Detecting chimerism contributes to diagnosis of graft versus host disease after orthotopic liver transplantation

正To the Editor:Graft versus host disease(GVHD)occurs when the immunocompetent cells from the donor mount an immune response against the tissues of the host[1].It is commonly seen in the patients who received hematopoietic stem cell transplantation(HSCT).GVHD is a rare but lethal complication in orthotopic liver     

Gastroenterologic findings in graft versus host disease after allogenic bone marrow transplantation

We are reporting on a 25 years old patient with acute myelogenous leukemia, who developed an acute graft-versus-host disease (GVHD) 43 days after allogeneic bone marrow transplantation (BMT). The clinical symptoms included exanthema, diarrhea and abdominal cramps. The patient was treated with cyclosporine A and prednisone and the clinical symptoms disappeared subsequently. At day 225 post BMT the patient became icteric as the clinical manifestation of chronic GVHD. We describe in this case report endoscopical and histological findings during the episodes of acute and chronic graft-versus-host disease. The results obtained by sigmoidoscopy and liver biopsy confirmed the clinical diagnosis. The clinical work up of patients with acute or/and chronic GVHD should also include sigmoidoscopy in order to verify this transplantation related complication.     

Lack of association between cytomegalovirus infection, HLA matching and the vanishing bile duct syndrome after liver transplantation.

In this study we evaluated the association between cytomegalovirus infection alone or in relation to human leukocyte antigen matching and the development of vanishing bile duct syndrome, a form of chronic hepatic allograft rejection. A total of 81 consecutive liver transplant recipients were studied. Cytomegalovirus infection developed in 46 recipients (57%), and vanishing bile duct syndrome occurred in 9 recipients (11%). Cytomegalovirus infection developed in only five of the nine patients with vanishing bile duct syndrome. Univariate analysis of pretransplant recipient/donor cytomegalovirus serological tests and human leukocyte antigen typing showed they were not significant risk factors for the development of vanishing bile duct syndrome. Time-dependent analysis of cytomegalovirus infection after transplantation as a risk factor for vanishing bile duct syndrome, in a multivariate analysis with human leukocyte antigen match, showed no statistical significance. In our study, no association was found between cytomegalovirus infection alone or in relation to class I or II human leukocyte antigen match and the subsequent development of vanishing bile duct syndrome.     

肝移植移植物抗宿主病的嵌合体检测及意义

肝移植移植物抗宿主病（GVHD）是一罕见并发症，发病率约占1％。1994-2002年行原位肝移植（OLT）的23452例患者中19例发生GVHD。GVHD通常发生在肝移植术后2～8周，病程急、病情凶险。典型临床表现为发热、皮疹、腹泻、全血细胞减少。但也有例外，Kuball等报道1例50岁女性原发性胆汁性肝硬化患者，接受32岁HLA纯合型儿子的肝脏，术后114d发生GVHD。2003年全球发生4例慢性GVHD。[第一段]     

Acute graft versus host disease following living donor liver transplantation: first Korean report

Graft-versus-host disease (GVHD) after liver transplantation is an uncommon fatal complication and no effective preventive or therapeutic measure is available. We report the first case of fatal GVHD after liver transplantation in Korea. A 51-year-old male underwent living donor liver transplantation for hepatitis B virus (HBV)-related liver cirrhosis and hepatocellular carcinoma. The donor was his 21-year-old son. The patient was discharged uneventfully. However, 56 days after transplantation, he was readmitted due to watery diarrhea, which was subsequently accom-panied by a skin rash and leukopenia. Diagnosis was made by skin biopsy and by donor DNA chimerism testing in recipient tissue. A one-way donor-recipient HLA match was identified by HLA typing for both donor and recipient. The patient was treated by increasing immunosuppression, but died of septic shock. A pretransplant HLA typing of both donor and recipient should be taken, and in cases of one-way donor-recipient HLA matching, liver transplantation should be avoided.     

骨髓移植术后急性移植物抗宿主病的肠镜及病理表现

目的 探讨非亲缘异基因骨髓移植术后出现肠道症状的急性移植物抗宿主病(GVHD)患者的结肠镜、病理特征及治疗情况.方法 分析总结4例急性GVHD中、重度肠道受损患者的内镜病理资料.结果 4例患者分别于移植后的21～57 d发生不同程度肠道黏膜受损所致的腹痛、腹泻等症状,肠镜和活检病理示肠黏膜允血水肿或上皮层坏死脱落,肠腔正常结构消失,直、结肠多发性溃疡,见较多淋巴细胞和浆细胞浸润,未见巨细胞病毒(CMV)包涵体和巨细胞,诊断为急性GVHD.予以糖皮质激素等治疗,1例治疗无效死亡,其余得到有效控制.结论 非亲缘异基因骨髓移植后发生急性GVHD的肠道受损,诊断有赖于肠镜和活检病理,据此及时正确治疗后多能得到有效控制.     

