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J Clin Invest. Sep 1, 1997; 100(5): 1015–1027.
PMCID: PMC508276

The critical early proinflammatory events associated with idiopathic pneumonia syndrome in irradiated murine allogeneic recipients are due to donor T cell infusion and potentiated by cyclophosphamide.

Abstract

We have hypothesized that lung damage occurring in the peri-bone marrow transplant (BMT) period is critical for the subsequent generation of idiopathic pneumonia syndrome (IPS), a major complication following human BMT. The proinflammatory events induced by a common pre-BMT conditioning regimen, cyclophosphamide (Cytoxan(R)) (Cy) and total body irradiation, were analyzed in a murine BMT model. Electron microscopy indicated that Cy exacerbated irradiation-induced epithelial cell injury as early as day 3 after BMT. Allogenicity was an important contributing factor to lung injury as measured by lung wet and dry weights and decreased specific lung compliance. The most significant pulmonary dysfunction was seen in mice receiving both allogeneic T cells and Cy conditioning. IPS was associated with an influx of T cells, macrophages, and neutrophils early post-BMT. Hydroxyproline levels were not increased, indicating that the injury was not fibrotic early post-BMT. As early as 2 h after chemoradiation, host macrophages increased in number in the lung parenchyma. Continued increases in macrophages occurred if splenic T cells were administered with the donor graft. The expression of costimulatory B7 molecules correlated with macrophage numbers. Frequencies of cells expressing mRNA for the inflammatory proteins TNF-alpha, IL-1beta, and TGFbeta were increased. Cy accelerated the upregulation of TGFbeta and increase in host macrophages. The exacerbation of macrophage activation and severity of IPS was dependent on allogeneic T cells, implicating immune-mediated mechanisms as critical to the outcome of IPS. This demonstration of early injury after BMT indicates the need for very early therapeutic intervention before lung damage becomes profound and irreversible.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Clark JG, Hansen JA, Hertz MI, Parkman R, Jensen L, Peavy HH. NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis. 1993 Jun;147(6 Pt 1):1601–1606. [PubMed]
  • Weiner RS, Bortin MM, Gale RP, Gluckman E, Kay HE, Kolb HJ, Hartz AJ, Rimm AA. Interstitial pneumonitis after bone marrow transplantation. Assessment of risk factors. Ann Intern Med. 1986 Feb;104(2):168–175. [PubMed]
  • Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen FB, Fisher LD, Anasetti C, Beatty P, Bensinger WI, Doney K, et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood. 1990 Nov 1;76(9):1867–1871. [PubMed]
  • Petersen FB, Deeg HJ, Buckner CD, Appelbaum FR, Storb R, Clift RA, Sanders JE, Bensinger WI, Witherspoon RP, Sullivan KM, et al. Marrow transplantation following escalating doses of fractionated total body irradiation and cyclophosphamide--a phase I trial. Int J Radiat Oncol Biol Phys. 1992;23(5):1027–1032. [PubMed]
  • Soderling CC, Song CW, Blazar BR, Vallera DA. A correlation between conditioning and engraftment in recipients of MHC-mismatched T cell-depleted murine bone marrow transplants. J Immunol. 1985 Aug;135(2):941–946. [PubMed]
  • Down JD, Mauch P, Warhol M, Neben S, Ferrara JL. The effect of donor T lymphocytes and total-body irradiation on hemopoietic engraftment and pulmonary toxicity following experimental allogeneic bone marrow transplantation. Transplantation. 1992 Nov;54(5):802–808. [PubMed]
  • Gassmann W, Uharek L, Wottge HU, Schmitz N, Löffler H, Mueller-Ruchholtz W. Comparison of cyclophosphamide, cytarabine, and etoposide as immunosuppressive agents before allogeneic bone marrow transplantation. Blood. 1988 Nov;72(5):1574–1579. [PubMed]
