肝移植后移植物抗宿主病的诊断和治疗

目的 探讨肝移植后发生移植物抗宿主病(GVHD)的诊断和治疗方法.方法 回顾性分析2002年4月至2006年3月间8例肝移植后发生GVHD受者的临床资料,通过观察这8例受者的临床症状与体征,以及分析肝功能、血常规、骨髓细胞学、细菌培养、病毒检测和皮肤病理学等检查结果,总结诊断与治疗经验.结果 肝移植受者发生GVHD的临床表现为:术后1～4周出现发热、全身皮疹、全血细胞减少、腹泻和腹痛等,但肝功能正常.皮肤组织病理学表现为:表皮角化不良、松解,棘层细胞水肿,基底层液化变性,真皮浅层淋巴细胞浸润.8例受者经减少免疫抑制剂的用量、有效控制非特异性炎症反应、改善造血功能、防治感染和加强营养支持等治疗后,其中7例康复出院,并长期健康存活;仅1例治疗无效死亡.结论 肝移植后GVHD的诊断主要依据典型的临床表现和特异性的皮肤组织病理学改变.诊断明确后应最大程度的减少免疫抑制剂的用量,有效控制GVHD引起的急性炎症反应,促进造血功能恢复.     

供者源性骨髓间充质干细胞对大鼠异基因骨髓移植后造血功能重建和急性移植物抗宿主病的影响

目前,异基因骨髓移植(Allo-BMT)是根治血液恶性肿瘤的重要手段,但由于存在人类白细胞抗原(HLA)屏障,使正常造血干细胞的植入、免疫重建以及移植物抗宿主病(GVHD)成为影响受者骨髓移植后长期存活的主要原因.我们通过建立一个稳定的大鼠异基因骨髓移植急性移植物抗宿主病动物模型,探讨供者源性骨髓间充质干细胞(BM-MSC)对大鼠Allo-BMT后受者造血功能重建及急性GVHD(aGVHD)的影响.     

肾移植联合造血干细胞移植诱导治疗七例

目的 探讨肾移植联合造血干细胞移植诱导治疗的安全性和有效性,并总结其经验.方法 2009年实施7例亲属活体肾移植联合造血干细胞移植,其中1例为供受者HLA抗原全相合,其余为半相合.肾移植前5d使用粒细胞集落刺激因子动员供者造血干细胞,术前1d采集供者造血干细胞.肾移植前3d受者开始接受全身淋巴照射,连续3d,肾移植术中给予受者抗胸腺细胞球蛋白50 mg,术后第2、4、6天输注供者造血干细胞.术后常规采用三联免疫抑制方案,监测受者血常规、淋巴细胞亚型变化及移植肾功能等情况.结果 全身淋巴照射后受者淋巴细胞数进行性降低,以B淋巴细胞(CD19+)的比例下降幅度最大,其他血细胞数量变化不大.HLA全相合受者诱导出30％～50％的嵌合体,其余受者仅诱导出1％～5％的嵌合体.术后随访3年,7例受者移植肾功能稳定,均未出现骨髓抑制和移植物抗宿主病,未增加感染风险.经移植肾活检证实,1例受者出现轻度急性排斥反应,其余6例受者未发生排斥发生.7例受者中,有3例减少了免疫抑制剂的用量.结论 肾移植联合造血干细胞移植诱导治疗的方案安全、有效.     

肝移植术后并发以皮肤组织损伤为主的移植物抗宿主病一例

移植物抗宿主病(GVHD)主要发生于异基因造血干细胞移植后,肝移植术后发生GVHD较为罕见。我院1例患者肝移植术后出现GVHD的皮肤病理学改变,现报告如下。     

非清髓性无关供者脐血移植与同胞供者骨髓移植治疗再生障碍性贫血的比较

目的 对非清髓性无关供者脐血移植与同胞供者骨髓移植治疗重型再生障碍性贫血(SAA)的临床效果进行评价和比较.方法 回顾性分析15例SAA患者进行非清髓性造血干细胞移植的临床资料,根据造血干细胞(HSC)来源的不同,将患者分为骨髓移植组(BMT组;6例)和脐血移植组(UCBT组;9例).对两组患者术后的外周血象、骨髓象、细胞嵌合体状态、移植物抗宿主病(GVHD)以及存活率等长期随访结果进行了统计学分析.结果 BMT组和UCBT组造血干细胞植入率分别为100%和66.7%,两组比较,差异有统计学意义(P＜0.05).UCBT组移植后大多数形成了供、受者型细胞混合嵌合体,BMT组大多数形成了供者型完全嵌合体.BMT组血象恢复正常的中位时间为25 d、UCBT组为120 d,BMT组骨髓象恢复正常的中位时间为25 d,UCBT组为150 d.BMT组慢性GVHD的表现以肝功能异常为主,而UCBT组则以皮疹为主.UCBT组术后早期感染率为33.3%,BMT组为16.7%.结论 非清髓性无关供者脐血移植和同胞供者骨髓移植均可成功治疗SAA;但与BMT比较,UCBT的造血功能恢复较慢、血型转变少而延迟、早期感染率较高、而慢性GVHD的程度却较轻.     

