移植物抗宿主病与异种移植研究综述

目的对移植物抗宿主病的发生条件、发病机制、疾病特点及检测方法的研究进行简要综述。方法对近年来国内外有关文献进行检索,总结。结果移植物抗宿主病的发生需要一定的条件,细胞及体液免疫均参与该病的发病过程,根据其特点可用相应的监测方法进行诊断和分级。结论作为移植物与宿主相互作用的一种形式,移植物抗宿主病对宿主可产生严重危害;它在异种移植中也可出现,且因能用于异种移植免疫、肿瘤免疫等研究,正逐渐受到重视。     

以嵌合体为基础的器官移植操控性免疫耐受的研究进展

移植物的免疫耐受是器官移植领域的最终目标。尽管在小鼠器官移植中报道了诸多诱导免疫耐受的方案,但迄今为止,基于造血干细胞移植的嵌合体方案是人类肾移植中诱导免疫耐受的唯一可重复性方案。通过短暂的混合嵌合或稳定的完全嵌合均可诱导移植肾免疫耐受。尽管持久的完全嵌合状态可能会降低移植肾发生排斥反应的风险,但移植物抗宿主病(graft-versus-host disease,GVHD)的出现限制了此方案的广泛临床应用。相反,短暂的混合嵌合不会导致GVHD的发生,但造血干细胞嵌合消失后很难预测移植物排斥反应的风险。目前的努力旨在开发临床上更可行和可靠的方法来诱导持久的混合嵌合体,以便扩大这些治疗方案的临床适用性。     

自然杀伤T淋巴细胞与移植物抗宿主病的研究进展

移植物抗宿主病(GVHD)是目前导致异基因造血干细胞移植(allo-HSCT)失败和受者死亡的重要因素,与移植物抗白血病效应(GVL)和受者的生活质量密切相关.GVHD是由供者移植物巾的T淋巴细胞识别宿主抗原引起的免疫反应所导致受者多器官损伤,涉及各种免疫活性细胞、细胞因子和炎症因子[1].     

自然杀伤T淋巴细胞与移植物抗宿主病的研究进展

移植物抗宿主病(GVHD)是目前导致异基因造血干细胞移植(allo-HSCT)失败和受者死亡的重要因素,与移植物抗白血病效应(GVL)和受者的生活质量密切相关.GVHD是由供者移植物巾的T淋巴细胞识别宿主抗原引起的免疫反应所导致受者多器官损伤,涉及各种免疫活性细胞、细胞因子和炎症因子[1].     

自然杀伤T淋巴细胞与移植物抗宿主病的研究进展

移植物抗宿主病(GVHD)是目前导致异基因造血干细胞移植(allo-HSCT)失败和受者死亡的重要因素,与移植物抗白血病效应(GVL)和受者的生活质量密切相关.GVHD是由供者移植物巾的T淋巴细胞识别宿主抗原引起的免疫反应所导致受者多器官损伤,涉及各种免疫活性细胞、细胞因子和炎症因子[1].     

供者NK细胞及其嵌合状态在异基因造血干细胞移植中的研究进展

目前,异基因造血干细胞移植(allo-HSCT)已广泛应用于造血系统疾病的治疗,但移植术后也存在一系列并发症。NK细胞的运用为改善allo-HSCT受者预后带来希望,供者来源NK细胞通过其细胞膜上的杀伤细胞免疫球蛋白样受体与其配体错配发挥同种异体反应,该过程具有保留移植物抗白血病和减少移植物抗宿主病双重效应。NK细胞是allo-HSCT后受者体内最早重建的免疫细胞群,因此移植后供、受者NK细胞嵌合状态评估对预测疾病预后及指导干预治疗具有重要意义。基于NK细胞嵌合状态的供者NK细胞输注免疫干预疗法可改善疾病预后,在血液系统疾病治疗中表现出良好的应用前景。本文就近年来供者NK细胞及其嵌合状态在allo-HSCT中的研究进展作一综述。     

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.     

趋化因子CCR5可能作为移植物抗宿主病效应细胞的标记物

动物实验发现，趋化因子CCR5可引起移植物抗宿主病（graft—versLis—host disease，GVHD）和肝损伤，阻断其抗体可以减轻这种损伤。而CCR5在GVHD患者中的作用如何？美国研究者通过检测急性GVHD患者皮肤标本中浸润的淋巴细胞，发现主要为CCR5^＋T细胞，而且这些细胞绝大多数同时表达CD4和CD8。异基因混合淋巴细胞反应结果显示，     

移植物抗宿主病皮肤表现的临床研究进展

移植物抗宿主病(GVHD)是指供体移植物中的免疫活性细胞对宿主组织产生不相容的免疫攻击所致的临床综合征。GVHD常累及皮肤、肝脏、胃肠道等多个器官,其中以皮肤受累最常见,皮疹在病程早期出现,临床表现多样化,其在GVHD的早期诊治中起着关键作用。本文就GVHD的皮肤表现进行综述。     