  • Workman DL, Clancy J., Jr Interstitial pneumonitis and lymphocytic bronchiolitis/bronchitis as a direct result of acute lethal graft-versus-host disease duplicate the histopathology of lung allograft rejection. Transplantation. 1994 Jul 27;58(2):207–213. [PubMed]
  • Piguet PF, Grau GE, Collart MA, Vassalli P, Kapanci Y. Pneumopathies of the graft-versus-host reaction. Alveolitis associated with an increased level of tumor necrosis factor mRNA and chronic interstitial pneumonitis. Lab Invest. 1989 Jul;61(1):37–45. [PubMed]
  • Holler E, Kolb HJ, Möller A, Kempeni J, Liesenfeld S, Pechumer H, Lehmacher W, Ruckdeschel G, Gleixner B, Riedner C, et al. Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation. Blood. 1990 Feb 15;75(4):1011–1016. [PubMed]
  • Xing Z, Jordana M, Kirpalani H, Driscoll KE, Schall TJ, Gauldie J. Cytokine expression by neutrophils and macrophages in vivo: endotoxin induces tumor necrosis factor-alpha, macrophage inflammatory protein-2, interleukin-1 beta, and interleukin-6 but not RANTES or transforming growth factor-beta 1 mRNA expression in acute lung inflammation. Am J Respir Cell Mol Biol. 1994 Feb;10(2):148–153. [PubMed]
  • Ulich TR, Yi ES, Yin S, Smith C, Remick D. Intratracheal administration of endotoxin and cytokines. VII. The soluble interleukin-1 receptor and the soluble tumor necrosis factor receptor II (p80) inhibit acute inflammation. Clin Immunol Immunopathol. 1994 Jul;72(1):137–140. [PubMed]
  • Ulich TR, Yin S, Remick DG, Russell D, Eisenberg SP, Kohno T. Intratracheal administration of endotoxin and cytokines. IV. The soluble tumor necrosis factor receptor type I inhibits acute inflammation. Am J Pathol. 1993 May;142(5):1335–1338. [PMC free article] [PubMed]
  • Cooke KR, Kobzik L, Martin TR, Brewer J, Delmonte J, Jr, Crawford JM, Ferrara JL. An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: I. The roles of minor H antigens and endotoxin. Blood. 1996 Oct 15;88(8):3230–3239. [PubMed]
  • Haschek WM, Witschi H. Pulmonary fibrosis--a possible mechanism. Toxicol Appl Pharmacol. 1979 Dec;51(3):475–487. [PubMed]
  • Haschek WM, Klein-Szanto AJ, Last JA, Reiser KM, Witschi H. Long-term morphologic and biochemical features of experimentally induced lung fibrosis in the mouse. Lab Invest. 1982 Apr;46(4):438–449. [PubMed]
  • Fausto N. Multifunctional roles for transforming growth factor-beta 1. Lab Invest. 1991 Nov;65(5):497–499. [PubMed]
  • Hoyt DG, Lazo JS. Early increases in pulmonary mRNA encoding procollagens and transforming growth factor-beta in mice sensitive to cyclophosphamide-induced pulmonary fibrosis. J Pharmacol Exp Ther. 1989 Apr;249(1):38–43. [PubMed]
  • Bentzen SM, Skoczylas JZ, Overgaard M, Overgaard J. Radiotherapy-related lung fibrosis enhanced by tamoxifen. J Natl Cancer Inst. 1996 Jul 3;88(13):918–922. [PubMed]
  • Broekelmann TJ, Limper AH, Colby TV, McDonald JA. Transforming growth factor beta 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6642–6646. [PMC free article] [PubMed]
  • Khalil N, O'Connor RN, Unruh HW, Warren PW, Flanders KC, Kemp A, Bereznay OH, Greenberg AH. Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol. 1991 Aug;5(2):155–162. [PubMed]
  • Fine A, Goldstein RH. The effect of transforming growth factor-beta on cell proliferation and collagen formation by lung fibroblasts. J Biol Chem. 1987 Mar 15;262(8):3897–3902. [PubMed]
  • Kelley J, Kovacs EJ, Nicholson K, Fabisiak JP. Transforming growth factor-beta production by lung macrophages and fibroblasts. Chest. 1991 Mar;99(3 Suppl):85S–86S. [PubMed]
  • Dusenbery KE, Daniels KA, McClure JS, McGlave PB, Ramsay NK, Blazar BR, Neglia JP, Kersey JH, Woods WG. Randomized comparison of cyclophosphamide-total body irradiation versus busulfan-cyclophosphamide conditioning in autologous bone marrow transplantation for acute myeloid leukemia. Int J Radiat Oncol Biol Phys. 1995 Jan 1;31(1):119–128. [PubMed]
  • Blazar BR, Taylor PA, Snover DC, Bluestone JA, Vallera DA. Nonmitogenic anti-CD3F(ab')2 fragments inhibit lethal murine graft-versus-host disease induced across the major histocompatibility barrier. J Immunol. 1993 Jan 1;150(1):265–277. [PubMed]
