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• W2071927386 abstract "Bone marrow transplantation (BMT*) is currently indicated in the treatment of a number of malignant and non-malignant diseases, including acute and chronic leukemias, myelomas, lymphomas, aplastic anemia, solid tumors, and severe immunodeficiencies. Allogeneic BMT, i.e., transplantation between two genetically nonidentical individuals, is associated with serious side effects; its most common complication is graft-versus-host disease (GVHD). Recently, the use of unrelated donors and HLA-nonidentical family members has resulted in increased frequencies of severe GVHD (1). The development of acute and chronic GVHD and the immunosuppression used for GVHD prophylaxis represent significant risk factors for bacterial, fungal, and viral infections (2). Studies of experimental and clinical allogeneic BMT have shown that immunologically competent T cells must be present in the transplanted graft for GVHD to occur (3). Depletion of T cells or T-cell subsets prevents GVHD and eliminates the need for further immunosuppression but is associated with a higher rate of graft failure and increased incidence of leukemic relapse, resulting in equivalent disease-free survival for patients who receive conventional prophylaxis (4). GVHD thus remains a major barrier to allogeneic BMT for a variety of diseases, and further elucidation of the pathophysiological mechanisms involved is critical to its wider application. Advances in basic immunology during the last decade have demonstrated how interactions between immunologically competent cells are governed by cytokines, and much recent research has focused on the roles of these mediators in the pathogenesis of acute GVHD. In this Overview, we examine current evidence that dysregulated cytokine production occurs as a cascade during sequential monocyte and T-cell activation and is responsible for many of the manifestations of acute GVHD. Cytokine dysregulation can be conceptualized as three sequential phases (Fig. 1). Phase 1 is initiated by the conditioning of the host, which induces inflammatory processes in recipient tissues. Donor T-cell activation by host alloantigens and subsequent cytokine secretion in phase 2 are facilitated by the events of phase 1. The T cell-derived cytokines of phase 2 activate distal inflammatory mediators which, in synergy with T and natural killer (NK) cell-mediated cytotoxicity, produce the systemic morbidity of GVHD-associated immunosuppression (phase 3). Each of these three phases is considered in detail below. It should be noted that these mechanisms have been most clearly delineated in mouse BMT models. Although there is preliminary work to suggest that these cascades are important in clinical GVHD (5), detailed analysis of human tissue is required. PHASE 1: HOST CONDITIONING Induction of Inflammatory Cytokines during Host Conditioning Agents used for BMT conditioning, which often includes total body irradiation and/or chemotherapy, are important variables in the etiology of acute GVHD and other transplant-related complications for two major reasons. First, ionizing radiation activates host cells to secrete increased levels of inflammatory cytokines, e.g., tumor necrosis factor (TNF)-α and interleukins (IL) 1 and 6 (6, 7). Increased systemic levels of these cytokines are detectable within a few hours after conditioning, and their excess can lead to endothelial cell damage (8), which contributes to increased activation of donor T cells present in the donor marrow inoculum. Facilitation of T-cell activation by inflammatory cytokines may occur via their direct stimulatory action on T cells, or indirectly via enhanced antigen presentation or enhanced intercellular adhesion (reviewed in (9) and (10)). The conditioning regimen may have a second important role in the induction of GVHD: injury to the mucosal surface of the gastrointestinal tract may enable bacterial breakdown products, such as endotoxin or lipopolysaccharide (LPS), to enter the splanchnic circulation. LPS may subsequently stimulate preactivated gut-associated macrophages to release TNF-α and IL-1 (11) (see below). Clinically, the early appearance of increased TNF-α levels during phase 1 appears to be of value for the prediction of the subsequent severity of complications and overall survival after clinical allogeneic BMT (7, 12). A recent phase II study demonstrates that TNF-α blockade during conditioning can delay the onset of acute GVHD and decrease the incidence of severe disease (13). These data suggest that inhibitors of inflammatory cytokines may be efficacious when used in the immediate peritransplant period. It is possible that multiple cytokines contribute to this process, including those of macrophage and T-cell origin (e.g., TNF-α, IL-1, and interferon [IFN]-γ), offering several targets for inhibition. This may be particularly important in the unrelated donor or HLA-mismatched, related BMT setting, where current immunosuppression strategies are less than optimal. PHASE 2: DONOR T-CELL ACTIVATION Activation of alloreactive donor T cells occurs during