Hepatic veno-occlusive disease after high-dose mitomycin C and autologous bone marrow transplantation therapy

Three cases of veno-occlusive disease of the liver were diagnosed in four autopsied patients who had received high-dose mitomycin C therapy followed by autologous bone marrow transplantation, and the pathologic finding are reported. Review of 27 liver, examined post mortem, of patients receiving other high-dose chemotherapeutic regimens, 15 of them with subsequent autologous bone marrow transplantation, revealed no evidence of veno-occlusive disease. Veno-occlusive disease may now become a dose-limiting factor in the use of the combined high-dose mitomycin C-bone marrow transplantation therapy. Attention is also drawn to the increasing number of veno-occlusive disease cases being reported in associated with alkylating agents.     

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.     

Post-transplant HHV-6 Diseases

Human herpesvirus 6 (HHV-6) infection is common in the general population. Primary infection occurs mainly in childhood, after which the virus establishes latency in the host and can be reactivated in immunocompromised individuals such as recipients of a solid organ or bone marrow transplant (BMT). HHV-6 infection occurs in 38--60% of BMT recipients and in 14--82% of solid organ recipients, usually 2--4 weeks post-transplantation. Two HHV-6 variants are recognized (HHV-6A and HHV-6B) and transplant patients are infected almost exclusively with variant B. Following BMT, the clinical diseases most commonly associated with HHV-6 infection are bone marrow suppression, interstitial pneumonitis, encephalitis and graft versus host disease. It has also been suggested that HHV-6 infection may be associated with fever and bone marrow suppression following liver transplantation and may contribute to rejection episodes after kidney transplantation. Infection with HHV-6 induces marked immunodepression, and an association both with cytomegalovirus disease and with fungal infection in transplant recipients has been reported. A direct causal relationship between HHV-6 infection and disease following transplantation, however, has yet to be proven conclusively.     

肝移植患者围手术期骨髓细胞学改变的意义

背景：晚期肝病及肝移植后造血系统受累相关报道较少见。 目的：通过对肝移植患者围手术期骨髓细胞学的观察,探讨移植前造血功能的改变及移植后多种并发症对骨髓造血功能的影响。 方法：选择20例实施原位肝移植患者,因与血液系统疾病相关,需行骨髓细胞学检查进行诊断及鉴别诊断,其中移植前2例,移植后18例。 结果与结论：原位肝移植患者移植前容易出现骨髓细胞学改变为脾功能亢进、大红细胞性贫血,移植后出现：移植物抗宿主病、浆细胞白血病、反应性粒细胞增高、原发性血小板减少性紫癜、嗜血细胞综合征、粒细胞缺乏症、急性造血细胞停滞、转移癌、反应性血小板增高。说明通过骨髓细胞学检查,监测肝移植围手术期各种并发症对骨髓造血功的影响,特别对移植物抗宿主病的患者,实施及时抢救有重要意义。     

Allogeneic bone marrow transplantation in multiple myeloma. European Group for Bone Marrow Transplantation

BACKGROUND AND METHODS. In contrast to autologous bone marrow transplants for hematologic cancers, allogeneic transplants contain no tumor cells that might cause a relapse. We report the results of such allogeneic bone marrow transplantation using HLA-compatible sibling donors in 90 patients with multiple myeloma performed in 26 European centers between 1983 and 1989. RESULTS. At the time of the most recent follow-up, 79 months after the start of the study, 47 patients were alive and 43 were dead. The rate of complete remission after bone marrow transplantation was 43 percent for all patients and 58 percent for the patients who had engraftment. The actuarial survival at 76 months was 40 percent. The median duration of relapse-free survival among patients who were in complete remission after bone marrow transplantation was 48 months. The stage of the disease at diagnosis and the number of treatment regimens tried before bone marrow transplantation were predictive of the likelihood of complete remission after engraftment. There were trends toward longer survival among patients who were responsive to treatment before bone marrow transplantation, patients with Stage I disease at diagnosis, and patients who had received only first-line treatment before transplantation, as compared with those who were not responsive, those with Stage II or III disease at diagnosis, and those who had received three or more lines of treatment, but the differences in these factors were not statistically significant. Two post-transplantation factors predicted better long-term survival: complete remission after engraftment and grade I graft-versus-host disease, rather than grade II, III, or IV. CONCLUSIONS. Allogeneic bone marrow transplantation with the use of HLA-matched sibling donors appears to be a promising method of treatment for some patients with multiple myeloma.     