异基因造血干细胞移植患者血清抗HLA抗体检测的意义

目的研究血清抗HLA抗体与异基因造血干细胞移植（allo．HSCT）后移植物被排斥、疾病复发及移植物抗宿主病（GVHD）的关系。方法20例allo—HSCT患者在移植前与移植后1、3、6个月动态检测抗HLA抗体。结果移植前抗HLA抗体≥30％与〈30％的患者发生原发植入失败比较无显著性差异（P〉0．05）;在成功植入的17例患者中,移植前和（或）移植后抗HLA抗体I〉30％的5例患者均发生移植物被排斥或疾病复发,而抗HLA抗体均〈30％的12例患者中仅有1例发生,两者有显著性差异（P〈0．005）。移植后抗HLA抗体呈动态升高的3例患者均在植入后且抗HLA抗体〉130％时发生移植物被排斥和疾病复发,而呈动态降低的5例患者仅有1例在植入后发生移植物被排斥。移植前和（或）移植后抗HLA抗体≥30％的5例患者均未发生GVHD;而抗HLA抗体〈30％的12例患者中有9例发生急性和（或）慢性GVHD,发生率75％,两者有显著性差异（P〈0．005）。结论对allo．HSCT受者在移植前、后动态检测抗HLA抗体有助于预测移植物被排斥、疾病复发与GVHD的发生,抗HLA抗体〉130％或呈动态升高者继发植入失败或疾病复发的发生率高,而GVHD发生率较低。     

Risk factors analysis for steroid-resistant acute graft versus host disease after haploidentical hemato-poietic stem cell transplantation

正Objective To analyze the risk factors of steroid resistant acute graft-versus-host disease (aGVHD) after haploidentical hematopoietic stem cell transplantation(haplo-HSCT).Methods The clinical data of adult patients with acute myeloid leukemia (AML)/Myelodysplastic syndrome (MDS) who developed aGVHD after haplo-HSCT in Peking University Institute of Hematology from January 1st,2010 to December 31st,2012 were retrospectively reviewed.Results A total of 85 patients     

Optimized postconditioning algorithm protects liver graft after liver transplantation in rats

Background: Ischemia reperfusion injury(IRI) causes postoperative complications and influences the outcome of the patients undergoing liver surgery and transplantation. Postconditioning(Post C) is a known manual conditioning to decrease the hepatic IRI. Here we aimed to optimize the applicable Post C protocols and investigate the potential protective mechanism.Methods: Thirty Sprague–Dawley rats were randomly divided into 3 groups: the sham group(n = 5),standard orthotopic liver transplantation group(OLT, n = 5), Post C group(OLT followed by clamping and re-opening the portal vein for different time intervals, n = 20). Post C group was then subdivided into 4 groups according to the different time intervals:(10 s × 3, 10 s × 6, 30 s × 3, 60 s × 3, n = 5 in each subgroup). Liver function, histopathology, malondialdehyde(MDA), myeloperoxidase(MPO), expressions of p-Akt and endoplasmic reticulum stress(ERS) related genes were evaluated.Results: Compared to the OLT group, the grafts subjected to Post C algorithm(without significant prolonging the total ischemic time) especially with short stimulus and more cycles(10 s × 6) showed significant alleviation of morphological damage and graft function. Besides, the production of reactive oxidative agents(MDA) and neutrophil infiltration(MPO) were significantly depressed by Post C algorithm. Most of ERS related genes were down-regulated by Post C(10 s × 6), especially ATF4, Casp12, hspa4, ATF6 and ELF2, while p-Akt was up-regulated.Conclusions: Post C algorithm, especially 10 s × 6 algorithm, showed to be effective against rat liver graft IRI. These protective effects may be associated with its antioxidant, inhibition of ERS and activation of p-Akt expression of reperfusion injury salvage kinase pathway.     