肝移植术后急性造血功能障碍病因探讨

目的 初步探讨肝移植术后病人发生急性造血功能障碍的原因.方法 回顾性分析2005-2006年天津市第一中心医院肝移植术后发生高热、皮疹、急性造血功能障碍6例病人的病因和临床表现.结果 6例病人术后出现病毒感染、免疫损伤、应用骨髓毒性药物和多器官功能衰竭可能导致急性造血功能障碍.结论 感染、病毒、药物、移植物抗宿主病、免疫等因素是肝移植术后病人发生急性造血功能障碍的主要原因.     

肝移植后以窒息为主要症状的移植物抗宿主病一例

我院近年来有4例肝移植受者术后发生移植物抗宿主病(GVHD),其中1例以术后2周起不明原因的发热伴渐进性低氧血症为主要表现,经过治疗后好转,现报告如下.@@临床资料@@患者为女性,60岁,因原发性胆汁性肝硬变、肝功能衰竭于2011年1月接受肝移植.术后第1天和第4天给予巴利昔单抗,并持续给予他克莫司4mg/d.术后10 d,受者的肝功能即恢复正常.     

子-母微量嵌合体基础上同胞间非T淋巴细胞去除HLA半相合造血干细胞移植一例

目的为扩大供者来源,探讨在子-母微量嵌合体基础上同胞间非T淋巴细胞去除(Non-TCD)HLA半相合造血干细胞移植的可行性。方法受者的原发病为慢性粒细胞白血病(CML)急性淋巴细胞病变,供者为其胞弟,供、受者HLA有3个抗原不同,经套式序列特异引物聚合酶链反应技术检测,供者微量嵌合体阳性。采用全身照射、司莫司汀、阿糖胞苷、环磷酰胺及兔源抗胸腺细胞球蛋白等对受者进行预处理;采用环孢素A、霉酚酸酯及甲氨蝶呤预防移植物抗宿主病(GVHD)。结果移植后受者的外周血中性粒细胞>0.5×109/L和血小板>20×109/L的时间分别为11、18d,骨髓检查显示增生活跃,粒细胞系、红细胞系形态和比例正常;1、2、3、6个月和1年时完全供者型嵌合>90%。术后发生Ⅱ度急性GVHD及慢性局限性GVHD,经调整免疫抑制治疗方案后缓解。受者现基本恢复正常生活。结论子-母微嵌合体阳性的HLA半相合同胞可作为Non-TCD造血干细胞移植的供者。     

非清髓性造血干细胞移植后并发移植物抗宿主病的相关因素分析

目的 探讨和分析非清髓性造血干细胞移植(NST)后并发移植物抗宿主病(GVHD)的相关因素.方法 选择34例血液病患者,其中重型再生障碍性贫血(SAA)15例,重型β-地中海贫血(TM)1例,肿瘤性血液病18例;进行无关供者脐带血造血干细胞移植(UCBT)11例,同胞供者骨髓联合外周血干细胞移植7例,外周血造血干细胞移植(PBSCT)16例.移植前采用以抗胸腺细胞球蛋白(ATG)、抗淋巴细胞球蛋白(ALG)或者氟达拉滨强效免疫抑制为基础的非清髓性预处理方案.GVHD的预防采用短程的甲氨蝶呤(MTX)联合环孢素A(CsA).观察非清髓性造血干细胞移植后的临床特点以及急、慢性移植物抗宿主病的发生情况;分析发生慢性移植物抗宿主病(cGVHD)的相关因素.结果 NST的植入率为91.2%.移植后7例肿瘤性血液病患者形成了供、受者造血细胞混合嵌合体(MC),给予供者淋巴细胞输注(DLI)2～9次后,例由MC转变为供者造血细胞完全嵌合体(FDC).随访12(3～96)个月,共发生Ⅰ～Ⅱ度急性移植物抗宿主病(aGVHD)5例,GVHD 15例.经统计学分析,发现年龄大的肿瘤性血液病患者经以ATG为基础的NST后,再给予DLI,其cGVHD的发生率高,且合并感染,对治疗的反应差;而以氟达拉滨为基础的NST患者发生cGVHD后治疗反应较好.移植100 d前后患者分别死亡3例和5例,其中3例死于广泛性cGVHD.结论 患者的年龄大、有合并症、以ATG为基础的预处理方案、肿瘤性血液病是NST后患者并发cGVHD的危险因素.     

