皮肤移植物抗宿主病发病机制研究进展

移植物抗宿主病(GVHD)是目前造成异基因造血干细胞移植广泛应用的主要阻碍,是一种可以累及皮肤、肝脏、肺脏、胃肠道等全身各个系统的并发症,其中皮肤是最易受累的器官。目前,皮肤GVHD的发病机制尚未完全阐明,且缺乏有效的治疗手段。重度或广泛型慢性GVHD极大地影响受者的生活质量,因此研究皮肤GVHD的发病机制,从中找到新的治疗方法非常迫切。研究发现白细胞介素(IL)-22、IL-17、IL-6和干扰素(IFN)-γ等细胞因子在皮肤GVHD的发生中扮演重要的角色,但具体作用机制仍不够明确。因此,本文就国内外关于这些细胞因子在皮肤GVHD中的作用机制研究进展做一综述,以期为皮肤GVHD的预防和治疗提供新的思路。     

肠道移植物抗宿主病研究进展

移植物抗宿主病(GVHD)是异基因造血干细胞移植最严重的并发症之一，主要累及皮肤、肝脏和肠道。其中，肠道GVHD发病率较高、程度较重，重度肠道GVHD往往难以逆转，并且会引起一系列并发症，加重全身GVHD，影响移植疗效，增加病死率。肠道GVHD的早期诊断与有效治疗直接关系到疾病的预后，在GVHD的诊治中处于重要的地位。本文对肠道GVHD的症状表现、诊断及鉴别诊断、病理机制、治疗进展等方面作一综述。     

早期使用抗CD25单克隆抗体治疗耐糖皮质激素的急性移植物抗宿主病

造血干细胞移植是治疗血液系统恶性肿瘤的有效方法之一,移植物抗宿主病(GVHD)是造血干细胞移植后患者死亡的重要原因,采用大剂量糖皮质激素冲击是治疗急性GVHD的首选,但仍有60%患者激素治疗无效或耐药,而采用抗CD25单克隆抗体治疗急性GVHD,目前尚无统一标准,常常在其它二线治疗无效时才考虑使用.我们早期利用抗CD25单克隆抗体治疗耐激素的急性GVHD患者19例,报告如下.     

肝移植术后急性移植物抗宿主病的研究进展

肝移植术后急性移植物抗宿主病(a GVHD)很罕见,其发病机制尚不明确,预后极差。目前并无统一的标准用于诊断肝移植术后a GVHD,且a GVHD很难与药物反应以及病毒感染鉴别,亦无标准治疗方案。本文就肝移植术后a GVHD的发生机制、高危因素、诊断和治疗进行综述,以期为肝移植术后a GVHD的防治提供参考经验。     

间充质干细胞治疗激素耐药的重度急性移植物抗宿主病的Ⅱ期临床研究

重度移植物抗宿主病(GVHD)是异基因造血干细胞移植的致命性并发症,糖皮质激素是急性GVHD的一线治疗药物,但激素治疗的有效率仅为30%～50%,且激素耐药的重度急性GVHD患者预后极差.间充质干细胞(MSC)可以调节体内外的免疫反应,因此MSC可用于治疗异基因造血干细胞移植后急性GVHD.本研究旨在观察骨髓MSC治疗激素耐药的重度急性GVHD的疗效.     

肠道移植物抗宿主病研究进展

移植物抗宿主病(GVHD)是异基因造血干细胞移植最严重的并发症之一,主要累及皮肤、肝脏和肠道。其中,肠道GVHD发病率较高、程度较重,重度肠道GVHD往往难以逆转,并且会引起一系列并发症,加重全身GVHD,影响移植疗效,增加病死率。肠道GVHD的早期诊断与有效治疗直接关系到疾病的预后,在GVHD的诊治中处于重要的地位。本文对肠道GVHD的症状表现、诊断及鉴别诊断、病理机制、治疗进展等方方面作一综述。     

