Cell‐specific elevation of NRF2 and sulfiredoxin‐1 as markers of oxidative stress in the lungs of idiopathic pulmonary fibrosis and non‐specific interstitial pneumonia

Mazur W, Lindholm P, Vuorinen K, Myllärniemi M, Salmenkivi K, Kinnula VL. Cell‐specific elevation of NRF2 and sulfiredoxin‐1 as markers of oxidative stress in the lungs of idiopathic pulmonary fibrosis and non‐specific interstitial pneumonia. APMIS 2010; 118: 703–12. Human idiopathic pulmonary fibrosis (IPF) and non‐specific interstitial pneumonia (NSIP) have been proposed to be attributable to oxidative stress. The nuclear factor, erythroid derived 2, like protein (NRF2)–sulfiredoxin‐1 (SRX1) pathway was hypothesized to be associated with the pathogenesis of human pulmonary fibrosis. Several methods including digital morphometry were used in the assessment of the cell‐specific localization and expression of NRF2 and SRX1 and selected proteins linked to their activation/stability in human IPF/usual interstitial pneumonia (UIP) and NSIP lung. The proteins of the NRF2 pathway were localized in the hyperplastic alveolar epithelium and inflammatory cells in IPF and NSIP, but were absent in the fibroblastic foci characteristic of IPF. Morphometric evaluation revealed NRF2 and KEAP1 to be significantly elevated in the hyperplastic alveolar epithelium compared with the normal alveolar epithelium, and NRF2 was remarkably expressed in the nuclear compartment of the hyperplastic cells. SRX1 was expressed mainly in alveolar macrophages, and the number of SRX1‐positive macrophages/surface area was elevated in NSIP, a disease which contains more marked inflammatory reaction compared with the IPF/UIP lung. The expression of the NRF2 pathway in human IPF and NSIP is further evidence that the pathogenesis of human fibrotic lung diseases is oxidant‐mediated and originates from the alveolar epithelium.     

骨髓移植治疗重型地中海贫血

目的　探讨骨髓移植治疗重型地中海贫血的可行性。方法　对 1例确诊为重型 β地中海贫血的患儿进行骨髓移植 ,患儿基因突变型为 CD41- 42 /6 5 4,移植同胞哥哥的骨髓 85 0 m l,有核细胞 :5 .6×10 8/kg,CD34 细胞 :7.8× 10 6 /kg,粒 -巨噬细胞集落形成单位 :5 .7× 10 5 /kg,HL A- DR一个位点不合 ,血型相同 ,预处理方案为白消安 :16 mg/kg、环磷酰胺 :2 0 0 m g/kg、抗人胸腺细胞免疫球蛋白 :88mg/kg,环孢 A和甲氨喋呤预防移植物抗宿主病 (Graft- versus- hostdisease,GVHD)。结果　移植后出现 度急性 GVHD和巨细胞病毒间质性肺炎 ,均获得控制。白细胞 (WBC)移植后 14天为 1.1× 10 9/L,中性粒细胞 0 .4× 10 9/L ,18天 WBC 4.5× 10 9/L ,由于受更昔洛韦副作用影响 ,WBC曾一度下降 ,3个月后恢复正常 ,血小板(Plt)移植后 86天 >5 0× 10 9/L ,5个半月恢复正常 ,移植后 12 8天血红蛋白 (Hb)升至 10 6 g/L ,最后一次输血时间为移植后 10 3天。移植前平均每月输血 2 0 0 ml,移植 10 3天后至今 6个多月未输血 ,Hb保持在 110 g/L以上。地中海贫血基因型已转为供者的。结论　骨髓造血干细胞移植可根治重型地中海贫血 ,为该病的治疗提供了新思路与途径。治疗移植后巨细胞病毒感染 (间质性肺炎 ) ,更昔洛韦     

Whole‐lung pathology of pleuroparenchymal fibroelastosis (PPFE) in an explanted lung: Significance of elastic fiber‐rich,non‐specific interstitial pneumonia‐like change in chemotherapy‐related PPFE