肝移植术后移植物抗宿主病一例

移植物抗宿主病（graft versus host disease GVHD）多见于异基因造血干细胞移植术后，是导致移植失败和患者死亡的主要原因之一。肝移植术后的GVHD十分罕见，文献报道发生率为1％左右。我院于2005年10月至2006年1月成功诊治1例肝移植术后GVHD，现对该患者的临床资料进行总结，分析肝移植术后GVHD的早期诊断和治疗。     

Acute Graft Versus Host Disease Following Liver Transplantation: The Enemy Within

This article reviews acute graft vs. host disease (GVHD) as a complication of orthotopic liver transplantation (OLT). The incidence, presentation, clinical course and outcome of GVHD after OLT are summarized and the pathogenesis is discussed, drawing parallels with GVHD after allogeneic haematopoietic stem cell transplantation. Risk factors for GVHD after OLT are examined and the potential role of donor lymphocyte macrochimerism in the recipient peripheral blood as a diagnostic aid for GVHD is discussed. Finally, treatment of GVHD after OLT is reviewed with particular emphasis on the potential role of some of the newer biological agents.     

The Liver Graft as Trojan Horse–Multilineage Donor-Derived Hematopoiesis After Liver Transplantation: Case Report

Hematopoietic macrochimerism, which is rarely seen after orthotopic liver transplantation (OLT), has been linked to the development of graft versus host disease (GvHD). We report on a patient with GvHD after OLT in whom full engraftment of donor-derived, multilineage hematopoiesis occurred, indicating that the liver contains pluripotent hematopoietic progenitor cells (HPC) capable to restore hematopoiesis in recipients. Although preventing graft rejection, standard immunosuppressive therapy may be under certain immunological conditions not sufficient to prevent GvHD. Age-, disease-, and treatment-related variables might be critical determinants for the development of an effective alloreactive T-cell response leading to the establishment of full hematopoietic chimerism.     

Mixed chimerism and immunosuppressive drug withdrawal after HLA-mismatched kidney and hematopoietic progenitor transplantation

BACKGROUND: Rodents and dogs conditioned with total-lymphoid irradiation (TLI), with or without antithymocyte globulin (ATG), have been shown to develop mixed chimerism and immune tolerance without graft-versus-host disease (GVHD) after the infusion of major histocompatability complex (MHC)-mismatched donor bone marrow cells given alone or in combination with an organ allograft. METHODS: Four human leukocyte antigen (HLA)-mismatched recipients of living donor kidney transplants were conditioned with TLI and ATG posttransplantation and infused with cyropreserved donor granulocyte colony-stimulating factor (G-CSF) "mobilized" hematopoietic progenitor (CD34+) cells (3-5x10(6) cells/kg) thereafter. Maintenance prednisone and cyclosporine dosages were tapered, and recipients were monitored for chimerism, GVHD, graft function, T-cell subsets in the blood, and antidonor reactivity in the mixed leukocyte reaction (MLR). RESULTS: Three of the four patients achieved multilineage macrochimerism, with up to 16% of donor-type cells among blood mononuclear cells without evidence of GVHD. Prolonged depletion of CD4+ T cells was observed in all four patients. Rejection episodes were not observed in the three macrochimeric recipients, and immunosuppressive drugs were withdrawn in the first patient by 12 months. Prednisone was withdrawn from a second patient at 9 months, and cyclosporine was tapered thereafter. CONCLUSIONS: Multilineage macrochimerism can be achieved without GVHD in HLA-mismatched recipients of combined kidney and hematopoietic progenitor transplants. Conditioning of the host with posttransplant TLI and ATG was nonmyeloablative and was not associated with severe infections. Recipients continue to be studied for the development of immune tolerance.     

Transplantation of autologous and allogeneic bone marrow with liver from a cadaveric donor for primary liver cancer