肝移植术后移植物抗宿主病的初步临床探讨

目的总结肝移植术后移植物抗宿主病(GVHD)诊治的临床经验。方法对3例肝移植术后GVHD患者的临床表现、诊断、治疗及效果进行分析总结。3例患者均于术后3~4周左右出现不明原因高热、皮疹及胃肠道症状,继之出现全血细胞减少,肝功能无明显受损。第1例患得曾考虑为感染及变态反应,但治疗无效。第2例患者早期高度疑似GVHD,应用了大剂量甲基强地松龙激素冲击治疗。第3例患者高热后4天停用所有免疫抑制剂,但患者有FK506中毒表现。3例患者最终实验检查运动GVHD诊断。结果3例GVHD患者分别于术后37d、34d及38d死亡,死亡原因为感染及多器官功能衰竭。结论不明原因发热、皮疹、胃肠道症状应警惕GVHD的发生。通过PCR-SSP方法在外周血中检测到供体淋巴细胞嵌合体有助于GVHD的诊断。停用免疫抑制剂,提高机体免疫力对抗入侵的淋巴细胞可能为更好的治疗方法。对GVHD危险因素的认识有助于预防GVHD的发生。     

间充质干细胞治疗肝移植术后难治性急性移植物抗宿主病临床研究

目的探讨间充质干细胞(MSCs)治疗肝移植术后难治性急性移植物抗宿主病(GVHD)的疗效和安全性。方法回顾性分析中山大学附属第三医院肝脏移植中心1例应用第三方脐带来源的MSCs治疗肝移植术后激素治疗无效的急性GVHD患者的临床资料。结果患者男性,60岁,因"原发性肝癌、乙肝肝硬化"在我院行同种异体原位肝移植术,供受者血型相同。术后免疫抑制方案为糖皮质激素联合他克莫司。术后19 d患者出现发热、全身皮疹,并出现白细胞减少症、口腔溃疡和腹泻,但肝功能正常。皮肤活检病理组织学检查见淋巴细胞浸润,结合临床表现诊断为GVHD。给予停用免疫抑制剂、大剂量糖皮质激素冲击治疗、营养支持、大剂量丙种球蛋白等治疗后,患者病情无好转,持续发热,于术后第40天开始周围静脉输注脐带来源的MSCs治疗,治疗3 d后患者体温和白细胞恢复正常,腹泻好转。MSCs治疗方案为:细胞数5×107/次,每次间隔1周,共3次。患者无不适及其他并发症发生,GVHD获得完全缓解,于术后55 d痊愈出院,随访20个月未观察到MSCs输注相关的不良反应发生,未发现肝癌复发和MSCs相关的恶性肿瘤发生。结论输注体外培养扩增的第三方来源的MSCs是治疗肝移植术后激素治疗无效的急性GVHD的有效措施,值得进一步研究。     

依那西普(Etanercept)联合甲强龙治疗急性移植物抗宿主病的临床研究

移植物抗宿主病(GVHD)是异基因造血干细胞移植术后死亡的重要原因.GVHD标准治疗方案为大剂量糖皮质激素,35%的患者可获得完全缓解.TNF-α被认为是GVHD发生过程中一种重要的炎症因子,应用TNF-α抑制剂,克隆如英夫利昔单抗体(Infliximab)或是依那西普(Etanercept),治疗激素难治的GVHD的完全缓解率可达18%～62%.本研究总结了2001年9月至2006年9月61例应用依那西普联合甲强龙治疗初发的急性GVHD的前瞻性临床研究,并以同期99例仅使用激素治疗急性GVHD的患者为对照组.     

糖皮质激素和免疫抑制剂在IgA肾病中的应用

IgA肾病(IgAN)目前尚无统一的治疗方案，糖皮质激素和免疫抑制剂的应用已成为重要的手段，尤其对持续蛋白尿和重症患者，可以延缓肾功能衰竭。下面谈谈我们在IgAN的治疗中运用糖皮质激素和免疫抑制剂的体会，供大家参考。     

Graft‐versus‐host disease of the central nervous system after liver transplantation: A rare complication

Graft‐versus‐host disease (GVHD) of the central nervous system (CNS) following solid organ transplantation is a rare but serious complication and has been previously reported after bone marrow transplantation. GVHD after liver transplantation is a rare entity with a high mortality rate. We report the case of a patient who developed GVHD and subsequently had seizures and altered mental status after deceased donor liver transplantation. The diagnosis of GVHD of the CNS was established by short tandem repeat loci analysis of the cerebrospinal fluid using the polymerase chain reaction technique and gene mapping software. To our knowledge, this is the first reported case of CNS‐GVHD following liver transplantation. He eventually died of sepsis and multiorgan failure, in keeping with the overall poor prognosis of CNS‐GVHD.     