phase 2 in this pathophysiological model of acute GVHD. The nature of host alloantigens determines which subset of donor T cells proliferates and differentiates. In mouse models of GVHD, where genetic differences between multiple inbred strain combinations can be carefully controlled, CD4+ cells primarily induce GVHD to major histocompatibility complex (MHC) class II differences, whereas CD8+ cells primarily induce GVHD to MHC class I differences (14). In MHC-identical BMT, GVHD may be induced by either or both subsets (15). Activated donor T cells secrete several cytokines, predominantly IL-2 and IFN-γ (“type I” cytokines), which can be produced by CD4+ as well as CD8+ T cells (“Th1” and “Tc1” cells) (16, 17). Much evidence has implicated IL-2 and IFN-γ as pivotal mediators of acute GVHD, controlling and amplifying the immune response against alloantigens (10), inducing cytotoxic T lymphocyte (CTL) and NK cell responses, and priming monocytes to produce the proinflammatory cytokines IL-1 and TNF-α (11). Interleukin 2 The importance of the T-cell growth factor IL-2 for the initiation of GVHD has been demonstrated in both experimental and clinical BMT. First, IL-2 is secreted by donor CD4+ T cells in the first days after experimental allogeneic BMT (18). Second, the blockade of IL-2 with antibodies to IL-2 or its receptor can inhibit the development of experimental disease (18). Clinically, the precursor frequency of host-specific, IL-2-producing T cells (precursor frequency of helper T cells) is predictive for the risk of acute GVHD (19, 20). In addition, soluble IL-2 receptor levels may be a sensitive indicator of impending GVHD onset, and they correlate with disease severity (21). IL-2-producing donor T cells have been the target of many experimental designs to control GVHD. Cyclosporine, a powerful inhibitor of IL-2 production, is effective prophylaxis against GVHD (22). Although a humanized antibody (anti-Tac) to the IL-2 receptor appears promising, the addition of murine anti-human IL-2 receptor antibodies to corticosteroids for the treatment of steroid-resistant acute GVHD has failed to show a benefit in a randomized study (reviewed in (23). The addition of an anti-IL-2 receptor antibody to standard cyclosporine/methotrexate prophylaxis has also been disappointing in large randomized studies of the unrelated or mismatched related BMT settings (23). The administration of exogenous IL-2 to BMT hosts has interesting and multivalent effects. Low-dose recombinant IL-2 induces and exacerbates a histological and clinical GVHD-like syndrome after human autologous BMT (24), although it can be administered safely after allogeneic BMT with little evidence of increased incidence of GVHD (25, 26). Paradoxically, administration of IL-2 can protect against GVHD: Sykes et al. (27) established that a short course of high-dose IL-2 early after fully H2-mismatched BMT results in a decrease of GVHD-related mortality. This protective effect, which is augmented by the co-transplantation of syngeneic bone marrow, is associated with specific inhibition of early IFN-γ secretion (28, 29) and may result in the functional impairment of donor T cells. Interferon-γ Increased serum levels of IFN-γ are associated with acute GVHD, and lymphocytes from animals with GVHD secrete significantly greater amounts of IFN-γ than lymphocytes from non-GVHD controls (28, 30-33). Additional evidence of a role for IFN-γ in experimental acute GVHD includes: priming of macrophages by IFN-γ during acute GVHD to produce inflammatory cytokines (11); induction of pathology in skin tissues and the gastrointestinal tract by IFN-γ (34, 35); suppression of T lymphocyte function characteristic of acute GVHD by IFN-γ (36, 37); prevention of acute GVHD when CD8+ cells are incapable of IFN-γ production (38); and inhibition of acute GVHD by direct or indirect blockade of IFN-γ (34, 39-41). Modestly elevated serum IFN-γ levels are associated with the onset of acute GVHD in human allogeneic BMT (42), and the administration of IFN-γ augments acute GVHD (43). Furthermore, supernatants from two-way patient/donor mixed lymphocyte reactions contain IFN-γ, and the occurrence of high levels of this cytokine correlates well with the development of GVHD grade II or above, which suggests that IFN-γ may be of value as a predictor of subsequent disease (44, 45). Interestingly, umbilical cord blood cells produce little IFN-γ (46), but whether this difference accounts for the reduced incidence of GVHD after umbilical cord blood transplantation (47) remains to be determined. Acute GVHD and the “Th1/Th2” Paradigm Collectively, the data above indicate that activation of type 1 T cells is primarily responsible for initiating acute GVHD. It is now well known that type 1 cytokines and type 2 cytokines are cross-regulatory, i.e., IL-4 and IL-10 produced by activated type 2 T cells (CD4+ “Th2” cells or CD8+ “Tc2” cells) (16, 17) prevent the secretion of IFN-γ. The secretion of type 1 cytokines is generally associated with activation of macrophages, inflammatory cytokine production, and the activation of NK and CTL cells, whereas the