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Background: Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication of allogeneic bone marrow transplantation (BMT). IPS is associated with elevated bronchoalveolar lavage (BAL) fluid levels of tumor necrosis factor-alpha and lipopolysaccharide, both of which are potent activators of endothelial cells (ECs). EC expression of the adhesion molecule CD54 (intercellular adhesion molecule [ICAM]-1) has been shown to be a major regulator of pulmonary inflammation in various experimental models., Methods: Using a well-established murine BMT system in which lung injury and graft-versus-host disease (GvHD) are induced by minor histocompatibility antigenic differences between donor and host, the RNase Protection Assay, mice deficient in ICAM-1 expression, and a monoclonal blocking antibody to ICAM, we evaluated the role of the pulmonary vascular expression of CD54 in the development of IPS., Results: Enhanced pulmonary vascular expression of ICAM-1 coincided with the development of IPS. When ICAM-1 -/- mice were used as allogeneic BMT recipients, IPS severity (measured by lung histopathology, BAL cellularity, and cytokine expression) was significantly reduced compared with wild-type controls. Similar results were also observed when wild-type recipients were treated with a monoclonal blocking antibody to ICAM-1. Surprisingly, ICAM-1 had differential effects on leukocyte infiltration into GvHD target organs; ICAM-1 deficiency had no impact on intestinal histopathology, whereas ICAM-1-/- BMT recipients had significantly enhanced hepatic injury., Conclusions: These data demonstrate that although the expression of ICAM-1 is critical for the development of IPS, different mechanisms of leukocyte recruitment are operative in other GvHD target organs.

Background: Idiopathic pneumonia syndrome (IPS) is a frequent and often fatal complication of allogeneic bone marrow transplantation (BMT). We have previously shown that experimental IPS is associated with alloreactive donor T cells and the inflammatory mediators TNF-alpha and lipopolysaccharide. Both TNF-alpha and lipopolysaccharide are known contributors to endothelial injury. Although damage to vascular endothelia has been associated with other complications after BMT, its relationship to lung injury has not been explored., Methods: We used a well-established murine BMT system, in which lung injury and graft-versus-host disease are induced by minor histocompatibility antigenic differences between donor and host, and the DNA terminal transferase nick-end labeling (TUNEL) procedure to evaluate whether significant pulmonary vascular endothelial cell (EC) apoptosis is present during the development of IPS., Results: Our data demonstrate that pulmonary histopathology after allogeneic BMT is accompanied by significant EC apoptosis and the appearance of activated caspase 3. Further evaluation reveals that EC injury coincides with the onset of pulmonary pathology, is associated with elevations in bronchoalveolar lavage fluid tumor necrosis factor (TNF)-alpha levels, and is accompanied by evidence for EC activation. Administration of a soluble TNF-alpha binding protein (recombinant human TNF-alpha receptor:Fc) from week 4 to week 6 after allogeneic BMT significantly reduces EC apoptosis and lung histopathology observed in this setting., Conclusions: EC damage mediated by TNF-alpha is directly linked to the development of experimental IPS. Methods that protect or maintain the integrity of the pulmonary vascular endothelium may therefore prove effective in reducing the severity of lung injury after BMT.

Acute graft-versus-host disease (aGVHD) remains one of the main obstacles after allogeneic bone marrow transplantation (BMT). Using a well-established mouse BMT model in which aGVHD is induced across a haploidentical mismatch, we show that the expression of heme oxygenase-1 (HO-1) can be induced by cobalt-protoporphyrin IX (CoPP) in aGVHD target organs such as liver and bowel and that the induction of HO-1 before BMT results in improved overall survival and reduced aGVHD. Serum levels of proinflammatory cytokines were markedly reduced in CoPP-treated animals. Recipients displayed less damage to the intestinal mucosa, and this resulted in reduced serum lipopolysaccharide levels at day 6 after transplantation. Peritoneal cells and CD45(+) liver cells isolated from mice that received transplants strongly expressed HO-1 and displayed a reduction in the expression of activation markers such as CD11b, CD80, and major histocompatibility complex class I. This resulted in reduced T-cell activation ex vivo. These results demonstrate that the induction of HO-1 before high-dose conditioning protects the host in multiple ways and effectively ameliorates aGVHD.