  • Blazar BR, Taylor PA, Linsley PS, Vallera DA. In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice. Blood. 1994 Jun 15;83(12):3815–3825. [PubMed]
  • Wangensteen D, Piper R, Johnson JA, Sinha AA, Niewoehner D. Solute conductance of blood-gas barrier in hamsters exposed to hyperoxia. J Appl Physiol (1985) 1986 Jun;60(6):1908–1916. [PubMed]
  • Berg RA. Determination of 3- and 4-hydroxyproline. Methods Enzymol. 1982;82(Pt A):372–398. [PubMed]
  • Wangensteen D, Yankovich R, Hoidal J, Niewoehner D. Bleomycin-induced changes in pulmonary microvascular albumin permeability and extravascular albumin space. Am Rev Respir Dis. 1983 Feb;127(2):204–208. [PubMed]
  • Bachofen H, Hildebrandt J, Bachofen M. Pressure-volume curves of air- and liquid-filled excised lungs-surface tension in situ. J Appl Physiol. 1970 Oct;29(4):422–431. [PubMed]
  • Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Gray GS, Vallera DA. Coblockade of the LFA1:ICAM and CD28/CTLA4:B7 pathways is a highly effective means of preventing acute lethal graft-versus-host disease induced by fully major histocompatibility complex-disparate donor grafts. Blood. 1995 May 1;85(9):2607–2618. [PubMed]
  • Panoskaltsis-Mortari A, Bucy RP. In situ hybridization with digoxigenin-labeled RNA probes: facts and artifacts. Biotechniques. 1995 Feb;18(2):300–307. [PubMed]
  • Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966 Mar;50(3):163–170. [PubMed]
  • Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol. 1988 Apr;41(4):467–470. [PMC free article] [PubMed]
  • Berry GJ, Brunt EM, Chamberlain D, Hruban RH, Sibley RK, Stewart S, Tazelaar HD. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Lung Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant. 1990 Nov-Dec;9(6):593–601. [PubMed]
  • Pearson AE, Phelps TA. Radiation effects on mouse incisor teeth following whole-body doses of up to 16 gray. Int J Radiat Biol Relat Stud Phys Chem Med. 1981 Apr;39(4):409–417. [PubMed]
  • Down JD, Tarbell NJ, Warhol M, Mauch P. Dose-limiting complications from upper half body irradiation in C3H mice. Int J Radiat Oncol Biol Phys. 1988 Mar;14(3):483–489. [PubMed]
  • Goad ME, Tryka AF, Witschi HP. Acute respiratory failure induced by bleomycin and hyperoxia: pulmonary edema, cell kinetics, and morphology. Toxicol Appl Pharmacol. 1987 Aug;90(1):10–22. [PubMed]
  • Bitterman PB, Saltzman LE, Adelberg S, Ferrans VJ, Crystal RG. Alveolar macrophage replication. One mechanism for the expansion of the mononuclear phagocyte population in the chronically inflamed lung. J Clin Invest. 1984 Aug;74(2):460–469. [PMC free article] [PubMed]
  • Shami SG, Evans MJ, Martinez LA. Type II cell proliferation related to migration of inflammatory cells into the lung. Exp Mol Pathol. 1986 Jun;44(3):344–352. [PubMed]
  • Curtis JL, Byrd PK, Warnock ML, Kaltreider HB. Requirement of CD4-positive T cells for cellular recruitment to the lungs of mice in response to a particulate intratracheal antigen. J Clin Invest. 1991 Oct;88(4):1244–1254. [PMC free article] [PubMed]
  • Braciak TA, Bacon K, Xing Z, Torry DJ, Graham FL, Schall TJ, Richards CD, Croitoru K, Gauldie J. Overexpression of RANTES using a recombinant adenovirus vector induces the tissue-directed recruitment of monocytes to the lung. J Immunol. 1996 Dec 1;157(11):5076–5084. [PubMed]
  • Wahl SM, Hunt DA, Wakefield LM, McCartney-Francis N, Wahl LM, Roberts AB, Sporn MB. Transforming growth factor type beta induces monocyte chemotaxis and growth factor production. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5788–5792. [PMC free article] [PubMed]
  • Postlethwaite AE, Keski-Oja J, Moses HL, Kang AH. Stimulation of the chemotactic migration of human fibroblasts by transforming growth factor beta. J Exp Med. 1987 Jan 1;165(1):251–256. [PMC free article] [PubMed]