secretion of type 2 cytokines is generally associated with the down-regulation of cell-mediated immune responses (reviewed in (10). Differential activation of donor T-cell subsets has been evoked in the immunopathogenesis of various other autoimmune, infectious, and immunodeficiency diseases (48, 49), and there is thus a significant interest in the potential relevance of the Th1/Th2 paradigm for acute GVHD. There is now considerable evidence that a type 1→type 2 immune deviation after allogeneic transplantation is associated either with decreased acute GVHD or with the development of a “chronic” GVHD syndrome that is characterized by decreased lethality and autoantibody formation (18, 32, 50-52). However, a type 1→type 2 polarization has not always improved allogeneic solid organ graft survival in experimental models (53, 54). While the type 1/type 2 model has provided a valuable framework for many immune responses, including alloreactivity, it should also be noted that processes that lead to different clinical outcomes after experimental BMT are not always clearly associated with a strict delineation of type 1 or type 2 responses (30, 55). It is likely that more subtle balances between local levels of type 1 and type 2 T-cell cytokines in vivo may be critical factors that determine the degree to which a systemic inflammatory response develops (53). The modulation of the initial cytokine response of donor T cells to alloantigens may be an alternative, and potentially superior, approach to T-cell depletion (TCD) prior to BMT. The ultimate goal of these manipulations is to prevent the induction of inflammatory effector phase processes without deleting the beneficial effects that are usually mediated by alloreactive donor T cells. Initial approaches to alter cytokine profiles included the administration of type 2 cytokines to BMT hosts. However, it now seems clear that there is little therapeutic potential of exogenously administered IL-4 or IL-10 after BMT for the prevention of experimental acute GVHD because of toxicity or inefficacy of these cytokines in vivo (56, 57). Recent approaches have attempted to engineer a type 1→type2 shift in the cytokine profile of specific hostreactive donor T cells before BMT as a way to attenuate inflammatory processes of acute GVHD (52, 58). These findings are encouraging, but with respect to BMT for malignant diseases, effects on graft-versus-leukemia and engraftment must be further evaluated. Another interesting approach that modulates donor T-cell function comes from an unexpected source. The use of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPC) for allogeneic transplantation in high-risk patients does not lead to a higher incidence of GVHD, despite the presence of 10- to 20-fold more T cells in the PBPC infusion (reviewed in (59). Suprisingly, G-CSF pretreatment of donor mice leads to partial polarization of T cells toward a type 2 cytokine phenotype (60), despite the lack of G-CSF receptors on T cells. This immunomodulatory effect of G-CSF may prove useful in the mobilization of PBPC for allogeneic transplantation. PHASE 3: INFLAMMATORY EFFECTOR MECHANISMS Inflammatory Cytokines TNF-α and IL-1 as Effector Molecules of GVHD Phase 3 of the pathophysiology of acute GVHD is a complex cascade of multiple effectors. At a minimum, these components include (1) several inflammatory cytokines, (2) specific anti-host cytotoxicity mediated by CTL via Fas and perforin pathways (61, 62), (3) large granular lymphocytes or NK cells (63), and (4) nitric oxide (64). There is now strong evidence that TNF-α and IL-1, secreted by non-T effector cells, act either alone or in concert with CTL- and NK-mediated cytotoxicity to cause the full spectrum of deleterious effects during acute GVHD, including cachexia and target cell destruction. Murine BMT models have demonstrated the link between excessive production of TNF-α/IL-1 and manifestations of acute GVHD. As mentioned above, the secretion of type 1 cytokines during phase 2 of GVHD can cause the priming of mononuclear phagocytes for the generation of inflammatory cytokines (11). Actual secretion of TNF-α and IL-1 occurs after primed macrophages are triggered by a secondary signal, such as LPS, which can leak through the intestinal mucosa damaged during phase 1. Toxins in contact with the skin may also stimulate keratinocytes, dermal fibroblasts, and macrophages to induce inflammatory cytokines in skin tissues. Lesions in GVHD target tissues are clearly associated with high levels of TNF-α and IL-1 (65-67). The systemic infusion of these inflammatory cytokines induces cell necrosis and cachexia (57), and TNF-α appears to be partially responsible for the pronounced lymphocyte suppression associated with acute GVHD. The latter effect is mediated, at least in part, by excess nitric oxide secretion (68). Collectively, these observations show that dysregulated TNF-α and IL-1 secretion induce a wide spectrum of deleterious effects that are characteristic for acute GVHD. A review of clinical BMT data regarding systemic TNF-α levels demonstrates that TNF-α serum levels and mRNA expression