Differential diagnosis between graft-versus-host disease and hemophagocytic syndrome after living-related liver transplantation by mixed lymphocyte reaction assay.

Graft-versus-host disease (GVHD) after liver transplantation is uncommon but is a serious complication that can be fatal. Hemophagocytic syndrome (HPS), which is caused by activation of autologous T lymphocytes, is also a serious complication that can occur after liver transplantation. Because these complications share the clinical triad of skin rash, marrow failure, and diarrhea, differential diagnosis is difficult. We describe a case of severe GVHD resembling HPS in clinical features that occurred after living-related liver transplantation. The patient who had undergone the transplantation had high fever, pancytopenia, and skin rash 3 wk after the operation. Examination of a bone-marrow biopsy sample revealed the presence of abundant monocytes with phagocytosis, suggesting either GVHD or HPS. Donor human leukocyte antigens were detected in the peripheral blood of the patient by polymerase chain reaction, but this finding is not specific for GVHD. A definitive diagnosis was made by demonstration of remarkable anti-self response and undetectable anti-donor response in a mixed lymphocyte reaction assay using carboxyfluorescein diacetate succinimidyl ester.     

Temporary Cessation of Immunosuppression for Infection May Contribute to the Development of Graft-vs-Host Disease After ABO-Incompatible Living Donor Liver Transplantation: A Case Report

Graft-vs-host disease (GVHD) after liver transplantation is a rare complication with a high mortality rate. A complex interplay between donor and recipient immunity plays a role in the development of GVHD. Infection following liver transplantation is one of the most common complications in a recipient of an organ transplant who is immunosuppressed. On clinical signs of infection, the immune reaction of the recipient can be reconstituted by withdrawal of immunosuppression in order to help combat infection. However, the discontinuation of immunosuppression could restore the donor’s immune activity rather than that of the recipient. There is little information available as to whether the discontinuation of immunosuppression for severe infection could contribute to the development of GVHD in a patient who underwent ABO-incompatible (ABO-I) living donor liver transplantation (LDLT). Herein, we present a unique case of GVHD following ABO-I LDLT, for which the cessation of immunosuppression could be responsible.     

Graft vs. host disease after liver transplantation: a new approach is needed.

Graft-vs.-host disease (GVHD) is a rare, serious complication of orthotopic liver transplantation (OLT). We have treated 5 patients to date with GVHD after OLT. A total of 78 patients worldwide have been reported to have experienced this complication. The means by which GVHD after OLT has been managed is guided by experience with the more common GVHD that occurs after stem cell transplantation. However, despite the use of various treatment modalities, the mortality of GVHD after OLT remains high. This case series and review of the literature demonstrates that successful resolution of GVHD after OLT cannot be expected with the use of those modalities that have been tried to date. It is imperative that new treatments be applied to GVHD after OLT in order to improve the prognosis of patients with this diagnosis.     

肝移植术后移植物抗宿主病(附1例报告)

目的:探讨与总结肝移植术后移植物抗宿主病(graft versus host disease,GVHD)的诊断及治疗经验。方法:分析1例男性53岁病人,因肝癌行原位肝移植,术后1个月发生GVHD的临床经过和实验室检查结果。临床表现和皮肤活检为其诊断依据。结果:病人在术后出现不明原因的发热、皮疹、腹泻、全血细胞减少,经减少免疫抑制剂,加用激素冲击等治疗后,术后3个月病人治愈。结论:肝移植术后GVHD早期易被误诊,治疗效果不佳,但可以临床治愈。     

Diagnosis and treatment for graft-versus-host disease after liver transplantation: two case reports

AIM: The diagnosis and treatments were of 2 cases of graft-versus-host disease (GVHD) after liver transplantation are presented herein. METHODS: The 2 cases were diagnosed at 24 and 32 days after liver transplantation, respectively. Fever, diarrhea, skin rash, and leukopenia were symptoms in both of them. They were treated with methylprednisolone (0.5 g/d, for 3 days), G-CSF, and GM-CSF. The dose of CsA was decreased in 1 of them. RESULTS: One patient died of cerebral hemorrhage at 31 days after transplantation. The other 1 responded well to the methylprednisolone and the skin rash disappeared within 1 week after the treatment. He was discharged 50 days after transplantation. CONCLUSION: Clinicians should be familiar with the risk factors, signs, and symptoms associated with GVHD after liver transplantation. Corticosteroids are the choice of treatment for GVHD after liver transplantation. Immunosuppressive agents should be decreased when GVHD is diagnosed.     

