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The procedural requirements of bone marrow transplantation (BMT) predispose to the dramatic induction of local and systemic inflammatory states and can be conceived in relation to transplant conditioning, the activation of alloreactive T cells and finally, the effector stage of graft-versus-host disease (GVHD). It is now clear that alloreactive T cell responses result in a dramatic and often fulminant amplification of systemic inflammation that is responsible for many of the characteristic causes of transplant-related mortality. The pathways by which inflammatory cytokines are induced after BMT and the resultant pathologies will be discussed. The procedural requirements of bone marrow transplantation (BMT) predispose to the dramatic induction of local and systemic inflammatory states and can be conceived in relation to transplant conditioning, the activation of alloreactive T cells and finally, the effector stage of graft-versus-host disease (GVHD). It is now clear that alloreactive T cell responses result in a dramatic and often fulminant amplification of systemic inflammation that is responsible for many of the characteristic causes of transplant-related mortality. The pathways by which inflammatory cytokines are induced after BMT and the resultant pathologies will be discussed. This report explores the role of inflammation in the complications of bone marrow transplantation (BMT). The procedural requirements of BMT predispose to the dramatic induction of local and systemic inflammatory states and can be conceived in relation to transplantation conditioning, activation and expansion of alloreactive T cells, and the final effector stage of graft-versus-host disease (GVHD). Additive alloreactive T cell effects lead to the dramatic and often fulminant inflammatory states characteristic of allogeneic BMT. For the purpose of this discussion, the action of pathogenic proinflammatory cytokines (eg, tumor necrosis factor TNF, interleukin IL-1, interferon IFN-γ) induced at transplantation is considered the predominant paradigm of inflammation. The vast majority of transplantation candidates are heavily pretreated with chemoradiotherapy into a state of relative minimal residual disease (ie, remission). The impact of this on the induction of subsequent inflammation has not been well studied, but there are indications that this has an influence on transplantation outcome. It is logical (although not yet experimentally validated) that parenchymal tissue may be sensitized to the potentially toxic effects of transplantation conditioning by previous therapy, which will predispose to increased inflammation in these patients. Studies demonstrating enhanced induction of TNF in patients with advanced disease undergoing transplantation 1Holler E. Kolb H.J. Mittermueller J. et al.Modulation of acute graft-versus-host disease after allogeneic bone marrow transplantation by tumor necrosis factor a (TNFa) release in the course of pretransplant conditioning: role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNFa (MAK 195F).Blood. 1995; 86: 890-899PubMed Google Scholar are consistent with this. Conversely, at the time of transplantation, such recipients may be relatively depleted of important cellular populations (eg, tissue macrophages, B cells) 2Hill G.R. Cooke K.R. Teshima T. et al.Pretransplant chemotherapy reduces inflammatory cytokine production and acute graft-versus-host disease after allogeneic bone marrow transplantation.Transplantation. 1999; 67: 1478-1480Crossref PubMed Scopus (30) Google Scholar, 3Banovic T. MacDonald K.P. Morris E.S. et al.TGF-beta in allogeneic stem cell transplantation: friend or foe?.Blood. 2005; 106: 2206-2214Crossref PubMed Scopus (126) Google Scholar that contribute to inflammation during transplantation and thus may be at increased risk for inflammatory cytokine generation during conditioning. Experimental data demonstrating lower inflammatory cytokine levels after transplantation in recipients pretreated with chemotherapy 2Hill G.R. Cooke K.R. Teshima T. et al.Pretransplant chemotherapy reduces inflammatory cytokine production and acute graft-versus-host disease after allogeneic bone marrow transplantation.Transplantation. 1999; 67: 1478-1480Crossref PubMed Scopus (30) Google Scholar and the enhanced inflammatory cytokine levels seen in chemotherapy-naïve patients undergoing transplantation for chronic myelogenous leukemia support this concept 4Remberger M. Ringden O. Markling L. TNFa levels are increased during bone marrow transplantation conditioning in patients who develop acute GVHD.Bone Marrow Transplant. 1995; 15: 99-104PubMed Google Scholar, 5Holler E. Kolb H.J. Moller A. et al.Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation.Blood. 1990; 75: 1011-1016PubMed Google Scholar. Thus, the effects of previous therapy on both hematopoietic and nonhematopoietic tissue likely will influence the generation of inflammation during subsequent transplantation. The initiation of acute GVHD depends the presence of naïve T cells within the donor graft and their interaction with allodisparate antigen-presenting cells (APCs) 6Shlomchik W.D. Couzens M.S. Tang C.B. et al.Prevention of graft-versus-host disease by inactivation of host antigen presenting cells.Science. 