are increased in the posttransplant period (reviewed in (5). Serum levels as they relate to disease intensity and the assays for these cytokines are often problematic. These problems include the assay conditions, the compartmentalization of TNF-α, which may produce local effects that are not reflected in systemic serum levels, and the presence of naturally occurring binding proteins that can both neutralize and prolong TNF-α bioactivity (69). Furthermore, increases in serum inflammatory cytokines and mRNA expression do not appear to be specific for GVHD, since they also occur in BMT hosts during other transplant-related complications, such as veno-occlusive disease and infection. This association of systemic TNF-α levels with a range of pathological conditions in addition to GVHD has so far precluded its use as a predictive parameter for acute GVHD. Treatment of Acute GVHD with Cytokine Antagonists Administration of inflammatory cytokine antagonists, such as anti-TNF-α antibodies, the solublized TNF-α receptor, or IL-1 receptor antagonist, prevents tissue lesions and reduces mortality from GVHD in experimental BMT (reviewed in (23). In clinical BMT, several antagonists have been tested for the treatment of steroid-resistant GVHD, with sometimes dramatic but short-lived responses (23). Several clinical trials are currently in progress. Whether anti-tumor effects can be spared (since TNF-α has well-documented cytotoxic effects against tumor cells) and whether cytokine neutralization impairs antimicrobial defense are still unresolved. Moreover, it is unlikely that individual cytokine antagonists alone will be useful for the treatment of established GVHD; no single cytokine antagonist has yet been efficacious in the limited randomized trials so far performed in this setting. Steroids are the first-line treatment of GVHD and in themselves reduce both TNF-α and IL-1 secretion. The use of specific antagonists to these cytokines may therefore prove redundant in this setting. Combinational approaches may include methods of in vivo T-cell depletion (such as antithymocyte globulin) in an attempt to modify anti-host as well as cytokine reactivity in newly maturating T cells (rather than mature established T cells). CONCLUSIONS The problems associated with current GVHD prophylaxis (either immunosupressive agents or TCD) demonstrate the need for alternative methods to reduce GVHD and improve BMT outcomes. TNF-α blockade alone is less effective than TCD of the bone marrow in preventing GVHD, which suggests that there are interactions among cytokines and emphasizes the importance of blocking more than a single phase of GVHD pathophysiology. Recent advances in the understanding of cytokine networks have led to an improved comprehension of this complex disease process. Cytokine dysregulation can now be analyzed at both the cellular and molecular levels in vitro, and insights from these systems are currently being tested in animal models and in clinical trials. Future clinical protocols may approach GVHD prophylaxis and treatment at each of the three phases of these cytokine cascades.Figure 1: The immunopathophysiology of GVHD: Schematic representation of the interactions of T-cell cytokines and mononuclear phagocyte-derived cytokines during GVHD. Acute GVHD is proposed to develop in a three-step process in which mononuclear phagocytes and other accessory cells are responsible for both initiation of a graft-versus-host reaction and the subsequent injury to host tissues after complex interactions with cytokines. In phase 1, the conditioning regimen (irradiation and/or chemotherapy) leads to the damage and activation of host tissues, including intestinal mucosa, liver, and other tissues, and induces the secretion of the inflammatory cytokines TNF-α and IL-1. The consequences of the action of these cytokines are increased expression of MHC antigens and adhesion molecules, enhancing the recognition of host MHC and/or minor histocompatibility antigens by mature donor T cells after allogeneic BMT. Donor T-cell activation in phase 2 is characterized by proliferation of Th1 T cells and secretion of IL-2 and IFN-γ. IL-2 and IFN-γ induce further T-cell expansion, induce CTL and NK cell responses, and prime additional mononuclear phagocytes to produce IL-1 and TNF-α. Effector functions of mononuclear phagocytes (phase 3) are triggered via a secondary signal provided by LPS that leaks through the intestinal mucosa that was damaged during phase I. LPS subsequently may stimulate gut-associated lymphocytes and macrophages. LPS that reaches skin tissues may also stimulate keratinocytes, dermal fibroblasts, and macrophages to produce similar cytokines in the dermis and epidermis. This mechanism may result in the amplification of local tissue injury and further promote an inflammatory response which, together with the CTL and NK component, leads to target tissue destruction in the BMT host." @default.
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• W2071927386 title "CYTOKINE CASCADES IN ACUTE GRAFT-VERSUS-HOST DISEASE1" @default.
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