Liver transplantation for severe hepatic graft-versus-host disease in two children after hematopoietic stem cell transplantation

Chronic graft-versus-host disease (GVHD) is a frequent complication of bone marrow transplantation (BMT). After the skin, the liver is the second, most frequent target of GVHD, which presenting with hyperbilirubinemia, elevated liver enzymes, and coagulopathy. Progressive destruction of small intrahepatic bile ducts causes vanishing bile duct syndrome and leads to end-stage liver disease. We report 2 successful cases of orthotopic liver transplantation performed in children with severe GVHD after hematopoietic stem cell transplantation from a matched unrelated donor (HSCT-MUD).     

Enlargement of the human spleen in graft-versus-host disease

The spleens of 49 patients who had undergone allogeneic bone marrow transplantation for leukemia were compared at autopsy to determine the pathological changes associated with graft-versus-host disease (GVHD). The only significant finding was an increase in weight of about 1.7 times that of spleens from patients without GVHD. This was not explained by differences in the patients' sex, length of survival after transplantation, presence of infection, or liver pathology. On histological examination, there was no detectable increase in congestion, siderosis, or numbers of lymphocytes, macrophages, antigen-presenting cells, blast cells, pyknotic cells, plasma cells, or hemopoietic cells to explain the increase in spleen weight. On the contrary, there was actually a reduction in CD8+ T lymphocytes. No proliferative phase of GVHD could be identified, possibly due to a lack of specimens examined less than 8 days after transplantation and to prophylactic measures undertaken to minimize GVHD. The pathogenesis of splenomegaly in human GVHD is unclear.     

Acute Graft-Versus-Host-Disease in Kidney Transplantation: Case Report and Review of Literature

Graft-versus-host-disease (GVHD) is a complication of solid organ transplantation, most commonly of the small bowel or liver. Herein, we have presented a case of GVHD in a 27-year-old man who underwent an human leukocyte antigen (HLA) minor mismatch renal transplantation from his father. After the procedure, the patient presented with a fever, skin rash, and watery diarrhea. An allograft kidney biopsy demonstrated no sign of rejection; however, anti-A antibody was detected in plasma and progressive anemia was attributed to hemolytic anemia owing to a passenger lymphocyte syndrome. From those findings, we suspected that the clinical symptoms were caused by acute GVHD. An endoscopic biopsy of the colon revealed apoptotic cells consistent with the disease. We found reports of only 5 other GVHD cases after kidney transplantation. Several risk factors are associated with GVHD, such as transfer of graft lymphocytes, donor HLA homozygosity, and a relationship between recipient immunogenicity and immunosuppression. In this case, detection led to early diagnosis of donor-derived GVHD due to passenger lymphocyte syndrome. It is important keep GVHD in mind and to understand its risk factors as the mortality rate is high.     

Successful outcome of acute graft-versus-host disease in a liver allograft recipient by withdrawal of immunosuppression

BACKGROUND: Graft-versus-host disease (GVHD) after liver transplantation is uncommon, and the outcome is almost always fatal. Since 1987, about 30 cases have been described, and patient survival is mostly exceptional. METHODS: A 29-year-old man underwent retransplantation due to chronic cholestatic syndrome, 5 years after his first liver transplantation. Indication for the first liver transplantation was acute liver failure caused by exsiccosis. After the second transplantation, the patient had an initially uneventful course, developing thrombocytopenia at day 21 followed by skin rash and septic complications. Diagnosis of acute GVHD was made by using serological techniques for HLA-A and HLA-DRB and subsequently by fluorogenic sequence-specific primed polymerase chain reaction. In addition, donor lymphocytes were marked by immunohistochemical methods via biopsies of the skin. Immunosuppressive therapy was withdrawn to allow the patient's own immune system to eliminate donor cells. RESULTS: By withdrawing the immunosuppressive therapy, clinical and morphological signs of GVHD vanished. The patient is doing well without recurrence 13 months after transplantation. CONCLUSION: Withdrawal of immunosuppressive therapy is a promising approach in the treatment of acute GVHD to allow the patient's immune system to reconstitute itself, reject offending lymphocytes, and avoid lethal septic complications.