Translational and clinical advances in acute graft-versus-host disease

Gooptu, Mahasweta; Koreth, John

doi:10.3324/haematol.2019.240309

Cited by 24 publications

(19 citation statements)

References 109 publications

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“…Acute GVHD is driven by donor's lymphocytes and inflammatory cytokine cascade, while chronic GVHD involves inflammation, immune dysregulation and fibrosis. (3,4) In children with malignant disorders, graft-versus-host effect may correlate with graft-versus-leukemia effect and contribute to reduction of relapse; (5,6) however, there is no benefit of GVHD in patients with NMD, and any degree of GVHD in this population is considered an undesirable iatrogenic effect. Understanding the incidence and risk factors for GVHD in children with NMD is in important step in developing strategies for its prevention.…”

Section: Introductionmentioning

confidence: 99%

The Impact of Graft-Versus-Host Disease on Survival in Children with Non-Malignant Disorders Receiving Allogeneic Hematopoietic Cell Transplant

Horn

Castillo

Hanif

et al. 2021

Preprint

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Background: Graft-versus-host disease (GVHD) is a common and undesirable complication of hematopoietic cell transplant (HCT) for non-malignant disorders (NMD). Understanding the incidence and risk factors for GVHD in children with NMD is an important step in developing strategies for its prevention. Study Design: This is a retrospective, registry, study that included children with NMD receiving HCT in 5 centers in Florida between 2010 and 2019. Results: Among 183 patients evaluable for GVHD, acute GVHD (aGVHD) grades I, II, III, and IV were present in 18%, 12.6%, 3.8% and 5.5% of patients, respectively. Limited and extensive chronic GVHD (cGVHD), were observed in 8.7% and 12.6% of patients. Patients with aGVHD grade III/IV had significantly lower 3-year survival rates than those without aGVHD, or those with aGVHD grade I/II (52.9% [95% confidence interval (CI) 34-83] vs. 90.1% [95% CI 84-96], vs. 98.1% [95%CI 95-100], p<0.001). Patients without cGVHD and those with limited and extensive cGVHD had 3-year survival rates of 88.9% [95%CI 84-94], 91.7% [95%CI 77-100], and 84.8% [95%CI 70-100], respectively, log rank p=0.3. Receiving transplant from an HLA-mismatched unrelated donor (MMUD), as compared to a matched related donor (MRD), increased the risk for aGVHD grade III/IV (Odds ratio 10.4 [95% CI 2.5-47.6]). There were no cases of aGVHD grade III/IV among recipients of mismatched related/haploidentical transplants. Conclusions: Grade III/IV aGVHD, which significantly reduced overall survival, was reported in 9.3% of children with NMD receiving HCT. Risk factors included HCT from a MMUD but not mismatched related donors.

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Section: Introductionmentioning

confidence: 99%

The Impact of Graft-Versus-Host Disease on Survival in Children with Non-Malignant Disorders Receiving Allogeneic Hematopoietic Cell Transplant

Horn

Castillo

Hanif

et al. 2021

Preprint

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“…The pathogenesis of GVHD involves migration of donor T cells into the target organs in the recipient, including liver, small intestine, and skin (33,34). GVHD occurs in a subset of organs and involves early migration of alloreactive T cells into these organs followed by T cell expansion and later tissue destruction (16,35).…”

Section: Wnt/β-catenin Over-expression Results In Reduced Cytokine Production and Donor T Cell Proliferation Without Affecting Tcr Signalmentioning

confidence: 99%

Wnt/β-catenin regulates alloreactive T cells for the treatment of hematological malignancies

Mammadli

Harris

Mahmudlu

et al. 2021

Preprint

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most widely applied forms of adaptive immunotherapy. Both the detrimental graft-versus-host disease (GVHD) and the beneficial graft-versus-leukemia (GVL) effects occurring after allo-HSCT are largely mediated by alloantigen-reactive donor T cells in the graft. Separating GVHD from GVL effects is a formidable challenge, and a greater understanding of donor T cell biology is required to accomplish the uncoupling of GVHD from GVL. Here, we tested a novel mouse model of transgenic over-expression of human β-catenin (Cat-Tg) in an allo-HSCT model. Our data show that T cells from Cat-Tg mice did not cause GVHD. Surprisingly, Cat-Tg T cells maintained the GVL effect. Donor T cells from Cat-Tg mice exhibited significantly lower inflammatory cytokine production and reduced donor T cell proliferation, while upregulating cytotoxic mediators that resulted in enhanced cytotoxicity. RNA sequencing data revealed changes in the expression of over 150 genes for CD4, and over 250 genes for CD8+T cells involved in essential aspects of immune response and GVHD pathophysiology. Transgenic over-expression of human β-catenin primarily affects CD8+ T cell phenotype. Altogether, our data suggest that β-catenin is a druggable target for developing therapeutic strategies to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

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“…The pathogenesis of GVHD involves the migration of donor T cells into the target organs in the recipient, including the liver, small intestine, and skin [24,25]. GVHD occurs in a subset of organs and involves early migration of alloreactive T cells into these organs followed by T cell expansion and later tissue destruction [16,26].…”

Section: Wnt/β-catenin Overexpression Specifically Affects Cd8 + T Cell Functionsmentioning

confidence: 99%

Human Wnt/β-Catenin Regulates Alloimmune Signaling during Allogeneic Transplantation

Mammadli

Harris

Mahmudlu

et al. 2021

Cancers

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most widely applied forms of adoptive immunotherapy for the treatment of hematological malignancies. Detrimental graft-versus-host disease (GVHD), but also beneficial graft-versus-leukemia (GVL) effects occurring after allo-HSCT are largely mediated by alloantigen-reactive donor T cells in the graft. Separating GVHD from GVL effects is a formidable challenge, and a greater understanding of donor T cell biology is required to accomplish the uncoupling of GVHD from GVL. Here, we evaluated the role of β-catenin in this process. Using a unique mouse model of transgenic overexpression of human β-catenin (Cat-Tg) in an allo-HSCT model, we show here that T cells from Cat-Tg mice did not cause GVHD, and surprisingly, Cat-Tg T cells maintained the GVL effect. Donor T cells from Cat-Tg mice exhibited significantly lower inflammatory cytokine production and reduced donor T cell proliferation, while upregulating cytotoxic mediators that resulted in enhanced cytotoxicity. RNA sequencing revealed changes in the expression of 1169 genes for CD4, and 1006 genes for CD8+ T cells involved in essential aspects of immune response and GVHD pathophysiology. Altogether, our data suggest that β-catenin is a druggable target for developing therapeutic strategies to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

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Translational and clinical advances in acute graft-versus-host disease

Cited by 24 publications

References 109 publications

The Impact of Graft-Versus-Host Disease on Survival in Children with Non-Malignant Disorders Receiving Allogeneic Hematopoietic Cell Transplant

The Impact of Graft-Versus-Host Disease on Survival in Children with Non-Malignant Disorders Receiving Allogeneic Hematopoietic Cell Transplant

Wnt/β-catenin regulates alloreactive T cells for the treatment of hematological malignancies

Human Wnt/β-Catenin Regulates Alloimmune Signaling during Allogeneic Transplantation

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