25
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Blockade of Vascular Endothelial Growth Factor (VEGF) Aggravates the Severity of Acute Graft-versus-host Disease (GVHD) after Experimental Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT)

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background

          Recent clinical observation reported that there was a significant correlation between change in circulating vascular endothelial growth factor (VEGF) levels and the occurrence of severe acute graft-versus-host disease (GVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the action mechanisms of VEGF in GVHD have not been demonstrated.

          Methods

          This study investigated whether or not blockade of VEGF has an effect on acute GVHD in a lethally irradiated murine allo-HSCT model of B6 (H-2 b)→B6D2F1 (H-2 b/d). Syngeneic or allogeneic recipient mice were injected subcutaneously with anti-VEGF peptides, dRK6 (50 µg/dose) or control diluent every other day for 2 weeks (total 7 doses).

          Results

          Administration of the dRK6 peptide after allo-HSCT significantly reduced survival with greaterclinical GVHD scores and body weight loss. Allogeneic recipients injected with the dRK6 peptide exhibited significantly increased circulating levels of VEGF and expansion of donor CD3 + T cells on day +7 compared to control treated animals. The donor CD4 + and CD8 + T-cell subsets have differential expansion caused by the dRK6 injection. The circulating VEGF levels were reduced on day +14 regardless of blockade of VEGF.

          Conclusion

          Together these findings demonstrate that the allo-reactive responses after allo-HSCT are exaggerated by the blockade of VEGF. VEGF seems to be consumed during the progression of acute GVHD in this murine allo-HSCT model.

          Related collections

          Most cited references25

          • Record: found
          • Abstract: found
          • Article: not found

          American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.

          (1992)
          To define the terms "sepsis" and "organ failure" in a precise manner. Review of the medical literature and the use of expert testimony at a consensus conference. American College of Chest Physicians (ACCP) headquarters in Northbrook, IL. Leadership members of ACCP/Society of Critical Care Medicine (SCCM). An ACCP/SCCM Consensus Conference was held in August of 1991 with the goal of agreeing on a set of definitions that could be applied to patients with sepsis and its sequelae. New definitions were offered for some terms, while others were discarded. Broad definitions of sepsis and the systemic inflammatory response syndrome were proposed, along with detailed physiologic variables by which a patient could be categorized. Definitions for severe sepsis, septic shock, hypotension, and multiple organ dysfunction syndrome were also offered. The use of severity scoring methods were recommended when dealing with septic patients as an adjunctive tool to assess mortality. Appropriate methods and applications for the use and testing of new therapies were recommended. The use of these terms and techniques should assist clinicians and researchers who deal with sepsis and its sequelae.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines.

            The influence of bone marrow transplantation (BMT) conditioning regimens on the incidence and severity of graft-versus-host disease (GVHD) has been suggested in clinical BMT. Using murine BMT models, we show here an increase in GVHD severity in several donor-recipient strain combinations after intensification of the conditioning regimen by increasing the total body irradiation (TBI) dose from 900 cGy to 1,300 cGy. Increased GVHD was mediated by systemic increases in tumor necrosis factor alpha (TNF alpha). Histologic analysis of gastrointestinal tracts showed synergistic damage by increased TBI and allogeneic donor cells that permitted increased translocation of lipopolysacharide (LPS) into the systemic circulation. In vitro, LPS triggered excess TNF alpha from macrophages primed by the GVH reaction. In addition, macrophages isolated within 4 hours of conditioning were primed in proportion to the TBI dose itself to secrete TNF alpha. Thus, the higher TBI dose increased macrophage priming and increased gut damage after allogeneic BMT, causing higher systemic levels of inflammatory cytokines and subsequent severe GVHD. These data highlight the importance of conditioning in GVHD pathophysiology and suggest that interventions to prevent LPS stimulation of primed macrophages may limit the severity of GVHD after intensive conditioning for allogeneic BMT.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation.

              Acute graft-versus-host disease (GVHD), the major complication of allogeneic bone marrow transplantation (BMT), limits the application of this curative but toxic therapy. Studies of inflammatory pathways involved in GVHD in animals have shown that the gastrointestinal (GI) tract plays a major role in the amplification of systemic disease. Damage to the GI tract increases the translocation of inflammatory stimuli such as endotoxin, which promotes further inflammation and additional GI tract damage. The GI tract is therefore critical to the propagation of the "cytokine storm" characteristic of acute GVHD. Experimental approaches to the prevention of GVHD include reducing the damage to the GI tract by fortification of the GI mucosal barrier through novel "cytokine shields" such as IL-11 or keratinocyte growth factor. Such strategies have reduced GVHD while preserving a graft-versus-leukemia effect in animal models, and they now deserve formal testing in carefully designed clinical trials. (Blood. 2000;95:2754-2759)
                Bookmark

                Author and article information

                Journal
                Immune Netw
                IN
                Immune Network
                The Korean Association of Immunologists
                1598-2629
                2092-6685
                December 2011
                31 December 2011
                : 11
                : 6
                : 368-375
                Affiliations
                [1 ]Department of Pediatrics, The Catholic University of Korea, Seoul 137-701, Korea.
                [2 ]Department of Internal Medicine, The Catholic University of Korea, Seoul 137-701, Korea.
                [3 ]Department of Hospital Pathology, The Catholic University of Korea, Seoul 137-701, Korea.
                Author notes
                Corresponding Author. Tel: 82-2-2258-6053; Fax: 82-2-599-3589; ckmin@ 123456catholic.ac.kr
                Article
                10.4110/in.2011.11.6.368
                3275706
                22346777
                1695c3ac-a8e8-430a-a452-f3baad1aa4fe
                Copyright © 2011 The Korean Association of Immunologists

                This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 October 2011
                : 28 October 2011
                : 03 November 2011
                Categories
                Original Article

                Immunology
                drk6,vascular endothelial growth factors (vegf),allogeneic hematopoietic stem cell transplantation,acute graft-versus-host disease,vegf blockade

                Comments

                Comment on this article