo, [43][44][45][46][47][48][49] the functional immaturity of T cells in circulating umbilical cord blood typically prevents ex vivo identification of endogenous leukemia/ lymphoma-specific T cells. Therefore, we developed a genetic engineering strategy to introduce a chimeric immunoreceptor in order to generate UCB-derived T cells with desired specificity.…”

Section: Discussionmentioning

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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Effect of interleukin‐15 on anti‐CD3/anti‐CD28 induced apoptosis of umbilical cord blood CD4⁺ T cells

Abstract: IL-15 preferentially resulted in an activation-enhancing effect on CB CD4+ T cells, accompanied by increased apoptosis. Our finding may have therapeutic implications while designing IL-15 immunotherapy for patients receiving CB transplant.

Cited by 12 publications

References 31 publications

Tumor-derived macrophage migration inhibitory factor (MIF) inhibits T lymphocyte activation

Tumor-derived macrophage migration inhibitory factor (MIF) inhibits T lymphocyte activation

Differential effect of IL‐15 and IL‐2 on survival of phytohemagglutinin‐activated umbilical cord blood T cells

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

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Effect of interleukin‐15 on anti‐CD3/anti‐CD28 induced apoptosis of umbilical cord blood CD4+ T cells

Abstract: IL-15 preferentially resulted in an activation-enhancing effect on CB CD4+ T cells, accompanied by increased apoptosis. Our finding may have therapeutic implications while designing IL-15 immunotherapy for patients receiving CB transplant.

Cited by 12 publications

References 31 publications

Tumor-derived macrophage migration inhibitory factor (MIF) inhibits T lymphocyte activation

Tumor-derived macrophage migration inhibitory factor (MIF) inhibits T lymphocyte activation

Differential effect of IL‐15 and IL‐2 on survival of phytohemagglutinin‐activated umbilical cord blood T cells

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

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Effect of interleukin‐15 on anti‐CD3/anti‐CD28 induced apoptosis of umbilical cord blood CD4⁺ T cells