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Ferrara From the Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; and the Department of Pathology, Yale University School of Medicine, New Haven, CT. 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  (TNF). 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 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. 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. Blood, Vol. 90 No. 8 (July 15), 1997: pp. 3204-3213 © 1997 by The American Society of Hematology. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: K. A. Markey, A. C. Burman, T. Banovic, R. D. Kuns, N. C. Raffelt, V. Rowe, S. D. Olver, A. L. J. Don, E. S. Morris, A. R. Pettit, et al. 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Low-dose total body irradiation followed by allogeneic lymphocyte infusion may induce remission in patients with refractory hematologic malignancy Blood, June 28, 2002; 100(2): 442 - 450. [Abstract] [Full Text] [PDF] S. Chakrabarti, J. E. Levine, and R. H. Collins Jr Critical Factors in Optimizing Graft-Versus-Leukemia Effect for Relapsed Leukemias J. Clin. Oncol., June 1, 2002; 20(11): 2756 - 2757. [Full Text] [PDF] M. Daneshpouy, G. Socie, M. Lemann, J. Rivet, E. Gluckman, and A. Janin Activated eosinophils in upper gastrointestinal tract of patients with graft-versus-host disease Blood, April 15, 2002; 99(8): 3033 - 3040. [Abstract] [Full Text] [PDF] P. Matzinger The Danger Model: A Renewed Sense of Self Science, April 12, 2002; 296(5566): 301 - 305. [Abstract] [Full Text] [PDF] Q. Ge, H. Hu, H. N. Eisen, and J. Chen Different contributions of thymopoiesis and homeostasis-driven proliferation to the reconstitution of naive and memory T cell compartments PNAS, March 5, 2002; 99(5): 2989 - 2994. [Abstract] [Full Text] [PDF] T. Teshima, C. Liu, K. P. Lowler, G. Dranoff, and J. L. M. Ferrara Donor Leukocyte Infusion from Immunized Donors Increases Tumor Vaccine Efficacy after Allogeneic Bone Marrow Transplantation Cancer Res., February 1, 2002; 62(3): 796 - 800. [Abstract] [Full Text] [PDF] D. L. Flanagan, R. Gross, C. D. Jennings, B. E. Caywood, S. Goes, A. M. Kaplan, and J. S. Bryson Induction of syngeneic graft-versus-host disease in LPS hyporesponsive C3H/HeJ mice J. Leukoc. Biol., December 1, 2001; 70(6): 873 - 880. [Abstract] [Full Text] [PDF] P. Reddy, T. Teshima, M. Kukuruga, R. Ordemann, C. Liu, K. Lowler, and J. L.M. Ferrara Interleukin-18 Regulates Acute Graft-Versus-Host Disease by Enhancing Fas-mediated Donor T Cell Apoptosis J. Exp. Med., November 12, 2001; 194(10): 1433 - 1440. [Abstract] [Full Text] [PDF] H. J. Deeg, B. R. Blazar, B. J. Bolwell, G. D. Long, F. Schuening, J. Cunningham, R. M. Rifkin, S. Abhyankar, A. D. Briggs, R. Burt, et al. Treatment of steroid-refractory acute graft-versus-host disease with anti-CD147 monoclonal antibody ABX-CBL Blood, October 1, 2001; 98(7): 2052 - 2058. [Abstract] [Full Text] [PDF] J. W. J. van Esser, B. van der Holt, E. Meijer, H. G. M. Niesters, R. Trenschel, S. F. T. Thijsen, A. M. van Loon, F. Frassoni, A. Bacigalupo, U. W. Schaefer, et al. Epstein-Barr virus (EBV) reactivation is a frequent event after allogeneic stem cell transplantation (SCT) and quantitatively predicts EBV-lymphoproliferative disease following T-cell-depleted SCT Blood, August 15, 2001; 98(4): 972 - 978. [Abstract] [Full Text] [PDF] M. d. C. Bittencourt, S. Perruche, E. Contassot, S. Fresnay, M.-H. Baron, R. Angonin, F. Aubin, P. Herve, P. Tiberghien, and P. Saas Intravenous injection of apoptotic leukocytes enhances bone marrow engraftment across major histocompatibility barriers Blood, July 1, 2001; 98(1): 224 - 230. [Abstract] [Full Text] [PDF] K. R. Cooke, G. R. Hill, A. Gerbitz, L. Kobzik, T. R. Martin, J. M. Crawford, J. P. Brewer, and J. L. M. Ferrara Hyporesponsiveness of Donor Cells to Lipopolysaccharide Stimulation Reduces the Severity of Experimental Idiopathic Pneumonia Syndrome: Potential Role for a Gut-Lung Axis of Inflammation J. Immunol., December 1, 2000; 165(11): 6612 - 6619. [Abstract] [Full Text] [PDF] C. Ferreira, T. Barthlott, S. Garcia, R. Zamoyska, and B. Stockinger Differential Survival of Naive CD4 and CD8 T Cells J. Immunol., October 1, 2000; 165(7): 3689 - 3694. [Abstract] [Full Text] [PDF] F. P. Nestel, R. N. Greene, K. Kichian, P. Ponka, and W. S. Lapp Activation of macrophage cytostatic effector mechanisms during acute graft-versus-host disease: release of intracellular iron and nitric oxide-mediated cytostasis Blood, September 1, 2000; 96(5): 1836 - 1843. [Abstract] [Full Text] [PDF] G. R. Hill and J. L. M. Ferrara 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 Blood, May 1, 2000; 95(9): 2754 - 2759. [Abstract] [Full Text] [PDF] G. R. Hill, T. Teshima, V. I. Rebel, O. I. Krijanovski, K. R. Cooke, Y. S. Brinson, and J. L. M. Ferrara The p55 TNF-{alpha} Receptor Plays a Critical Role in T Cell Alloreactivity J. Immunol., January 15, 2000; 164(2): 656 - 663. [Abstract] [Full Text] [PDF] M. R. M. van den Brink, E. Moore, K. J. Horndasch, J. M. Crawford, J. Hoffman, G. F. Murphy, and S. J. Burakoff Fas-Deficient lpr Mice Are More Susceptible to Graft-Versus-Host Disease J. 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L.M. Ferrara Keratinocyte Growth Factor Separates Graft-Versus-Leukemia Effects From Graft-Versus-Host Disease Blood, July 15, 1999; 94(2): 825 - 831. [Abstract] [Full Text] [PDF] L. Pan, T. Teshima, G. R. Hill, D. Bungard, Y. S. Brinson, V. S. Reddy, K. R. Cooke, and J. L.M. Ferrara Granulocyte Colony-Stimulating Factor-Mobilized Allogeneic Stem Cell Transplantation Maintains Graft-Versus-Leukemia Effects Through a Perforin-Dependent Pathway While Preventing Graft-Versus-Host Disease Blood, June 15, 1999; 93(12): 4071 - 4078. [Abstract] [Full Text] [PDF] G. Shankar, J. Scott Bryson, C. Darrell Jennings, A. M. Kaplan, and D. A. Cohen Idiopathic Pneumonia Syndrome after Allogeneic Bone Marrow Transplantation in Mice . Role of Pretransplant Radiation Conditioning Am. J. Respir. Cell Mol. Biol., June 1, 1999; 20(6): 1116 - 1124. [Abstract] [Full Text]

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