Acyclovir for prevention of cytomegalovirus infection and disease after allogeneic marrow transplantation

Patients undergoing allogeneic bone marrow transplantation who are seropositive for cytomegalovirus are vulnerable to serious cytomegalovirus infection, presumably because of reactivation of latent endogenous virus and severe immunosuppression. We administered intravenous acyclovir from 5 days before to 30 days after allogeneic marrow transplantation for hematologic neoplasms in an effort to prevent cytomegalovirus infection and disease in patients seropositive for cytomegalovirus before transplantation. Eighty-six patients seropositive for both cytomegalovirus and herpes simplex virus before transplantation received acyclovir, whereas 65 patients seropositive only for cytomegalovirus served as controls (acyclovir is the standard prophylactic agent against herpes simplex virus in this setting). The probability that cytomegalovirus infection would develop within the first 100 days after transplantation was 0.70 among acyclovir recipients and 0.87 among control patients at medians of 62 and 40 days after transplantation, respectively (P = 0.0001 by log-rank test). Invasive cytomegalovirus disease developed in 19 acyclovir recipients (22 percent) and 25 control patients (38 percent) (P = 0.008). Survival within the first 100 days after transplantation was better among acyclovir recipients (P = 0.002). Acyclovir prophylaxis was associated with a relative risk of 0.5 or less for the development of cytomegalovirus infection or disease or for death within the first 100 days after transplantation (P less than or equal to 0.04), in proportional-hazards regression analysis. We conclude that prophylaxis with intravenous acyclovir significantly reduced the risk of both cytomegalovirus infection and cytomegalovirus disease in seropositive patients after allogeneic bone marrow transplantation and that it was also associated with significantly improved survival.     

Transplanted bone marrow cells repair heart tissue and reduce myocarditis in chronic chagasic mice

A progressive destruction of the myocardium occurs in approximately 30% of Trypanosoma cruzi-infected individuals, causing chronic chagasic cardiomyopathy, a disease so far without effective treatment. Syngeneic bone marrow cell transplantation has been shown to cause repair and improvement of heart function in a number of studies in patients and animal models of ischemic cardiopathy. The effects of bone marrow transplant in a mouse model of chronic chagasic cardiomyopathy, in the presence of the disease causal agent, ie, the T. cruzi, are described herein. Bone marrow cells injected intravenously into chronic chagasic mice migrated to the heart and caused a significant reduction in the inflammatory infiltrates and in the interstitial fibrosis characteristics of chronic chagasic cardiomyopathy. The beneficial effects were observed up to 6 months after bone marrow cell transplantation. A massive apoptosis of myocardial inflammatory cells was observed after the therapy with bone marrow cells. Transplanted bone marrow cells obtained from chagasic mice and from normal mice had similar effects in terms of mediating chagasic heart repair. These results show that bone marrow cell transplantation is effective for treatment of chronic chagasic myocarditis and indicate that autologous bone marrow transplant may be used as an efficient therapy for patients with chronic chagasic cardiomyopathy.     

Dissociation between onset of natural killer E-rosette forming cells and of T3-positive cells following HLA-mismatched T cell depleted bone marrow transplantation.

We have studied immunological reconstitution following partially HLA-incompatible T cell depleted bone marrow transplantation, compared with reconstitution following HLA identical T cell depleted and HLA identical untreated bone marrow transplantation. We often observed an early emergence of E-rosette forming cells that were T3 negative and displayed strong natural killer activity in the first group of patients. This activity was shown with fresh leucocytes as well as interleukin 2 grown cells. The appearance of T3+ cells was delayed in this situation compared to that observed in HLA identical bone marrow transplantation. The delay in T3+ cell differentiation and in cellular immune function development probably explains why NK rosette forming cells are early detected within 3-4 months following HLA mismatched bone marrow transplantation. This NK subset is likely to be present at an early stage in all types of bone marrow transplantation, but is most commonly observed simultaneously with the T3+ cells in HLA identical untreated bone marrow transplantation. The respective role of T cell depletion and HLA incompatibility in this phenomenon are discussed while patients' conditioning, cyclosporine A and graft-versus-host disease have been shown to be irrelevant for the dissociation between NK E-rosette forming cells and T3+ subset onsets.     

The use of immunoglobulin in bone marrow transplantation

The role of bone marrow transplantation is to restore lymphohematopoietic function of a recipient whose marrow has been destroyed, either by disease or by the preparative therapy employed in an attempt to eradicate the patient's lymphohematopoietic malignancy. The restoration of lymphohematopoietic function through the donor graft occurs in stages, requires several months, and is often not completed until 1 to 2 years after transplantation. These sequential steps of immuno-reconstitution are associated with a number of definable and predictable immune deficiencies and seem to be responsible for the pattern of complications that emerges after transplantation. Most of these complications are either the result of, or associated with, infections that also occur in an almost predictable pattern. In the various phases of immune deficiency following sequentially after transplantation, the humoral immune system is greatly affected, thus raising the possibility that passively administered antibodies in the form of immune globulin therapy might be beneficial in all phases of the marrow transplant procedure. This paper attempts to summarize the use of immune globulin preparations in clinical bone marrow transplantation, showing the rationale for and some of the results of therapeutic immune globulin administration.     