1999; 285: 412-415Crossref PubMed Scopus (1011) Google Scholar, 7Anderson B.E. McNiff J. Yan J. et al.Memory CD4+ T cells do not induce graft-versus-host disease.J Clin Invest. 2003; 112: 101-108Crossref PubMed Scopus (254) Google Scholar. This process is intimately influenced by the BMT conditioning process and its ability to modulate this process by: 1)Depletion of host APC2)Activation of residual host APC3)Damage to gastrointestinal luminal integrity, allowing escape of toll receptor ligands into the systemic circulation (e.g. LPS, CpG). Thus, the type (ie, total body irradiation TBI or chemically based) 8Hill G.R. Teshima T. Gerbita A. et al.Differential roles of IL-1 and TNFa on graft-versus-host disease and graft-versus-leukemia.J Clin Invest. 1999; 104: 459-467Crossref PubMed Scopus (221) Google Scholar and intensity (eg, myeloablative vs nonmyeloablative) 9Hill G.R. Crawford J.M. Cooke K.J. et al.Total body irradiation and acute graft versus host disease: the role of gastrointestinal damage and inflammatory cytokines.Blood. 1997; 90: 3204-3213Crossref PubMed Google Scholar of conditioning will result in differential states of inflammation after allogeneic BMT. This effect is heavily influenced by the ability of these conditioning protocols to maintain differential numbers of activated APCs at the time of transplantation, thereby dictating the efficiency of the donor T cell–host APC encounter). Thus, the hyperacute inflammatory states induced after TBI-based conditioning is the result of donor T cells encountering small numbers of highly activated allodisparate host APC. In contrast, the later-onset acute inflammatory state occurring after nonablative allogeneic BMT likely is the result of donor T cells interacting with large numbers of less activated host APCs surviving for prolonged periods. The propensity of acute GVHD for target organs with an environmental interface and thus direct pathogen exposure (eg skin, GI tract, and lung) may not be coincidental. TBI is known to promote inflammatory cytokine generation from macrophages in response to TLR ligands 9Hill G.R. Crawford J.M. Cooke K.J. et al.Total body irradiation and acute graft versus host disease: the role of gastrointestinal damage and inflammatory cytokines.Blood. 1997; 90: 3204-3213Crossref PubMed Google Scholar, and sensitivity to LPS is enhanced markedly in GVHD, resulting in enormous inflammatory cytokine generation relative to most other disease states. This effect depends in large part on the priming effect of IFN-γ generation from alloreactive donor T cells 10Nestel F.P. Price K.S. Seemayer T.A. et al.Macrophage priming and lipopolysaccharide-triggered release of tumor necrosis factor alpha during graft-versus-host disease.J Exp Med. 1992; 175: 405-413Crossref PubMed Scopus (328) Google Scholar. A large body of evidence indicates that TBI promotes the release of TLR ligands from bacterial flora within the GI tract into the systemic circulation 11Hill G.R. Ferrara J.L.M. The primacy of the gastrointestinal tract as a target organ of graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation.Blood. 2000; 95: 2754-2759PubMed Google Scholar. Significant ongoing efforts have been aimed at limiting mucosal damage during conditioning by providing protective cytokines (especially KGF, 11Hill G.R. Ferrara J.L.M. The primacy of the gastrointestinal tract as a target organ of graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation.Blood. 2000; 95: 2754-2759PubMed Google Scholar) or reducing the dose intensity of preparative chemoradiotherapy. The intensity of the inflammatory response after transplantation is dictated in large part by the presence or absence of allodisparate T cells and the dramatic amplification of this response in the former setting. Indeed, the activation of donor T cells by host APCs characteristically results in Th1 differentiation and the generation of large amounts of IFN-γ. IFN-γ promotes the maturation (eg, CD40 expression) of APCs and the generation of IL-12 secretion, serving as a positive feedback loop to further promote Th1 differentiation and the secretion of large amounts of cytokine into the systemic circulation 12Morris E.S. Hill G.R. Advances in the understanding of acute graft-versus-host disease.Br J Haematol. 2007; 137: 3-19Crossref PubMed Scopus (43) Google Scholar. Although TNF also is produced in large amounts by donor T cells and plays an important role in the induction of acute GVHD 13Schmaltz C. Alpdogan O. Muriglan S.J. et al.Donor T cell–derived TNF is required for graft-versus-host disease and graft-versus-tumor activity after bone marrow transplantation.Blood. 2003; 101: 2440-2445Crossref PubMed Scopus (111) Google Scholar, 14Borsotti C. Franklin A.R. Lu S.X. et al.Absence of donor T-cell–derived soluble TNF decreases graft-versus-host disease without impairing graft-versus-tumor activity.Blood. 2007; 110: 783-786Crossref PubMed Scopus (24) Google Scholar, experimental evidence confirms that mononuclear cell and macrophage populations also are important sources of this cytokine and are generated in response to TLR ligation 15Cooke K.R. Hill G.R. Gerbitz A. et al.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. 