  • Cooper JA, Jr, Merrill WW, Reynolds HY. Cyclophosphamide modulation of bronchoalveolar cellular populations and macrophage oxidative metabolism. Possible mechanisms of pulmonary pharmacotoxicity. Am Rev Respir Dis. 1986 Jul;134(1):108–114. [PubMed]
  • Pelton RW, Johnson MD, Perkett EA, Gold LI, Moses HL. Expression of transforming growth factor-beta 1, -beta 2, and -beta 3 mRNA and protein in the murine lung. Am J Respir Cell Mol Biol. 1991 Dec;5(6):522–530. [PubMed]
  • Corrin B, Butcher D, McAnulty BJ, Dubois RM, Black CM, Laurent GJ, Harrison NK. Immunohistochemical localization of transforming growth factor-beta 1 in the lungs of patients with systemic sclerosis, cryptogenic fibrosing alveolitis and other lung disorders. Histopathology. 1994 Feb;24(2):145–150. [PubMed]
  • Zugmaier G, Paik S, Wilding G, Knabbe C, Bano M, Lupu R, Deschauer B, Simpson S, Dickson RB, Lippman M. Transforming growth factor beta 1 induces cachexia and systemic fibrosis without an antitumor effect in nude mice. Cancer Res. 1991 Jul 1;51(13):3590–3594. [PubMed]
  • Anscher MS, Peters WP, Reisenbichler H, Petros WP, Jirtle RL. Transforming growth factor beta as a predictor of liver and lung fibrosis after autologous bone marrow transplantation for advanced breast cancer. N Engl J Med. 1993 Jun 3;328(22):1592–1598. [PubMed]
  • Murase T, Anscher MS, Petros WP, Peters WP, Jirtle RL. Changes in plasma transforming growth factor beta in response to high-dose chemotherapy for stage II breast cancer: possible implications for the prevention of hepatic veno-occlusive disease and pulmonary drug toxicity. Bone Marrow Transplant. 1995 Feb;15(2):173–178. [PubMed]
  • Nagelkerken L, Gollob KJ, Tielemans M, Coffman RL. Role of transforming growth factor-beta in the preferential induction of T helper cells of type 1 by staphylococcal enterotoxin B. Eur J Immunol. 1993 Sep;23(9):2306–2310. [PubMed]
  • Elias JA, Freundlich B, Kern JA, Rosenbloom J. Cytokine networks in the regulation of inflammation and fibrosis in the lung. Chest. 1990 Jun;97(6):1439–1445. [PubMed]
  • Xun CQ, Thompson JS, Jennings CD, Brown SA, Widmer MB. Effect of total body irradiation, busulfan-cyclophosphamide, or cyclophosphamide conditioning on inflammatory cytokine release and development of acute and chronic graft-versus-host disease in H-2-incompatible transplanted SCID mice. Blood. 1994 Apr 15;83(8):2360–2367. [PubMed]
  • Down JD, Nicholas D, Steel GG. Lung damage after hemithoracic irradiation: dependence on mouse strain. Radiother Oncol. 1986 May;6(1):43–50. [PubMed]
  • Kallenberg CG, Schilizzi BM, Beaumont F, De Leij L, Poppema S, The TH. Expression of class II major histocompatibility complex antigens on alveolar epithelium in interstitial lung disease: relevance to pathogenesis of idiopathic pulmonary fibrosis. J Clin Pathol. 1987 Jul;40(7):725–733. [PMC free article] [PubMed]
  • Komatsu T, Yamamoto M, Shimokata K, Nagura H. Phenotypic characterization of alveolar capillary endothelial cells, alveolar epithelial cells and alveolar macrophages in patients with pulmonary fibrosis, with special reference to MHC class II antigens. Virchows Arch A Pathol Anat Histopathol. 1989;415(1):79–90. [PubMed]
  • June CH, Bluestone JA, Nadler LM, Thompson CB. The B7 and CD28 receptor families. Immunol Today. 1994 Jul;15(7):321–331. [PubMed]
  • Schwartz RH. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065–1068. [PubMed]
  • Blazar BR, Sharpe AH, Taylor PA, Panoskaltsis-Mortari A, Gray GS, Korngold R, Vallera DA. Infusion of anti-B7.1 (CD80) and anti-B7.2 (CD86) monoclonal antibodies inhibits murine graft-versus-host disease lethality in part via direct effects on CD4+ and CD8+ T cells. J Immunol. 1996 Oct 15;157(8):3250–3259. [PubMed]
  • Morse CC, Sigler C, Lock S, Hakkinen PJ, Haschek WM, Witschi HP. Pulmonary toxicity of cyclophosphamide: a 1-year study. Exp Mol Pathol. 1985 Apr;42(2):251–260. [PubMed]

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