The role of total body irradiation in preparation for bone marrow transplantation in acute leukaemia. A review.

From extrapolation obtained from animal studies and radiation accidents, it is assumed that for man the LD 50 (30) will be between 300-500 rads total body irradiation (TBI) and the LD 100 at least 600 rads TBI. A dose of 1000 rads TBI is generally used in man for conditionning for bone marrow transplantation. In acute leukemia, total body irradiation is usually associated with cytoreductive chemotherapy. In Seattle 110 patients underwent bone marrow transplantation for acute leukemia in relapse. 15 patients became long term survivors. The main cause of failure were GVH, interstitial pneumonitis and leukemic relapse. New attempts are being made to improve the results : (1) better cytoreductive therapy preceding transplanation, (2) bone marrow transplantation during remission of the disease, (3) prevention of interstitial pneumonitis by modifications of the TBI technique.     

Tolerance established in autoimmune disease by mating or bone marrow transplantation that target autoantigen to thymus

Autoimmune diseases are a significant cause of death and morbidity, affecting up to 5% of the population. At present, there is no cure. Autologous bone marrow transplantation has been promoted as a treatment for achieving disease reversal and long-term remission. However, clinical trials in progress in Europe and North America report a significant risk of relapse. Here, we have addressed whether we can establish tolerance in an active autoimmune disease model by thymic expression of autoantigen. We show that tolerance and disease resistance can indeed be established in transgenic mice that spontaneously develop granulocyte macrophage colony stimulating factor-induced autoimmune gastritis, by mating them with disease-resistant transgenic mice that target autoantigen to the thymus. T cells from these double-transgenic mice are non-responsive to gastric antigen in vitro and fail to initiate disease following transfer to naive recipients. Further, we show that transplantation with bone marrow from disease-resistant transgenic mice renders recipient mice with gastritis tolerant to autoantigen as shown by a dramatic fall in autoantibody levels and T cell non-responsiveness to antigen in vitro. We suggest that genetically modified bone marrow targeting autoantigen to the thymus may be used to establish tolerance and prevent relapse of autoimmune disease following autologous bone marrow transplantation.     

Chronic granulomatous disease: overview and hematopoietic stem cell transplantation

Chronic granulomatous disease (CGD) still causes significant morbidity and mortality. The difficulty in considering high-risk yet curative treatments, such as allogeneic bone marrow transplantation, lies in the unpredictable courses of both CGD and bone marrow transplantation in different patients. Some patients with CGD can have frequent infections, granulomatous or autoimmune disorders necessitating immunosuppressive therapy, or both but also experience long periods of relative good health. However, the risk of death is clearly higher in patients with CGD of all types, and the complications of CGD short of death can still cause significant morbidity. Therefore, with recent developments and improvements, bone marrow transplantation, previously considered an experimental or high-risk procedure, has emerged as an important option for patients with CGD. We will discuss the complications of CGD that result in significant morbidity and mortality, particularly the most common infections and autoimmune/inflammatory complications, as well as their typical management. We will then discuss the status of bone marrow transplantation.     

9a: risk factor in bone marrow transplantation?

Graft-versus-host disease is a severe complication which may occur even after bone marrow transplantation between HLA identical siblings. Minor transplantation antigens have been implicated as a causal factor. Therefore the influence of the monocyte/granulocyte antigen 9a on GvHD was studied. No influence on GvHD was observed, but absence of the 9a antigen in the donor was associated with an early death of the recipient.     

Suppression of disease phenotypes of adult mito-mice carrying pathogenic mtDNA by bone marrow transplantation

For directly addressing the issue of gene therapy of adult patients with mitochondrial diseases, we carried out bone marrow transplantation to adult mito-mice with mutated mtDNA and expressing respiration defects for improvement of disease phenotypes. We supposed that bone marrow cells transdifferentiated into various tissues, so that their transplantation would suppress disease phenotypes. The results showed improvement of survival and delayed expression of renal failure. As most mito-mice without a transplant died due to renal failure, we examined whether transplanted bone marrow cells transdifferentiated into renal tissues carrying improved renal function. Histochemical analyses showed that the suppression of disease phenotypes was not due to transdifferentiation, but due to suppression of apoptosis of renal cells. Thus, bone marrow cells possess a novel function of supporting tissues by suppressing apoptosis induced by respiration defects.     