BACKGROUND: In histocompatibility mismatched experimental animals, a combination of T-cell-depleted autologous and allogeneic marrow may induce mixed chimerism and tolerance. Patients with large primary liver tumors have a poor outcome. We investigated whether it were possible to induce mixed chimerism and obtain an antitumor effect in a patient with a large primary liver cancer after combined liver and bone marrow transplantation (BMT). METHODS: A 46-year-old female with a primary non resectable liver cancer received a liver transplant from a cadaveric donor. Subsequently, she was conditioned with 4x2 Gy of total lymphoid irradiation, 120 mg/kg cyclophosphamide, and 7.5 Gy total body irradiation. Twelve days after liver transplantation, she received T-cell-depleted autologous:cadaveric 5/6 antigen HLA-mismatched marrow in a proportion of CD34+ cells of 0.5:3.0x10(6)/kg. Chimerism status was determined with polymerase chain reaction amplification of variable number tandem repeats from DNA obtained from CD3+, CD19+, and CD45+ magnetic-bead-separated cells. RESULTS: The early posttransplant period was uneventful; liver function was normal and the hematopoietic engraftment of donor and recipient origin was prompt. Alpha-fetoprotein levels dropped from 440 to 35 microg/l. One month after marrow transplantation, donor T-cells decreased markedly. Monoclonal antibody OKT-3 and 10(5)/kg donor T-cells were given. One month later, the patient developed diarrhea and abdominal pain. A colonoscopy showed moderate gastrointestinal acute graft-versus-host disease and a Cryptosporidium infection. Three months after BMT, she became a complete donor chimera. Chimera cells showed little, if any, reactivity in mixed lymphocyte cultures to recipient and donor cells, but reacted to third party. Five months after BMT, she developed progressive Aspergillus fumigatus pneumonia and died. No tumor was found at the autopsy. CONCLUSION: We obtained mixed donor-recipient hematopoietic chimerism without severe acute graft-versus-host-disease, after combined T-cell depleted autologous and allogeneic BMT and a transplantation of a liver from an HLA-mismatched cadaveric donor. Additional donor T-cells enhanced donor bone marrow engraftment, but rejected the autograft. On the basis of this first attempt, further clinical studies are warranted.     

The use of partially matched, unrelated donors in clinical bone marrow transplantation

It is estimated that 60-70% of patients who might benefit from a bone marrow transplant will not have a suitably matched, related donor. We have, therefore, designed a clinical experiment to test the safety and feasibility of using marrow from partially matched, unrelated donors. This paper details our transplant experience in the first eight patients with leukemia. The first four patients had advanced leukemia at the time of transplantation. Each showed hematopoietic recovery, but all died from septic complications largely related to extended neutropenia encompassing both the pre-marrow-grafting and the post-marrow-grafting period. The next four patients were in remission at the time of transplantation. Each showed prompt and sustained hematopoiesis with variable graft-versus-host disease (GVHD). No acute or chronic GVHD was seen in two patients, grade II (skin only) was seen in one patient, and grade IV (skin, liver, and gut) was seen in one patient. One patient has died from sepsis five-and-one-half months following transplantation, and three are alive and well six-and-one-half to nine-and-one-half months postengraftment. This preliminary experience, together with several case reports in the literature, leads us to conclude that bone marrow transplantation with partially matched, unrelated marrow is a safe and feasible approach. If these results are confirmed by longer follow-up in a larger group of patients, the development of marrow donor pools would appear to be justified.     

Treatment of Graft-Versus-Host Disease After Liver Transplantation with Basiliximab Followed by Bowel Resection

Graft-versus-host disease (GVHD) after orthotopic liver transplantation (OLT) is a serious complication with mortality rates over 80%. Two patients with established GVHD after OLT were treated with Basiliximab, a chimeric murine human monoclonal antibody which binds to the alpha-chain of interleukin-2 receptor (IL-2R). Two males, aged 45 and 56 years, presented after OLT with a clinical picture consistent with GVHD. Quantitative measurements of recipient peripheral blood donor lymphocyte chimerism were carried out by flow cytometric analysis, and showed peak chimerism levels of 5% and 8%, respectively. Treatment comprised 3 doses of 1 g methyl prednisolone followed by 2 doses of 20 mg of Basiliximab. In both, treatment resulted in complete disappearance of macro-chimerism in blood. There was resolution of skin rash by day 7; however, diarrhea persisted. White cell scan showed increased uptake in the terminal ileum and small-bowel resection was performed in both patients. One patient is alive and well 36 months after OLT. The other patient had resolution of GVHD, but died of recurrent hepatitis C 1 year after OLT. The combination of immunological and surgical treatment for GVHD following solid organ transplantation has not previously been described.     

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.     

Abdominal compartment syndrome after liver transplantation.

The abdominal compartment syndrome is a well-known complication after abdominal trauma and is increasingly recognized as a potential risk factor for renal failure and mortality after adult orthotopic liver transplantation (OLT). We present a case report of a young patient who presented with acute liver failure complicated by an acute pancreatitis. The patient developed an acute abdominal compartment syndrome after OLT. Transurethral measurement of intraabdominal pressure indicated an abdominal compartment syndrome associated with impaired abdominal vascular perfusion, including liver perfusion. Renal insufficiency was immediately reversed after decompressive bedside laparotomy. The abdominal compartment syndrome is a potential source of posttransplant renal insufficiency and liver necrosis in OLT. It remains, however, a rarely described complication after liver transplantation, despite the presence of significant factors that contribute to elevated intraabdominal pressure.