PD-L1 serves as a double agent in separating GVL from GVHD

Brennan, Todd V.; Yang, Yiping

doi:10.1172/jci94196

Cited by 10 publications

(10 citation statements)

References 31 publications

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“…The primary clinical approach to treating GVHD after allogeneic BMT is immunosuppression (7). However, immunosuppression also increases risk of infection; compromises graft viability; and, in the case of HSCT as part of cancer therapy, can dampen graft-versus-tumor activity (60)(61)(62)(63)(64)(65)(66). Thus, there is an urgent need for alternate approaches to prevent GVHD development or reduce its severity.…”

Section: Discussionmentioning

confidence: 99%

Graft-versus-host disease propagation depends on increased intestinal epithelial tight junction permeability

Nalle¹,

Zuo²,

Ong³

et al. 2019

Journal of Clinical Investigation

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Graft-versus-host disease (GVHD) is a complication of hematopoietic stem cell transplantation (HSCT) that affects multiple organs. GVHD-associated intestinal damage can be separated into two distinct phases, initiation and propagation, which correspond to conditioning-induced damage and effector T cell activation and infiltration, respectively. Substantial evidence indicates that intestinal damage induced by pretransplant conditioning is a key driver of GVHD initiation. Here, we aimed to determine the impact of dysregulated intestinal permeability on the subsequent GVHD propagation phase. The initiation phase of GVHD was unchanged in mice lacking long MLCK (MLCK210), an established regulator of epithelial tight junction permeability. However, MLCK210-deficient mice were protected from sustained barrier loss and exhibited limited GVHD propagation, as indicated by reduced histopathology, fewer CD8 + effector T cells in the gut, and improved overall survival. Consistent with these findings, intestinal epithelial MLCK210 expression and enzymatic activity were similarly increased in human and mouse GVHD biopsies. Intestinal epithelial barrier loss mediated by MLCK210 is therefore a key driver of the GVHD propagation. These data suggest that inhibition of MLCK210-dependent barrier regulation may be an effective approach to limiting GVHD progression.

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Section: Discussionmentioning

confidence: 99%

Graft-versus-host disease propagation depends on increased intestinal epithelial tight junction permeability

Nalle¹,

Zuo²,

Ong³

et al. 2019

Journal of Clinical Investigation

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“…Both HLA‐mismatched HSCT and DLI have a stronger antitumor effect than HLA‐matched HSCT, but they may also bring a greater risk of GVHD, one of the fatal complications after HSCT . Therefore, efforts have been made over the last 2 decades to explore the difference between the mechanism of GVT and GVHD and to design strategies to separate GVT from GVHD . One important difference is that the threshold number of T cells triggering GVT is relatively lower.…”

Section: Discussionmentioning

confidence: 99%

“…(31)(32)(33)(34) Therefore, efforts have been made over the last 2 decades to explore the difference between the mechanism of GVT and GVHD and to design strategies to separate GVT from GVHD. (35,36) One important difference is that the threshold number of T cells triggering GVT is relatively lower. This assumption is supported by clinical experience that low-dose DLI is generally sufficient to reduce the risk of relapse of the tumor without GVHD.…”

Section: Discussionmentioning

confidence: 99%

Graft‐Versus‐Tumor Effect in Major Histocompatibility Complex–Mismatched Mouse Liver Transplantation

Wang²,

et al. 2019

Liver Transpl

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Liver transplantation (LT) is currently considered an important method in treating hepatocellular carcinoma (HCC) and an alternative treatment for other liver malignancies. Here, we demonstrated that the graft‐versus‐tumor (GVT) effect exists in allogeneic liver transplantation (allo LT). Recipient‐derived T cells played a critical role in the GVT process of allo LT, as demonstrated by extensive infiltration and significant activation of recipient T cells in the tumor after surgery. Moreover, this process was related to donor‐derived T/B cells by improving the immune microenvironment in the tumor, as demonstrated by elevated levels of interferon‐γ (IFN‐γ), tumor necrosis factor‐α (TNF‐α), interleukin‐2 (IL‐2), IL‐6, IL‐16, chemokine (C‐X‐C motif) ligand 10 (CXCL10), and CXCL11 and decreased levels of IL‐10 and IL‐4 at tumor sites. Additionally, tacrolimus (FK506) treatment inhibited the GVT effect on allo LT. Donor liver‐derived T/B cells infiltrate extrahepatic tumors to trigger a strong T‐cell‐mediated immune response and thus improve the tumor immune microenvironment.

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“…The importance of MHC and miHC antigens in GVL is underlined by the close association between GVHD and GVL, although selective miHC antigens are considered to be attractive targets for anti-leukemia immunotherapy. More recently, a number of studies have demonstrated that the overall balance between regulatory cells, including Treg, MDSC, and effector cells might be related to the extent of organ damage in GVHD settings and the effects of GVL in anti-leukemia settings (Figures 1– 3 ) (21, 22, 25, 52, 53, 57).…”

Section: Mechanisms Relevant To Gvhd and Gvl Effectsmentioning

confidence: 99%

“…The challenge for the separation of GVL effects from GVHD is attributed to the underlying similarity of the alloreactive T responses between the two processes (4, 21, 22). In the past 20 years, great efforts have been made by researchers to elucidate specific distinguishing immune mechanisms of GVL vs. GVHD (23–25).…”

Section: Introductionmentioning

confidence: 99%

Strategies for Enhancing and Preserving Anti-leukemia Effects Without Aggravating Graft-Versus-Host Disease

2018

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Allogeneic stem cell transplantation (allo-SCT) is a curable method for the treatment of hematological malignancies. In the past two decades, the establishment of haploidentical transplant modalities make “everyone has a donor” become a reality. However, graft-versus-host disease (GVHD) and relapse remain the major two causes of death either in the human leukocyte antigen (HLA)-matched transplant or haploidentical transplant settings, both of which restrict the improvement of transplant outcomes. Preclinical mice model showed that both donor-derived T cells and natural killer (NK) cells play important role in the pathogenesis of GVHD and the effects of graft-versus-leukemia (GVL). Hence, understanding the immune mechanisms of GVHD and GVL would provide potential strategies for the control of leukemia relapse without aggravating GVHD. The purpose of the current review is to summarize the biology of GVHD and GVL responses in preclinical models and to discuss potential novel therapeutic strategies to reduce the relapse rate after allo-SCT. We will also review the approaches, including optimal donor selection and, conditioning regimens, donor lymphocyte infusion, BCR/ABL-specific CTL, and chimeric antigen receptor-modified T cells, which have been successfully used in the clinic to enhance and preserve anti-leukemia activity, especially GVL effects, without aggravating GVHD or alleviate GVHD.

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PD-L1 serves as a double agent in separating GVL from GVHD

Cited by 10 publications

References 31 publications

Graft-versus-host disease propagation depends on increased intestinal epithelial tight junction permeability

Graft-versus-host disease propagation depends on increased intestinal epithelial tight junction permeability

Graft‐Versus‐Tumor Effect in Major Histocompatibility Complex–Mismatched Mouse Liver Transplantation

Strategies for Enhancing and Preserving Anti-leukemia Effects Without Aggravating Graft-Versus-Host Disease

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