Successful treatment for a patient with hemophagocytic syndrome after a small-for-size graft liver transplantation

Hemophagocytic syndrome (HPS) is a hematological disorder caused by activated T lymphocytes, which leads to the proliferation of stimulated macrophages that phagocytose and destroy circulating blood elements and their precursors within bone marrow, and lead to the further production of inflammatory cytokines. Living donor liver transplantation (LDLT) between adults has been performed to compensate for the shortage of available organs. There have been some reports concerning HPS after LDLT; however, its prognosis is disappointingly poor. In particular, there is no report of treated HPS developed after LDLT using small-for-size left lobe grafts. We herein report a case of HPS in a 63-year old woman who underwent LDLT using left lobe graft weighing only 330g. The HPS was diagnosed on postoperative day 13, and was successfully treated using a combination of intravenous immunoglobulin, granulocyte colony stimulating factor, conversion of calcineurin inhibitor and steroid pulse. The trigger of HPS may not only be systemic infection, but also hypercytokinemia caused by various factors. HPS is a fatal complication in immunologically compromised patients; however, early and accurate diagnosis could lead to an adequate treatment and improve the outcome.     

Regulatory T cells and liver pathology in a murine graft versus host response model

Aim: We have previously reported in mice the hepatic inflammatory in graft versus host response (GVHR) model due to the disparity of major histocompatibility complex class‐II. The regulatory T (Treg) cells have been reported to control excessive immune response and prevent immune‐related diseases. This study aimed to investigate the pathogenesis profiles of chronic GVHR progression, focusing on the Treg cells. Methods: GVHR mice induced by parental spleen CD4⁺ T cell injection were sacrificed after 0, 2, 4, and 8 weeks (G0, G2, G4, G8). Further, one GVHR group received anti‐IL‐10 antibody in advance and were maintained for 2 weeks. Pathologic profiles of hepatic infiltrating inflammatory cells were evaluated by haematoxylin and eosin and immunohistochemistry staining with surface markers including Treg cell markers. Results: Remarkable hepatic inflammatory in G2 significantly and gradually improved over time up to G8. In immunohistochemical staining, the increased IL‐10 receptor β⁺ Tr1 cells in G2 were maintained through to G8; although other inflammatory cells decreased from G2 to G8. By contrast, in the anti‐IL‐10 antibody received‐GVHR mice, the Tr1 cells were not detectable with significant inflammatory aggravation, while FoxP3⁺ Treg cells significantly enhanced. Conclusions: These findings in the GVHR mice suggest that the expression and activity of Treg cells, especially the Tr1 cells, might be key factors for pathologic alteration in immune‐related liver disease.     

Chronic persistent parvovirus B19 bone marrow infection resulting in transfusion-dependent pure red cell aplasia in multiple myeloma after allogeneic haematopoietic stem cell transplantation and severe graft versus host disease

Introduction: We report a chronic persistent Parvovirus B19 (PVB19) infection despite long-term immunoglobulin substitution intravenous immunoglobulin (IVIG) and tapering of immune-suppressive therapy in a 41-year-old patient after allogeneic haematopoietic stem cell transplantation (alloHSCT) and long-term immune-suppressive therapy due to a steroid-refractory graft versus host disease (GvHD).

Clinical course: More than 18 month after alloHSCT the patient acquired a de novo transfusion-dependent pure red cell aplasia (PRCA) due to a PVB19 infection. Despite prompt tapering of GvHD-directed therapy and application of various IVIG regimens, transfusion-dependent anaemia (fourerythrocyte concentrates a month) persisted, and a high PVB19 replication is still evident for more than 3.5 years. Virological analysis at different time points showed a very high PVB19 load in the blood (range: 6.79E9–1.56E11), as well as highly elevated PVB19-IgG (range: 1.95–3.34) and -IgM (range: 1.97–9.74) levels in serology testing. Other virological parameters were not significantly elevated. After 30 months, a bone marrow (BM) examination still revealed a highly dysplastic erythropoiesis without any cellular maturation, and a high-grade expression of PVB19 within the dysplastic erythropoietic progenitor cells, consistent with a PRCA due to a PVB19 infection of the BM. We suggest that PRCA was most probably caused by a primary PVB19 infection of unknown source following alloHSCT with a PVB19-negative donor.

Conclusion: PRCA due a PVB19 infection of the BM may persist over a long-time, despite prolonged administration of various IVIG regimen and tapering of GvHD-directed therapy. The case emphasizes the importance of PVB19 monitoring in heavily pre-treated haematological patients. Currently, PVB19-directed treatment options are extremely limited and optimized therapeutic strategies are urgently needed.