移植物抗宿主疾病皮肤损害的治疗进展

移植物抗宿主疾病(GVHD)是指供体移植物中的免疫活性细胞对宿主组织产生不相容的免疫攻击所致的临床综合征,是异基因造血干细胞移植等移植术后一种严重且致命的并发症。GVHD常累及皮肤、肝脏、胃肠道等多个器官,以皮肤受累最常见,并常在病程早期出现,有时也可以是唯一受累的器官。急性移植物抗宿主疾病(aGVHD)的皮肤损害发生率高达81%,皮疹以红斑、斑丘疹为     

Immune responses in small intestinal transplantation in the rat: correlation of histopathology and monocyte procoagulant activity

No predictive serologic marker exists for rejection or graft versus host disease (GVHD) reactions in small intestinal transplantation (SIT). SIT was performed in Lewis (Lew) and Lew X Brown Norway Fl hybrid (LBN) rats in the following combinations: group 1, Lew X Lew; group 2 (isolated rejection), LBN X Lew, and group 3 (isolated GVHD), Lew X LBN. Procoagulant activity (PCA), an index of monocyte immune activation, was measured in the peripheral blood mononuclear cells of graft recipients to assess its value as an immunologic monitor. Histologic findings and PCA were evaluated on days 1, 2, and 3 and every 2 to 3 days after SIT. No pathologic findings of graft or host tissue developed in group 1 (n = 14). Histologic rejection (blunted villi and mononuclear cell infiltration) was seen beginning on day 5 in group 2 (n = 19); early GVHD (loss of nodal and splenic architecture) was first noted on days 5 and 6 in group 3 (n = 17). PCA elevation in SIT was seen to precede histologic evidence of rejection or graft versus host disease in this model and may constitute an important marker for these immunologic events.     

Prevention of lethal graft-versus-host disease by monoclonal antibody treatment in vivo

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT). The disease is caused by mature T cells in the graft that recognize foreign antigens of the host and subsequently elicit an immune response to host tissues [1]. Although T-cell depletion of the graft strongly reduced the incidence and severity of GVHD, the overall survival of allogeneic BMT did not increase because of the increased rate of graft rejection and leukemic relapses [2]. New prophylactic and therapeutic approaches have to be developed to improve the outcome of allogeneic BMT. T-cell-specific monoclonal antibodies (mAb) administered in vivo to the allograft recipients seem to be promising in the prevention and treatment of lethal GVHD [3–5]. In this study we especially addressed the effect of in vivo treatment of recipients with anti-T-cell subset mAb in a murine model for acute GVHD. We also determined the long-term effects.     

Microbial metabolites and graft versus host disease

The health of mammals is a reflection of the diversity and composition of the intestinal microbiota. Alterations in the composition and functions of the intestinal microbiota have been implicated in multiple disease processes. The impact of the microbiota in health and disease is in part a function of the nutrient processing and release of metabolites. Recent studies have uncovered a major role for microbial metabolites in the function of the host immune system by which they influence disease processes such as acute graft versus host disease (GVHD), which is the main complication of allogeneic hematopoietic cell transplantation (allo‐HCT). The mechanisms of acute GVHD regulation by the complex microbial community and the metabolites released by them are unclear. In this review we summarize major findings of how microbial metabolites interact with the immune system and discuss how these interactions could impact acute GVHD.     

The use of FK-506 for small intestine allotransplantation. Inhibition of acute rejection and prevention of fatal graft-versus-host disease.

Small intestine allotransplantation in humans is not yet feasible due to the failure of the current methods of immunosuppression. FK-506, a powerful new immunosuppressive agent that is synergistic with cyclosporine, allows long-term survival of recipients of cardiac, renal, and hepatic allografts. This study compares the effects of FK-506 and cyclosporine on host survival, graft rejection, and graft-versus-host-disease in a rat small intestine transplantation model. Transplants between strongly histoincompatible ACI and Lewis (LEW) strain rats, and their F1 progeny are performed so that graft rejection alone is genetically permitted (F1----LEW) or GVHD alone permitted (LEW----F1) or that both immunologic processes are allowed to occur simultaneously (ACI----LEW). Specific doses of FK-506 result in prolonged graft and host survival in all genetic combinations tested. Furthermore, graft rejection is prevented (ACI----LEW model) or inhibited (rejection only model) and lethal acute GVHD is eliminated. Even at very high doses, cyclosporine did not prevent graft rejection or lethal GVHD, nor did it allow long-term survival of the intestinal graft or the host. Animals receiving low doses of cyclosporine have outcomes similar to the untreated control groups. No toxicity specific to FK-506 is noted, but earlier studies by other investigators suggest otherwise.     