2000; 165: 6612-6619PubMed Google Scholar. In addition, TNF can serve as an autocrine growth factor for the induction of alloreactive T cell expansion 16Hill G.R. Rebel V. Teshima T. et al.The p55 TNFa receptor plays a critical role in T cell alloreactivity.J Immunol. 2000; 164: 656-663PubMed Google Scholar. The Th2 cytokines generally are associated with delayed, less severe acute GVHD, although these cytokines contribute to the overall spectrum of disease 17Murphy W.J. Welniak L.A. Taub D.D. et al.Differential effects of the absence of interferon-gamma and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice.J Clin Invest. 1998; 102: 1742-1748Crossref PubMed Scopus (192) Google Scholar, 18Nikolic B. Lee S. Bronson R.T. et al.Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets.J Clin Invest. 2000; 105: 1289-1298Crossref PubMed Scopus (182) Google Scholar. The role of Th17 differentiation in GVHD remains largely unknown and will be defined more clearly over the next few years. The role of inflammatory cytokines as the second component of a dual-pronged attack on target tissues (in association with cellular cytolytic pathways) was established by Teshima et al. 19Teshima T. Ordemann R. Reddy P. et al.Acute graft-versus-host disease does not require alloantigen expression on host epithelium.Nat Med. 2002; 8: 575-581Crossref PubMed Scopus (451) Google Scholar. This study confirmed the ability to generate inflammatory cytokine–dependent GVHD target organ damage independent of major histocompatibility complex (MHC) expression on host target tissue. This effect was present in both CD4- and CD8-dependent GVHD, although it was most dominant in the former setting. Of the inflammatory cytokines, TNF is known to be a dominant mediator of pathology, particularly within the GI tract 11Hill G.R. Ferrara J.L.M. The primacy of the gastrointestinal tract as a target organ of graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation.Blood. 2000; 95: 2754-2759PubMed Google Scholar, and the neutralization of this cytokine shows particular promise in the treatment of acute GVHD 20Choi S.W. Kitko C.L. Braun T. et al.Change in plasma tumor necrosis factor receptor 1 levels in the first week after myeloablative allogeneic transplantation correlates with severity and incidence of GVHD and survival.Blood. 2008; 112: 1539-1542Crossref PubMed Scopus (109) Google Scholar. The role of IL-1 in acute GVHD remains well established in experimental models from numerous groups, although the importance in clinical acute GVHD is less clear, considering the failure of a soluble antagonist to demonstrate any benefit in a randomized clinical trial 21Antin J.H. Weisdorf D. Neuberg D. et al.Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation.Blood. 2002; 100: 3479-3482Crossref PubMed Scopus (137) Google Scholar. The effect of donor T cell–derived IFN-γ as an effector molecule in acute GVHD is complex, because this cytokine has organ-specific effects whereby it is directly pathogenic to the GI tract but prevents the induction of lung GVHD (idiopathic pneumonia syndrome) 22Burman A.C. Banovic T. Kuns R.D. et al.IFNgamma differentially controls the development of idiopathic pneumonia syndrome and GVHD of the gastrointestinal tract.Blood. 2007; 110: 1064-1072Crossref PubMed Scopus (135) Google Scholar. In addition, this cytokine appears to be responsible for much of the bone marrow suppression occurring during GVHD 23Delisle J.S. Gaboury L. Belanger M.P. et al.Graft-versus-host disease causes failure of donor hematopoiesis and lymphopoiesis in interferon-gamma receptor-deficient hosts.Blood. 2008; 112: 2111-2119Crossref PubMed Scopus (34) Google Scholar. The pathogenesis of chronic GVHD remains less well established, although both experimentally and clinically, it appears that autoantibodies and B cells contribute to the process through the stimulation of fibrosis 24Svegliati S. Olivieri A. Campelli N. et al.Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease.Blood. 2007; 110: 237-241Crossref PubMed Scopus (193) Google Scholar. The latter process is transforming growth factor (TGF)-γ dependent, and neutralization of TGF-γ appears to be efficacious in experimental models 3Banovic T. MacDonald K.P. Morris E.S. et al.TGF-beta in allogeneic stem cell transplantation: friend or foe?.Blood. 2005; 106: 2206-2214Crossref PubMed Scopus (126) Google Scholar, as does clinical B cell depletion with monoclonal antibodies 25Canninga-van Dijk M.R. van der Straaten H.M. Fijnheer R. et al.Anti-CD20 monoclonal antibody treatment in 6 patients with therapy-refractory chronic graft-versus-host disease.Blood. 2004; 104: 2603-2606Crossref PubMed Scopus (119) Google Scholar. Thus, although inflammation may contribute to thymic atrophy and the emergence of autoreactive T cells after transplantation, chronic GVHD itself does not appear to be characterized by a significant proinflammatory state. The recognition of the central role of inflammation as a pathogenic, MHC-indiscriminate effector pathway of host damage represents an important advance in our understanding of the complications of BMT and has opened the door for new therapies to block these soluble effectors of disease. Financial disclosure: The author has nothing to disclose.
Geoffrey R. Hill (Thu,) studied this question.