Pleuroparenchymal fibroelastosis (PPFE) is characterized by upper lobe‐predominant subpleural fibroelastosis. Despite its characteristic uneven distribution, detailed whole‐lung pathological features of PPFE have rarely been studied. We investigated PPFE in the explanted lungs from a 19‐year‐old male patient with a history of chemotherapy. Grossly, the explanted lungs showed upper lobe‐predominant shrinkage with subpleural and central consolidation. Histologically, fibroelastosis was prominent in the perilobular areas and along the bronchovascular bundles. The other areas of the lung showed diffuse, non‐specific interstitial pneumonia (NSIP)–like change with a characteristic increase of septal elastic fibers. In the digital image analysis, the ratio of elastic fibers to whole fibrosis (EF score) was lower in the subpleural areas than in the NSIP‐like lesions, but the EF scores of the latter showed no significant difference between upper and middle/lower lobes. In the present case, the diffusely distributed elastic fiber‐rich NSIP‐like change, probably caused by the earlier chemotherapy, may have been conducive to the development of PPFE. This suggests that some unknown vulnerability of the upper lobe may exist, various primary lesions converging to the upper lobe predominance of PPFE.     

Idiopathic pneumonia syndrome after bone marrow transplantation: the role of pre-transplant radiation conditioning and local cytokine dysregulation in promoting lung inflammation and fibrosis

Pulmonary complications and graft-vs.-host disease (GVHD) remain severe threats to survival after bone marrow transplantation (BMT). Idiopathic pneumonia syndrome (IPS) accounts for nearly 50% of all the cases of interstitial pneumonitis after BMT. IPS is characterized by an early inflammatory phase followed by chronic inflammation and fibrosis of lung tissue; however, the immunopathogenesis of this disease is not yet clearly understood. This biphasic syndrome has been reported to be associated with pre-transplant radiation conditioning in some studies while others have suggested that GVHD or autoimmune phenomena may be responsible for its development. The early post-BMT phase is characterized by the presence of inflammatory cytokines whose net effect is to promote lymphocyte influx into lungs with minimal fibrosis, that leads to an acute form of graft-vs.-host reaction-mediated pulmonary tissue damage. Gradual changes over time in leucocyte influx and activation lead to dysregulated wound repair mechanisms resulting from the shift in the balance of cytokines that promote fibrosis. Using data from new animal models of IPS and information from studies of human IPS, we hypothesize that cytokine-modulated immunological mechanisms which occur during the acute and chronic phases after bone marrow transplantation lead to the development of the progressive, inflammatory, and fibrotic lung disease typical of idiopathic pneumonia syndrome.     

Clinico-pathological Analysis of the Lungs from Patients with Lung Transplantation in a Single Institute in Korea

Recently, the numbers of lung transplantation (LT) has been increased in Korea. However, post-LT outcome has not been successful in all patients, which may be partially affected by the primary lung disease. Therefore comprehensive understanding in original pathological diagnosis of patients with LT would be needed for achieving better clinical outcome. To address this issue, we performed clinico-pathological analysis of the explanted lungs from 29 patients who underwent LT over a 9-yr period in Seoul National University Hospital. Among them, 26 patients received single (1/26) or double (25/26) LT, while heart-lung transplantation was performed in 3 patients. The final clinico-pathological diagnoses were idiopathic pulmonary fibrosis/usual interstitial pneumonia (UIP) (n = 6), acute interstitial pneumonia (AIP)/diffuse alveolar damage (DAD) (n = 4), AIP/non-specific interstitial pneumonia with DAD (n = 1), collagen vascular disease-related interstitial lung disease (CVD-ILD)/DAD (n = 3), CVD-ILD/UIP (n = 1), lymphangioleiomyomatosis (n = 1), bronchiectasis (n = 4), pulmonary arterial hypertension (n = 2), tuberculosis (n = 1), bronchiolitis obliterans (BO) (n = 1), and lung cancer (n = 1). Moreover, 4 patients who had chemotherapy and hematopoietic stem cell transplantation due to hematologic malignancy showed unclassifiable interstitial pneumonia with extensive fibrosis in the lungs. Our study demonstrates that pathology of the explanted lungs from Korean patients with LT is different from that of other countries except for interstitial lung disease and bronchiectasis, which may be helpful for optimization of selecting LT candidates for Korean patients.