Immunologic consequences of combined pancreas-spleen transplantation in the rat

A rat model of combined pancreas-spleen transplantation (PST) was used in order to characterize the immunologic consequences of PST when compared to pancreas transplantation (PT) alone. Weakly MHC disparate Fischer (F344) PST grafts survived significantly longer in LEW recipients than did F344 PT grafts (17.6 +/- 3.4 vs 12.1 +/- 1.0 days, respectively, P less than 0.001). However, graft versus host disease (GVHD) occurred regularly in the PST recipients. Similarly, in haploidentical LBN to LEW donor-recipient pairs, PST graft survival was also modestly but significantly increased over that of the PT controls (10.6 +/- 1.0 vs 8.5 +/- 0.8 days, respectively, P less than 0.001). Conversely, in the ACI to LEW combination where MCH differences are very strong, PST graft survival was not longer than PT controls (7.5 +/- 0.8 vs 7.0 +/- 0.6 days, respectively, P greater than 0.2). GVHD was not observed in either of the latter two experiments. Short-term immunosuppression with cyclosporine further improved the outcome in LEW recipients of F344 grafts by inducing long-term graft survivals in approximately one-fourth of the PST recipients. Host splenectomy did not improve graft survival in PST recipients but did increase the risk of GVHD in LEW recipients of F344 PST grafts. Graft irradiation prior to transplantation with 500 rad not only abrogated the GVHD potential of the F344 PST graft but also eliminated the graft survival prolonging effect of the donor spleen. Donor spleen cells injected at the time of PT in F344 to LEW transplants resulted in graft prolongation not different from spleen intact PST recipients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Graft versus host disease in small bowel transplantation

Quantities of organized lymphoid tissue in small bowel allografts may cause graft versus host disease (GVHD) following transplantation. This study examines the effect of graft mesenteric lymphadenectomy on development of GVHD following small bowel transplantation in rats. GVH reactivity was assessed by measuring the degree of graft cell emigration to the host. In the PVG to DA strain combination, graft mesenteric lymphadenectomy led to a significant reduction in graft cell colonization of host lymphoid tissues from 40-50 per cent to 25-35 per cent. Transplantation from PVG to (PVG x DA)F1 hybrids caused fatal GVHD within 21 days whereas when DA donors were used survival was over 30 days. When mesenteric lymphadenectomy was performed on PVG donors, host survival increased by only 3-4 days. Mesenteric lymphadenectomy in DA donors led to long-term recipient survival with no GVHD. Intensity of GVHD following rat small bowel transplantation is a strain-dependent phenomenon and graft mesenteric lymphadenectomy does not always prevent GVHD. The mucosa may have an important immunological role.     

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。     

Graft irradiation abrogates graft-versus-host disease in combined pancreas-spleen transplantation

A model of combined pancreas-spleen transplantation (PST) was studied in LBN F1 recipients of Lewis grafts in order to evaluate the efficacy of pretransplant graft irradiation in preventing lethal graft-versus-host disease (GVHD). Recipients of unmodified PST uniformly developed severe GVHD and died (MST = 16.7 +/- 3.8 days). Whole body donor irradiation with either 500 or 250 rad prevented lethal GVHD. Similarly, ex vivo graft irradiation with either 1000 or 500 rad also resulted in normal weight gain, graft function, and host survival for the 6-week study period. Conversely, delay of graft irradiation until 3 days after transplantation failed to prevent this complication (MST = 15.8 +/- 3.7 days). Recipients of irradiated grafts displayed glucose tolerance tests that were identical to those in the control group indicating that the doses of radiation employed in these experiments were not deleterious to islet function. Irradiated spleen grafts appeared histologically normal at 6 weeks after transplantation. Cells derived from these grafts failed to stimulate lymph node enlargement in a popliteal lymph node assay for GVHD, suggesting that these spleens may have become repopulated with host cells. These experiments confirm that PST has the potential to cause lethal GVHD and suggest that pretransplant graft irradiation may be used to prevent its occurrence.     

Relevance of HLA compatibility in living donor liver transplantation: the double‐edged sword associated with the patient outcome

HLA compatibility in living donor liver transplantation (LDLT) seems relevant to the acceptability of graft livers because LDLT recipients often share most or some part of HLAs with the respective donors. This study retrospectively investigated whether HLA compatibility affected the outcome of LDLT. Three hundred ninety LDLTs were performed in this hospital, and 346 pairs of HLAs (HLA‐A, B, DR) were retrieved from the medical record between October 1996 and March 2011. The dates of the deaths were censored when a recipient apparently died of or was retransplanted by other causes than graft failure because of host‐versus‐graft (HVG) response to purely analyze the outcomes of LDLT in view of HVG response. The relationship between HLA compatibility and graft‐versus‐host disease (GVHD) was also analyzed. No recipients with recipient‐against‐donor HLA mismatch (R→D MM) 0 experienced graft failure by HVG response. On the other hand, three of five recipients with “R→D MM 0” together with “donor‐against‐recipient MM 3” died of fatal GVHD. HLA compatibility in LDLT not only affected the long‐term acceptance of graft livers but also the risk of fatal GVHD.