Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

Leonhardt, Franziska; Zirlik, Katja; Buchner, Maike; Prinz, Gabriele; Ak, Hechinger; Uv, Gerlach; Fisch, Paul; Schmitt‐Gräff, Annette; Reichardt, Wilfried; Zeiser, Robert

doi:10.1038/leu.2012.10

Cited by 44 publications

(40 citation statements)

References 57 publications

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“…The intracellular staining for Foxp3 and cytokines and for effector memory Tc's (T EM 's), central memory Tc's (T CM 's), and naive Tc's (T N 's) was performed as previously described. 22 …”

Section: Flow Cytometrymentioning

confidence: 99%

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Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100

Leonhardt

Grundmann²,

Béhé

et al. 2013

Blood

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Section: Flow Cytometrymentioning

confidence: 99%

“…22 Briefly, recipients were injected intravenously with 5 3 10 6 bone marrow (BM) cells after lethal irradiation with 900 centi Gray (cGy). To induce acute GvHD (aGvHD), 3 3 10 5 CD4…”

Section: Bone Marrow Transplantation (Bmt) Model and Gvhd Histopathologymentioning

confidence: 99%

Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100

Leonhardt

Grundmann²,

Béhé

et al. 2013

Blood

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“…13 The severity of GvHD was determined according to a previously published histopathology scoring system. 14 …”

Section: Bone Marrow Transplantation Model and Histopathology Of Grafmentioning

confidence: 99%

Inhibition of protein geranylgeranylation and farnesylation protects against graft-versus-host disease via effects on CD4 effector T cells

et al. 2012

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ARTICLES 31 Graft-Versus-Host DiseaseDespite advances in immunosuppressive regimens, acute graft-versus-host disease remains a frequent complication of allogeneic hematopoietic cell transplantation. Pathogenic donor T cells are dependent on correct attachment of small GTPases to the cell membrane, mediated by farnesyl-or geranylgeranyl residues, which, therefore, constitute potential targets for graft-versus-host disease prophylaxis. A mouse model was used to study the impact of a farnesyl-transferase inhibitor and a geranylgeranyl-transferase inhibitor on acute graft-versus-host disease, anticytomegalovirus T-cell responses and graft-versus-leukemia activity. Treatment of mice undergoing allogeneic hematopoietic cell transplantation with farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor reduced the histological severity of graft-versus-host disease and prolonged survival significantly. Mechanistically, farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor treatment resulted in reduced alloantigen-driven expansion of CD4 T cells. In vivo treatment led to increased thymic cellularity and polyclonality of the T-cell receptor repertoire by reducing thymic graft-versus-host disease. These effects were absent when squalene production was blocked. The farnesyl-transferase inhibitor and geranylgeranyl-transferase inhibitor did not compromise CD8 function against leukemia cells or reconstitution of T cells that were subsequently responsible for anti-murine cytomegalovirus responses. In summary, we observed an immunomodulatory effect of inhibitors of farnesyl-transferase and geranylgeranyl-transferase on graft-versus-host disease, with enhanced functional immune reconstitution. In the light of the modest toxicity of farnesyl-transferase inhibitors such as tipifarnib in patients and the potent reduction of graft-versus-host disease in mice, farnesyl-transferase and geranylgeranyl-transferase inhibitors could help to reduce graft-versus-host disease significantly without having a negative impact on immune reconstitution. -access paper. doi:10.3324/haematol.2012.065789 Inhibition of protein geranylgeranylation and farnesylation protects against graft-versus-host disease via effects on CD4 effector T cells ©2013 Ferrata Storti Foundation. This is an open

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“…Other lines of promising future translation for aGVHD are: besides others, natural killer T-cell therapy, 121 IL-22 proteins that help to protect the intestinal stem cell mice, 122 and modifications of the microbiome. 123 cGVHD promising approaches include among others: Syk inhibitors that were shown to reduce disease severity in the mouse model 124,125 and are currently developed into a clinical trial, BTK inhibition, targeting of IL-21, and B-cell activating factor that may help to control this major complication after allo-HCT.…”

Section: Novel Promising Targets and Approachesmentioning

confidence: 99%

Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation?

Zeiser

Blazar

2016

Blood

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Despite major advances in recent years, graft-versus-host disease (GVHD) remains a major life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT). To improve our therapeutic armory against GVHD, preclinical evidence is most frequently generated in mouse and large animal models of GVHD. However, because every model has shortcomings, it is important to understand how predictive the different models are and why certain findings in these models could not be translated into the clinic. Weaknesses of the animal GVHD models include the irradiation only-based conditioning regimen, the homogenous donor/recipient genetics in mice, canine or non-human primates (NHP), anatomic site of T cells used for transfer in mice, the homogenous microbial environment in mice housed under specific pathogen-free conditions, and the lack of pharmacologic GVHD prevention in control groups. Despite these major differences toward clinical allo-HCT, findings generated in animal models of GVHD have led to the current gold standards for GVHD prophylaxis and therapy. The homogenous nature of the preclinical models allows for reproducibility, which is key for the characterization of the role of a new cytokine, chemokine, transcription factor, microRNA, kinase, or immune cell population in the context of GVHD. Therefore, when carefully balancing reasons to apply small and large animal models, it becomes evident that they are valuable tools to generate preclinical hypotheses, which then have to be rigorously evaluated in the clinical setting. In this study, we discuss several clinical approaches that were motivated by preclinical evidence, novel NHP models and their advantages, and highlight the recent advances in understanding the pathophysiology of GVHD. (Blood. 2016; 127(25):3117-3126)

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Spleen tyrosine kinase (Syk) is a potent target for GvHD prevention at different cellular levels

Cited by 44 publications

References 57 publications

Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100

Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100

Inhibition of protein geranylgeranylation and farnesylation protects against graft-versus-host disease via effects on CD4 effector T cells

Preclinical models of acute and chronic graft-versus-host disease: how predictive are they for a successful clinical translation?

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