Graphical Abstract

相似文献   

Mesenchymal Stromal Cells Fail to Alleviate Experimental Graft‐Versus‐Host Disease in Rats Transplanted with Major Histocompatibility Complex‐Mismatched Bone Marrow

Mesenchymal stromal cells (MSC) can be used to treat graft‐versus‐host disease (GVHD) caused by allogeneic stem cell transplantation (allo‐SCT). The effectiveness of this therapy has been variable in clinical trials and in experimental animal models. In this study, we investigated the ability of bone marrow (BM)‐derived MSC to alleviate GVHD in an experimental rat model of allo‐SCT using two different combinations of major histocompatibility complex (MHC) mismatch with survival as the primary endpoint. Recipient rats received total body irradiation and a transplant of T cell‐depleted donor BM cells with either a full [PVG.7B → BN] or a partial MHC mismatch [PVG.1U → PVG.R23] restricted to the class II and non‐classical class I sub‐regions (RT1‐B/D‐CE/N/M). GVHD was invoked by infusion of graded doses of donor leukocytes 2 weeks after allo‐SCT. Weekly doses of MSC were injected starting on the day of donor leukocyte infusion. No significant overall improvement of mortality and morbidity was observed in the two transplantation settings. Stimulation of MSC with exogenous tumor necrosis factor α and interferon (IFN)γ prior to infusion could not rescue BM‐transplanted rats from lethal acute GVHD. In conclusion, repeated administrations of MSC failed to alleviate GVHD after fully or partially MHC‐mismatched allo‐SCT in the rat.     

Lung miliary micro‐nodules in human T‐cell leukemia virus type I carriers

Human T‐cell leukemia virus type 1 (HTLV‐1) carriers are rarely subject to inflammatory disorders in multiple organs, other than the well‐known complication, adult T‐cell leukemia/lymphoma (ATLL). HTLV‐1 associated bronchiolo‐alveolar disorder (HABA) has been proposed as an immune mediated pulmonary reaction seen rarely in HTLV‐1 carriers. The reported clinico‐pathological patterns of HABA are diffuse panbronchiolitis (DPB) and lymphoid interstitial pneumonia (LIP). We here report three cases of HTLV‐1 carriers showing miliary micro‐nodules throughout both lungs. Microscopic examination in the video assisted thoracic surgery biopsies demonstrated that all cases had multiple discrete micro‐nodules which consisted of marked lymphoid infiltration, granulomas, eosinophils and a few foci of necrosis inside the granuloma. No findings indicating ATLL, other neoplastic conditions, infection or interstitial pneumonia, including DPB and LIP, were present following panels of special staining and immunohistochemical examinations. Two patients improved without treatment within one month, with no evidence of recurrence after 7 years. One patient showed slow deterioration of lung reticular shadows in spite of a low dose corticosteroid therapy (prednisolone 10 mg/day). We believe these cases may be a newly recognized variant of HABA.     

Variations in histological patterns of interstitial pneumonia between connective tissue disorders and their relationship to prognosis

Aims and methods: Pulmonary parenchymal disease is common in patients with connective tissue disorders (CTDs). However, most reports precede recognition of non‐specific interstitial pneumonia (NSIP). We have therefore reviewed 54 lung biopsies from 37 patients with polymyositis/dermatomyositis (PM/DM) (n = 13), Sjögren's syndrome (n = 5), rheumatoid arthritis (n = 17) and systemic lupus erythematosus (SLE) (n = 2) to assess the overall and relative frequencies of patterns of interstitial pneumonia and their impact on prognosis. Results and conclusions: NSIP was the most common pattern with an overall biopsy prevalence of 39% and patient prevalence of 41%. There was variation in prevalence between individual CTDs, with PM/DM commonly showing organizing pneumonia (n = 5), rheumatoid arthritis showing follicular bronchiolitis (n = 6) and Sjögren's syndrome showing chronic bronchiolitis (n = 4). These patterns presented either separately or in association with NSIP, occasionally with different patterns in biopsies from separate lobes. Only four patients showed a pattern of usual interstitial pneumonia (UIP): two with rheumatoid arthritis and one each with PM/DM and SLE. Overall mortality was 24%, the most frequently associated pattern being fibrotic NSIP (n = 5). In nine cases, pulmonary presentation preceded the systemic manifestation of the CTDs. When patients with CTDs present with chronic interstitial lung disease, the most common pattern is NSIP, although there is variation in pattern prevalence between individual disorders and patterns of interstitial pneumonia frequently overlap. These data suggest a different biology for intestitial pneumonias in CTDs when compared with the idiopathic interstitial pneumonias where UIP is the most common pattern. Mortality is similar to that seen in idiopathic NSIP and, coupled with pulmonary presentation occurring prior to the systemic manifestation of disease, this may have a bearing on the origin of some cases of putative idiopathic NSIP.     

