Programming of donor T cells using allogeneic δ-like ligand 4–positive dendritic cells to reduce GVHD in mice

Mochizuki, Kazuhiro; Meng, Lijun; Mochizuki, Izumi; Tong, Qing; He, Shan; Liu, Yongnian; Purushe, Janaki; Fung, Henry C.; Zaidi, M. Raza; Zhang, Yanyun; Reshef, Ran; Blazar, Bruce R.; Yagita, Hideo; Mineishi, Shin; Zhang, Yi

doi:10.1182/blood-2015-05-644476

Cited by 22 publications

(46 citation statements)

References 58 publications

(85 reference statements)

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“…The autologous lymphocytes isolated from a patient’s own peripheral blood are endowed with the ability of tumor antigen specificity and rendered capable of eliminating cancer cells expanded ex vivo, and then reinfused into the patient to attack any malignant tumor [7–10]. The majority of preclinical and clinical data regarding autologous T cells have highlighted the safety of using the cell therapy and the lack of potential for graft-versus-host disease (GvHD) mediated by the allogeneic T cells [11–13]. The T cell receptor (TCR), an α/β heterodimer, has the ability to redirect the tumor antigens in a major histocompatibility-complex-dependent (MHC) manner [14–16].…”

Section: Introductionmentioning

confidence: 99%

A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy

2017

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Adoptive cell therapy using chimeric antigen receptor (CAR)-engineered T cells has emerged as a very promising approach to combating cancer. Despite its ability to eliminate tumors shown in some clinical trials, CAR-T cell therapy involves some significant safety challenges, such as cytokine release syndrome (CRS) and “on-target, off-tumor” toxicity, which is related to poor control of the dose, location, and timing of T cell activity. In the past few years, some strategies to avoid the side effects of CAR-T cell therapy have been reported, including suicide gene, inhibitory CAR, dual-antigen receptor, and the use of exogenous molecules as switches to control the CAR-T cell functions. Because of the advances of the CAR paradigm and other forms of cancer immunotherapy, the most effective means of defeating the cancer has become the integration therapy with the combinatorial control system of switchable dual-receptor CAR-T cell and immune checkpoint blockade.

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Section: Introductionmentioning

confidence: 99%

A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy

2017

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“…10 These cells are CD8α − CD11b + and produce high levels of inducible nitric oxide synthase and arginase, resembling in vivo–generated inflammatory DCs. 14,72,73 Transcription factors, including CCAAT/enhancer-binding protein beta (CEBPB), IRF4, KLF4, STAT5, RELB, and CCAAT/enhancer-binding protein alpha, are able to regulate moDC differentiation. 24,26,29 Granulocyte macrophage colony-stimulating factor–driven moDC differentiation requires expression of functional IRF4 and CEBPB.…”

Section: Transcription Factors and Generation Of Distinct DC Subsetsmentioning

confidence: 99%

“…In contrast, despite inflammatory stimuli, activation of moDCs cannot induce DLL4. 72,73,97 Third, IRF8 binds more than 30,000 enhancer regions (e.g., H3K4me1) highly enriched in pDCs. Enforced IRF8 expression leads to down-regulation of IRF4 and CEBPB, thereby directing the epigenetic landscape toward a pDC-specific pattern.…”

Section: Epigenetic Programming Of DC Heterogeneity and Heritabilitymentioning

confidence: 99%

Epigenetic Regulation of Dendritic Cell Development and Function

Tian¹,

Meng²,

Zhang³

2017

Cancer J

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The immune system is characterized by the generation of structurally and functionally heterogeneous immune cells that constitute complex innate and adaptive immunity. This heterogeneity of immune cells results from changes in the expression of genes without altering DNA sequence. To achieve this heterogeneity, immune cells orchestrate the expression and functional status of transcription factor (TF) networks, which can be broadly categorized into 3 classes: pioneer TFs that facilitate initial commitment and differentiation of hematopoietic cells, subset-specific TFs that promote the generation of selected cell lineages, and immune-signaling TFs that regulate specialized function in differentiated cells. Epigenetic mechanisms are known to be critical for organizing the TF networks, thereby controlling immune cell lineage-fate decisions, plasticity, and function. The effects of epigenetic regulators can be heritable during cell mitosis, primarily through the modification of DNA and histone methylation patterns at gene loci. By doing so, the immune system is enabled to mount a selective but robust response to stimuli, such as pathogens, tumor cells, autoantigens, or allogeneic antigens in the setting of transplantation, while preserving the immune cell reservoir necessary for protecting the host against numerous other unexpected stimuli and limit detrimental effect of systemic inflammatory reactions.

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“…Donor naïve T cells were then primed with DLL4-hi iDCs in vitro , resulting in IFN-γ and IL-17 producing effector T cells. When these DLL4-hi iDC-primed T cells were transferred at the time of allo-HSCT, mice that received these cells developed minimal GVHD, while mice receiving naïve donor T cells developed lethal GVHD (56). Although these findings are interesting, this study did not assess if Notch signaling specifically was the responsible pathway for the outcome rather than other signaling pathways.…”

Section: Notch and Immune Regulation Of The Alloimmune Responsementioning

confidence: 99%

Notch Signaling and Immune Regulation in Alloimmunity

2016

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Notch signaling plays a pivotal role in the differentiation and fate determination of T cells, B cells, dendritic cells (DCs) and innate lymphoid cells (ILCs). Recent gene-targeting and antibody approaches advanced our knowledge of the importance of Notch signaling in fine-tuning the peripheral immune response. Here we review current knowledge of the Notch pathway, focusing on solid organ transplant and graft-versus-host disease preclinical models, and discuss the potential of targeting Notch to suppress the immune response and improve transplant outcomes.

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Programming of donor T cells using allogeneic δ-like ligand 4–positive dendritic cells to reduce GVHD in mice

Cited by 22 publications

References 58 publications

A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy

A new insight in chimeric antigen receptor-engineered T cells for cancer immunotherapy

Epigenetic Regulation of Dendritic Cell Development and Function

Notch Signaling and Immune Regulation in Alloimmunity

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