Acute graft-versus-host disease (GVHD) remains the major complication of allogeneic stem cell transplantation (SCT) with an incidence of 40-60% and a mortality of up to 50%. Several assays have been developed to try to predict the development of GVHD including the mixed lymphocyte culture reaction, cytotoxic and helper T lymphocyte precursor frequency assays. In the Northern region of England we have used an in vitro skin explant model for predicting GVHD in MHC compatible bone marrow transplant recipients since 1988. The aims of the present study was to test the reproducibility of the model in two other bone marrow transplant centers in Europe. The assay consists of incubating patient skin explants with effector cells from mixed donor versus recipient lymphocyte cultures and the subsequent detection of graft-versus-host reactions by histopathological grading (0-IV) of the skin explants. 503 slides from 134 patients were evaluated. All were graded for negative GVHR grade 0-I or positive grade II-IV. Results from control and test slides significantly correlated between centers to the p value of 0.0001 by Fisher's exact probability test. These results show that the skin explant assay is reproducible between centers and supports the continued use of the assay to predict GVHD in allogeneic stem cell transplant recipients.

IL-10 is a potent immunosuppressant which inhibits allo-antigen-specific T cell responses. In addition, IL-10 is a strong endogenous anti-inflammatory cytokine. To investigate the role of IL-10 in the induction of acute GVHD following allogeneic bone marrow transplantation (BMT) we performed a prospective study on spontaneous IL-10 production by peripheral blood mononuclear cells (PBMNC) in 84 patients admitted for allogeneic BMT. High spontaneous IL-10 production by PBMNC at the time of admission and prior to any preparative treatment correlated with a subsequent low incidence of GVHD and transplant-related mortality (8%), as compared to patients with low or intermediate IL-10 production (50%, P < 0. 01). Our data demonstrate the prognostic significance of increased IL-10 production in BMT patients and suggest a major role of IL-10 in maintaining immunobalance in the setting of allogeneic BMT. Bone Marrow Transplantation (2000) 25, 237-241.

Intensity of pretransplant conditioning has been closely correlated with regimen related toxicity in patients receiving allogeneic bone marrow transplantation (BMT). In this review, we summarize evidence for a direct link between inflammatory reactions induced by irradiation and cytotoxic treatment and occurrence of acute graft-versus-host disease (GvHD) as well as endothelial complications: In our studies, de novo release of TNFalpha during conditioning was associated with an increased risk of severe GvHD and mortality following BMT, whereas increased spontaneous production of IL-10, an endogenous TNF-antagonist, prior to conditioning protected from these complications. Immunogenetic differences in cytokine regulation and costimulation by endotoxin proved to be important cofactors determining the extent of inflammatory cytokine release in individual patients. Pathophysiological relevance of these findings seems to be confirmed by experimental as well as first clinical trials using TNF-antibodies and related antagonists during pretransplant conditioning. Preclinical experiments suggest additional, cytokine independent inflammatory reactions induced by irradiation such as expression of ICAM-1 and endothelial cell apoptosis. Although the exact impact of these findings on pathophysiology of BMT related complications needs further clarification by future studies, conditioning related inflammation as a first crucial step in induction of GvHD and complications has to be considered when designing new protocols for preparation of patients for allogeneic BMT.

Presents the findings of a study on the variations in 1a,25-dihydroxyvitamin D3 and 25-dihydroxyvitamin D3 serum levels during allogenic bone marrow transplantation (BMT). Effects of active form of 1.25(OH)2 D3 in BMT; Measurement of both vitamins in consecutive serum samples of patients before and after allogenic BMT; Observation of marked decline in serum levels; Superior effects on bone density and modulation of graft-versus-host disease with supplementation of patients with 1,25(OH)2 D3 analogs or 25(OH) D3.