Allogeneic Th1 Cells Home to Host Bone Marrow and Spleen and Mediate IFNγ-Dependent Aplasia

Bone marrow graft failure and poor graft function are frequent complications after hematopoietic stem cell transplantation and result in significant morbidity and mortality. Both conditions are associated with graft-versus-host disease (GVHD), although the mechanism remains undefined. Here we show, in 2 distinct murine models of GVHD (complete MHC- and class II-disparate) that mimic human peripheral blood stem cell transplantation, that Th1 CD4⁺ cells induce bone marrow failure in allogeneic recipients. Bone marrow failure after transplantation of allogeneic naïve CD4⁺ T cells was associated with increased CD4⁺ Th1 cell development within bone marrow and lymphoid tissues. Using IFNγ-reporter mice, we found that Th1 cells generated during GVHD induced bone marrow failure after transfers into secondary recipients. Homing studies demonstrated that transferred Th1 cells express CXCR4, which was associated with accumulation within bone marrow and spleen. Allogeneic Th1 cells were activated by radiation-resistant host bone marrow cells and induced bone marrow failure through an IFNγ-dependent mechanism. Thus, allogeneic Th1 CD4⁺ cells generated during GVHD traffic to hematopoietic sites and induce bone marrow failure via IFNγ-mediated toxicity. These results have important implications for prevention and treatment of bone marrow graft failure after hematopoietic stem cell transplantation.     

Nonspecific interstitial pneumonia: pathologic features and clinical implications

Nonspecific interstitial pneumonia (NSIP) is a form of chronic interstitial pneumonia that should be separated from the other idiopathic interstitial pneumonias, including most importantly, usual interstitial pneumonia (UIP). Diagnosis is predicated on identification of characteristic findings in a surgical lung biopsy in the appropriate clinical and radiological context. Affected patients may have a variety of underlying or associated conditions, although most have a form of idiopathic lung disease associated with a more favorable prognosis than UIP/idiopathic pulmonary fibrosis (IPF). Keys to distinguishing NSIP from UIP include absence of heterogeneous lung involvement, architectural distortion in the form of fibrotic scarring and/or honeycomb change, and fibroblast foci in NSIP.     

Essential role of stem cell factor–c‐Kit signalling pathway in bleomycin‐induced pulmonary fibrosis

Stem cell factor (SCF) and its receptor c‐Kit have been implicated in tissue remodelling and fibrosis. Alveolar fibroblasts from patients with diffuse interstitial fibrosis secrete more SCF. However, its precise role remains unclear. In this study the potential role of the SCF–c‐Kit axis in pulmonary fibrosis was examined. Fibrosis was induced by intratracheal instillation of bleomycin (BLM), which caused increased SCF levels in plasma, bronchoalveolar lavage fluid (BALF) and lung tissue, as well as increased expression by lung fibroblasts. These changes were accompanied by increased numbers of bone marrow‐derived c‐Kit⁺ cells in the lung, with corresponding depletion in bone marrow. Both recombinant SCF and lung extracts from BLM‐treated animals induced bone‐marrow cell migration, which was blocked by c‐Kit inhibitor. The migrated cells promoted myofibroblast differentiation when co‐cultured with fibroblasts, suggesting a paracrine pathogenic role. Interestingly, lung fibroblast cultures contained a subpopulation of cells that expressed functionally active c‐Kit, which were significantly greater and more responsive to SCF induction when isolated from fibrotic lungs, including those from patients with idiopathic pulmonary fibrosis (IPF). This c‐Kit⁺ subpopulation was αSMA‐negative and expressed lower levels of collagen I but significantly higher levels of TGFβ than c‐Kit‐negative cells. SCF deficiency achieved by intratracheal treatment with neutralizing anti‐SCF antibody or by use of Kitl^Sl/Kitl^Sl‐d mutant mice in vivo resulted in significant reduction in pulmonary fibrosis. Taken together, the SCF–c‐Kit pathway was activated in BLM‐injured lung and might play a direct role in pulmonary fibrosis by the recruitment of bone marrow progenitor cells capable of promoting lung myofibroblast differentiation. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

A randomized, controlled trial of prophylactic ganciclovir for cytomegalovirus pulmonary infection in recipients of allogeneic bone marrow transplants; The City of Hope-Stanford-Syntex CMV Study Group.

