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Review
. 2017 Nov 30;377(22):2167-2179.
doi: 10.1056/NEJMra1609337.

Acute Graft-versus-Host Disease - Biologic Process, Prevention, and Therapy

Robert Zeiser  1 , Bruce R Blazar  1
Affiliations
Review

Acute Graft-versus-Host Disease - Biologic Process, Prevention, and Therapy

Robert Zeiser et al. N Engl J Med. .
No abstract available

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Figures

Figure 1
Figure 1. Clinical features of aGVHD
Representative pictures for clinical aGVHD in early and advanced stages of the skin and intestinal tract are shown (A-D). Histologic aspects of skin (E), hepatic (F, G) and intestinal (H, I) lesions in GVHD. E. AGVHD of the skin, the black arrows indicate apoptotic cells in the basal layer of the epidermis. F. Damage to small interlobular bile ducts characterized by epithelial irregularities and rare apoptosis. Moderate inflammation of the adjacent portal area (hematoxylin & eosin, medium magnification). G. Infiltration of bile duct epithelium by CD3+ lymphocytes (anti-CD3 immunolabeling, high magnification). H. Mucosal surface denudation and partial crypt destruction in intestinal GVHD (hematoxylin & eosin, low magnification). I. Scattered apoptotic bodies in regenerating crypts in close association with exploding crypts containing karyorrhectic nuclear debris (hematoxylin & eosin, high magnification). Histological images were provided by Dr. Technau, Dept of Dermatology, Univ of Freiburg (skin), and Prof Schmitt-Gräff, Dept of Pathology, Univ. of Freiburg (liver, intestines).
Figure 2
Figure 2. Schematic overview of the early events of GVHD
A: DAMPs (e.g. uric acid, ATP, heparan sulfate, HMGB-1 or IL-33) that are released from the dying cells or disrupted extracellular matrix and activate the respective receptors, e.g. ATP activates P2X7 and P2Y2, uric acid activates the Nlrp3 inflammasome. PAMPS derived from invading bacteria activate innate immune cells including donor derived CD103+ dendritic cells, inflammatory monocytes and neutrophils. A fraction of these cells migrates from the damaged intestinal epithelium towards the draining mesenteric lymph nodes where donor T-cells are activated. ATP: Adenosine triphosphate, HMGB-1: High mobility group box 1 protein, ROS: reactive oxygen species, DAMPs: danger associated molecular patterns, PAMPs: pathogen associated molecular patterns. B: Anti-inflammatory events and repair mechanism. Cells in the GVHD target organs attempt to counterbalance inflammation via the release of tolerogenic soluble factors, upregulation of anti-inflammatory surface receptors and repair mechanisms. Activation signals and chemotactic signals for Treg and Tr1 cells are provided in the lymph nodes. KGF: keratinocyte growth factor.
Figure 2
Figure 2. Schematic overview of the early events of GVHD
A: DAMPs (e.g. uric acid, ATP, heparan sulfate, HMGB-1 or IL-33) that are released from the dying cells or disrupted extracellular matrix and activate the respective receptors, e.g. ATP activates P2X7 and P2Y2, uric acid activates the Nlrp3 inflammasome. PAMPS derived from invading bacteria activate innate immune cells including donor derived CD103+ dendritic cells, inflammatory monocytes and neutrophils. A fraction of these cells migrates from the damaged intestinal epithelium towards the draining mesenteric lymph nodes where donor T-cells are activated. ATP: Adenosine triphosphate, HMGB-1: High mobility group box 1 protein, ROS: reactive oxygen species, DAMPs: danger associated molecular patterns, PAMPs: pathogen associated molecular patterns. B: Anti-inflammatory events and repair mechanism. Cells in the GVHD target organs attempt to counterbalance inflammation via the release of tolerogenic soluble factors, upregulation of anti-inflammatory surface receptors and repair mechanisms. Activation signals and chemotactic signals for Treg and Tr1 cells are provided in the lymph nodes. KGF: keratinocyte growth factor.
Figure 3
Figure 3. Classical and novel approaches to target T-cell and dendritic cell activation
A: Sketch showing the mode of action of multiple immunosuppressive strategies that are currently applied in the clinic for prevention and therapy of aGVHD. mTOR: mammalian target of rapamycin, MTX: methotrexate, MMF: mycophenolate mofetil B: Kinases that have been subject to targeted therapy approaches in aGVHD are shown. Blockade of the kinases ROCK-1, Aurora A, CDK2, MEK-1/2, JAK1-3 and PI3K was shown to reduce aGVHD in mouse models. The different signaling pathways in which these kinases have a non-redundant function are displayed. Tc: T cell, TCR: T-cell receptor
See this image and copyright information in PMC

Comment in

  • Acute Graft-versus-Host Disease.
    Rezvani AR. Rezvani AR. N Engl J Med. 2018 Feb 8;378(6):585-586. doi: 10.1056/NEJMc1716969. N Engl J Med. 2018. PMID: 29419277 No abstract available.

References

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