Novel Biomarkers for Outcome After Allogeneic Hematopoietic Stem Cell Transplantation

Chen, Sophia; Zeiser, Robert

doi:10.3389/fimmu.2020.01854

Cited by 14 publications

(10 citation statements)

References 119 publications

(125 reference statements)

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“…Despite the idea from non-conditioned xenogeneic transplant studies that cytokines may not be essential for GVHD development, they have been one of the most heavily investigated potential mechanisms for GVHD prevention and treatment. Surprisingly though, there has not yet been a clinical study identifying any of these inflammatory cytokines as biomarkers of the GVH response ( 102 , 103 ). To date, the best biomarkers for HSCT are sST2 and REG3α, all of which are not secreted by immune cells ( 73 , 74 , 104 ).…”

Section: Extracellular Messengers: Signalmentioning

confidence: 99%

GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

2021

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Graft-vs-host disease (GVHD) is the most common cause of non-relapse mortality following allogeneic hematopoietic stem cell transplantation (HSCT) despite advances in conditioning regimens, HLA genotyping and immune suppression. While murine studies have yielded important insights into the cellular responses of GVHD, differences between murine and human biology has hindered the translation of novel therapies into the clinic. Recently, the field has expanded the ability to investigate primary human T cell responses through the transplantation of human T cells into immunodeficient mice. These xenogeneic HSCT models benefit from the human T cell receptors, CD4 and CD8 proteins having cross-reactivity to murine MHC in addition to several cytokines and co-stimulatory proteins. This has allowed for the direct assessment of key factors in GVHD pathogenesis to be investigated prior to entering clinical trials. In this review, we will summarize the current state of clinical GVHD research and discuss how xenogeneic HSCT models will aid in advancing the current pipeline of novel GVHD prophylaxis therapies into the clinic.

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Section: Extracellular Messengers: Signalmentioning

confidence: 99%

GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

2021

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“…The identification of novel predictive biomarkers of allo-HSCT outcome is an important endeavor that many groups have investigated in the past using serum analytes as biomarkers [17][18][19] . As such, the direct investigation of T cells as a source of predictive biomarkers represents an exciting new field of biomarker research.…”

Section: Discussionmentioning

confidence: 99%

“…While pre-transplant prognostic variables such as HLA-matching, conditioning regimens and graft source all influence allo-HSCT outcomes, these population-based variables are not able to predict individual patient outcomes [17][18][19] . Several post-transplant predictive variables have been discovered including sST2, REG3α, elafin and others [20][21][22][23][24][25][26] .…”

Section: Introductionmentioning

confidence: 99%

Inflammatory CD4/CD8 double positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology

Hess

Turicek

Nadiminti

et al. 2022

Preprint

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Acute graft-vs-host disease (aGVHD) and tumor relapse remain the primary complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT) for malignant blood disorders. While post-transplant cyclophosphamide has reduced the overall prevalence and severity of aGVHD, relapse rates remain a concern. Thus, there remains a need to identify the specific human T cell subsets mediating GVHD pathology versus graft-versus-leukemia (GVL) effects. In xenogeneic transplantation studies using primary human cells from a variety of donors and tissue sources, we observed the development of a mature CD4+/CD8αβ+ double positive T cell (DPT) population in mice succumbing to lethal aGVHD but not in mice that failed to develop aGVHD. The presence of DPT, irrespective of graft source, was predictive of lethal GVHD as early as one week after xenogeneic transplantation. DPT co-express the master transcription factors of the CD8 and CD4 lineages, RUNX3 and THPOK respectively, and produce both cytotoxic and modulatory cytokines. To identify the origin of DPT, we transplanted isolated human CD4 or CD8 T cells, which in turn revealed that DPT only arise from the CD8 pool. Interestingly, re-transplantation of sorted CD8 T cells from GVHD mice did not reveal a second wave of DPT differentiation. Re-transplantation of flow-sorted DPT, CD8 or CD4 T cells from GVHD mice revealed that DPT are sufficient to mediate GVHD pathology but not GVL effects versus B-cell acute lymphoblastic leukemia. Lastly, we confirmed the presence and correlation of DPT with aGVHD pathology in a small cohort of allo-HSCT patients that developed grade 2-4 aGVHD in our clinic. Further understanding of DPT differentiation and pathology may lead to targeted prophylaxis and/or treatment regimens for aGVHD and potentially other human chronic inflammatory diseases.

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“…While pretransplant prognostic variables such as HLA matching, conditioning regimens, and graft source all influence allo-HCT outcomes, these population-based variables are not able to predict individual patient outcomes (17)(18)(19). Several posttransplant predictive variables have been found, including sST2, REG3α, elafin, and others (20)(21)(22)(23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory CD4/CD8 double-positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology

et al. 2023

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An important paradigm in allogeneic hematopoietic cell transplantations (allo-HCTs) is the prevention of graft-versus-host disease (GVHD) while preserving the graft-versus-leukemia (GVL) activity of donor T cells. From an observational clinical study of adult allo-HCT recipients, we identified a CD4 + /CD8 + double-positive T cell (DPT) population, not present in starting grafts, whose presence was predictive of ≥ grade 2 GVHD. Using an established xenogeneic transplant model, we reveal that the DPT population develops from antigen-stimulated CD8 T cells, which become transcriptionally, metabolically, and phenotypically distinct from single-positive CD4 and CD8 T cells. Isolated DPTs were sufficient to mediate xeno-GVHD pathology when retransplanted into naïve mice but provided no survival benefit when mice were challenged with a human B-ALL cell line. Overall, this study reveals human DPTs as a T cell population directly involved with GVHD pathology.

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Novel Biomarkers for Outcome After Allogeneic Hematopoietic Stem Cell Transplantation

Cited by 14 publications

References 119 publications

GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

GVHD Pathogenesis, Prevention and Treatment: Lessons From Humanized Mouse Transplant Models

Inflammatory CD4/CD8 double positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology

Inflammatory CD4/CD8 double-positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology

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