BACKGROUND. Cytomegalovirus (CMV)-associated interstitial pneumonia is a major cause of death after allogeneic bone marrow transplantation. We conducted a controlled trial of ganciclovir in recipients of bone marrow transplants who had asymptomatic pulmonary CMV infection. We also sought to identify risk factors for the development of CMV interstitial pneumonia. METHODS. After bone marrow transplantation, 104 patients who had no evidence of respiratory disease underwent routine bronchoalveolar lavage on day 35. The 40 patients who had positive cultures for CMV were randomly assigned to either prophylactic ganciclovir or observation alone. Ganciclovir (5 mg per kilogram of body weight intravenously) was given twice daily for two weeks and then five times per week until day 120. RESULTS. Of the 20 culture-positive patients who received prophylactic ganciclovir, 5 (25 percent) died or had CMV pneumonia before day 120, as compared with 14 of the 20 culture-positive control patients (70 percent) who were not treated prophylactically (relative risk, 0.36; P = 0.01). No patient who received the full course of ganciclovir prophylaxis went on to have CMV interstitial pneumonia. Four patients treated with ganciclovir had maximal serum creatinine levels greater than or equal to 221 mumol per liter (2.5 mg per deciliter), as compared with none of the controls (P = 0.029). Of the 55 CMV-negative patients who could be evaluated, 12 (22 percent) had CMV pneumonia--a significantly lower rate than in the untreated CMV-positive control patients (relative risk, 0.33; P = 0.003). The strongest predictors of CMV pneumonia were a lavage-fluid culture that was positive for CMV and a CMV-positive blood culture, both from specimens obtained on day 35. CONCLUSION. In recipients of allogeneic bone marrow, asymptomatic CMV infection of the lung is a major risk factor for subsequent CMV interstitial pneumonia. Prophylactic ganciclovir is effective in preventing the development of CMV interstitial pneumonia in patients with asymptomatic infection.     

多种来源造血干细胞移植治疗重型再生障碍性贫血

背景：造血干细胞移植是年轻重型再生障碍性贫血患者首选方法,但在中国多数重型再生障碍性贫血患者无合适的供者,单倍体相合或非血缘造血干细胞移植国内外目前还处于探索阶段,联合间充质干细胞移植报道少见。 目的：观察不同干细胞来源造血干细胞移植治疗重型再生障碍性贫血的疗效。 方法：10例(3~52岁)重型再生障碍性贫血患者,分别接受了亲缘HLA相合(2例),单倍体相合(5例),非血缘(3例)的外周血和/或骨髓造血干细胞移植,其中5例患者同时联合了间充质干细胞共移植。预处理方案主要为环磷酰胺、氟达拉滨和抗人胸腺球蛋白,以霉酚酸酯、环孢素A加短疗程的甲氨蝶呤预防移植物抗宿主病,单倍体相合移植的患者在此基础上加马利兰和CD25单克隆抗体;同基因的例5患者预处理方案为抗人胸腺球蛋白+甲基泼尼龙。输注间充质干细胞的量为(0.27~1.85)×10⁶/kg。接受和未接受间充质干细胞组的患者回输的造血干细胞有核细胞分别为(7.4~17.38)×10⁸/kg和(6.09~13.68)×10⁸/kg。 结果与结论：除1例单倍体相合患者移植未成功,+36 d死于并发症外,余患者移植后染色体及DNA指纹检测等说明造血干细胞移植完全供者植入。移植后中性粒细胞达到0.5×10⁹ L^-1,血小板计数≥20×10⁹ L^-1中位时间分别为12 d和13 d;其中造血功能恢复快慢的趋势是同基因移植>外周血或/和骨髓+间充质干细胞移植>单纯外周血或/和骨髓干细胞移植,而亲缘HLA全相合的52岁患者造血恢复最慢。非血缘移植例1、6患者发生了Ⅰ度急性移植物抗宿主病,单倍体相合移植的例2和例10患者发生了Ⅱ度急性移植物抗宿主病后出现了局限性的慢性移植物抗宿主病,余下患者移植后生活质量良好,无慢性移植物抗宿主病;除未接受间充质干细胞的例3患者移植后出现严重感染外,其余患者移植后再未出现严重的感染和出血。结果提示造血干细胞是安全,高效治疗重型再生障碍性贫血的方法,联合应用间充质造血干细胞者患者造血恢复快,移植并发症少。     

IL‐27p28 is essential for parent‐to‐F1 acute graft‐versus‐host disease

Acute graft versus host disease (aGVHD) remains a life‐threatening complication of bone marrow transplantation. Here we show that IL‐27, a member of the IL‐12 cytokine family, plays an essential role in a parent‐to‐F1 murine aGVHD model, using B6 mice as parents and B6D2 mice as F1 recipients. IL‐27 is transiently detectable in the serum of B6D2 recipients of B6 spleen cells, with a peak at day 10. Treatment with anti‐IL‐27p28 mAb MM27.7B1 (αp28Ab), at the time of and six days after B6 cell transfer, blocked GVHD. Protection was associated with host cell survival and undiminished engraftment of donor cells, lack of host B‐cell depletion, increased Th2‐type immunoglobulin production, a decrease in serum IFN‐γ, a drop in anti‐H‐2D^d cytotoxic T lymphocyte activity and an increase in Foxp3⁺ T cells. We therefore conclude that IL‐27 plays a critical role in the parent‐to‐F1 model of aGVHD and that blocking IL‐27 could have therapeutic relevance.     

GM‐CSF therapy inhibits chronic graft‐versus‐host disease via expansion of regulatory T cells

Regulatory T cells (Tregs) attenuate excessive immune responses, making their expansion beneficial in immune‐mediated diseases, including allogeneic bone marrow transplantation associated with graft‐versus‐host disease (GVHD). In addition to interleukin‐2, Tregs require T‐cell receptor and costimulatory signals from antigen‐presenting cells, such as DCs, for their optimal proliferation. Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) increases DC number and may promote DC‐dependent Treg proliferation. Here, we demonstrate that GM‐CSF treatment increases CD4⁺CD8^– DCs, which are associated with Treg expansion. In a mouse model of chronic GVHD (cGVHD), GM‐CSF therapy expanded Tregs, protected against the development of skin GVHD, and regulated both Th1 and Th17 responses in the peripheral lymph nodes, resulting in an attenuation of skin cGVHD. Notably, the expanded Tregs were instrumental to GM‐CSF‐mediated cGVHD inhibition, which was dependent upon an increased ratio of Tregs to conventional T cells rather than augmentation of suppressive function. These data suggest that GM‐CSF induces Treg proliferation by expanding CD4⁺CD8^? DCs, which in turn regulate alloimmune responses in a cGVHD mouse model. Thus, GM‐CSF could be used as a therapeutic DC modulator to induce Treg expansion and to inhibit excessive alloimmune responses in immune‐related diseases.     

Reconstitution of self-tolerance after hematopoietic stem cell transplantation

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow or hematopoietic stem cell transplantation. GVHD is thought to be primarily due to the response of mature T cells transferred along with the bone marrow graft to foreign histocompatibility antigens expressed on host tissues. Recent studies, however, have challenged this paradigm set forth in the 1960s and have suggested that self-MHC class II antigens can be recognized in GVHD. Many questions still remain unanswered particularly in regard to the role of immune reconstitution, the ability to recognize and discriminate self and the re-establishment of self-tolerance. In fact, the failure to re-establish tolerance to self can lead to systemic autoimmunity that may exacerbate or even mimic GVHD. The present review summarizes our studies in autologous GVHD characterizing the underlying immune mechanisms and their potential impact in allogeneic hematopoietic stem cell transplantation.     

Efficacy of azithromycin in preventing lethal graft‐versus‐host disease

Acute graft‐versus‐host disease (GVHD) following allogeneic bone marrow transplantation (BMT) is initiated by donor T lymphocytes that recognize histocompatibility antigens presented by recipient dendritic cells (DCs). Current approaches to reduce GVHD are focused on suppressing donor T lymphocyte responses to alloantigens. However, these strategies may be inadequate in the setting of allogeneic transplants (particularly histoincompatible transplants), may increase the risk of tumour relapse and are associated with high rates of opportunistic infections. We hypothesized that inhibition of recipient DCs might suppress GVHD. We recently demonstrated in vitro that azithromycin, a macrolide antibiotic, also acts as a nuclear factor (NF)‐κB inhibitor of murine DCs and inhibits their maturation and functions, including allogeneic responses. We investigated whether azithromycin could prevent alloreactions in a murine histoincompatibility model. Oral administration of azithromycin to recipient mice for 5 days during major‐histoincompatible BMT suppressed lethal GVHD significantly, whereas ex‐vivo lymphocyte function was not affected by the drug. These data suggest that azithromycin has potential as a novel prophylactic drug for lethal GVHD.