Mesenchymal Bone Marrow Stem Cells More Effectively Stimulate Regeneration of Deep Burn Wounds than Embryonic Fibroblasts

Regeneration of deep burn wounds after transplantation of allogenic and autogenic fibroblast-like bone marrow mesenchymal stem cells and embryonic fibroblasts on burn surface was studied in 40 Wistar rats. Transplantation of allogenic and autogenic fibroblast-like bone marrow mesenchymal stem cells and transplantation of embryonic fibroblasts decreased cell infiltration of the wound and accelerated the formation of new vessels and granulation tissue in the wound in comparison with the control (burn wounds without cell transplantation). Regeneration processes were most active after transplantation of fibroblast-like bone marrow mesenchymal stem cells, in particular, autogenic cells, which was confirmed by more rapid decrease in burn surface area. Wound healing after transplantation of fibroblast-like bone marrow mesenchymal cells and embryonic fibroblasts was associated with long functioning of transplanted cells (as was shown by staining for -galactosidase, the cells were transfected with an adenovirus vector carrying the marker gene). It is hypothesized that more rapid regeneration of burn wounds after transplantation of fibroblast-like bone marrow mesenchymal stem cells was due to low differentiation of these cells in comparison with embryonic fibroblasts.     

Bone marrow transplantation: a review

Bone marrow transplantation represents the technical application of basic immunologic principles to the treatment of a variety of neoplastic and allied disorders that originate in the bone marrow. The results have improved during the past 15 years, being most striking for the treatment of the acute and chronic leukemias. The promise of autologous bone marrow transplantation for the treatment of leukemias and solid tumors is awaiting the perfection of techniques for the effective removal of residual neoplastic cells as well as more effective therapy. The use of this technique at its present stage of development for the treatment of benign hematologic disorders, which cause severe morbidity (ie, thalassemia or sickle cell anemia), is controversial, raises serious ethical issues, and cannot be recommended routinely at this time. Complications of bone marrow transplantation such as graft rejection, graft-versus-host disease, and opportunistic infections are discussed.     

Detection of residual acute lymphoblastic leukemia cells in cultures of bone marrow obtained during remission

We used a semisolid culture assay to quantitate leukemia cells in the bone marrow of patients with childhood acute lymphoblastic leukemia (ALL). In bone marrow cultures from 40 patients with newly diagnosed disease, the colonies that developed in vitro consisted of lymphoblasts with the same surface markers and abnormal karyotype as the original diagnostic marrow specimens. We also studied marrow cultures from 13 patients in chemotherapy-induced remission; 6 of these, including 1 obtained from a patient during successful engraftment after marrow transplantation, also yielded lymphoblast colonies in culture, with the same immunologic phenotype or abnormal karyotype as the original leukemic marrow. Four of these patients, including the one who underwent marrow transplantation, relapsed within 2 to 30 months of the abnormal cultures; the other two are still in remission, one of them 30 months after diagnosis. Bone marrow cultures from eight normal controls and from the other seven patients in remission did not yield lymphoblast colonies; all seven of the latter are still in remission. This assay appears to allow detection of small numbers of residual leukemic cells. We conclude that the technique will be valuable in monitoring the efficacy of chemotherapy and allogeneic bone marrow transplantation in acute lymphoblastic leukemia, as well as in evaluating the quality of purged marrow for autologous marrow transplantation.     

骨髓间充质干细胞移植治疗矽肺小鼠肺炎及肺纤维化

背景：矽肺对职业人群健康的影响日益严峻,目前没有有效治疗的方法。 目的：观察骨髓间充质干细胞移植对矽肺的治疗作用。 方法：36只C57BL/6小鼠随机摸球法均分为3组。对照组小鼠气管内注入生理盐水;矽肺模型组和骨髓间充质干细胞移植组小鼠气管内注入二氧化硅混悬液建立矽肺模型;骨髓间充质干细胞移植组于造模后6 h尾静脉输注骨髓间充质干细胞。 结果与结论：肺组织羟脯氨酸的含量矽肺模型组和骨髓间充质干细胞移植组高于对照组,差异均有显著性意义(P < 0.01);骨髓间充质干细胞移植组含量明显低于矽肺模型组,差异有显著性意义(P < 0.01)。矽肺模型组和骨髓间充质干细胞移植组小鼠的肺系数均高于对照组(P < 0.01),其中骨髓间充质干细胞移植组低于矽肺模型组,差异有显著性意义(P < 0.01)。白细胞介素1β的表达矽肺模型组和骨髓间充质干细胞移植组高于对照组 (P < 0.01);骨髓间充质干细胞移植组低于矽肺模型组,差异均有显著性意义(P < 0.01)。转化生长因子β1在肺组织中的表达同样为矽肺模型组(P < 0.01)和骨髓间充质干细胞移植组(P < 0.05)高于对照组;骨髓间充质干细胞移植组低于矽肺模型组,差异有显著性意义(P < 0.01)。说明骨髓间充质干细胞移植可以减轻肺部炎症反应和纤维化程度。     

Adenovirus type F subtype 41 causing disseminated disease following bone marrow transplantation for immunodeficiency

Adenovirus causes disseminated disease following bone marrow transplantation (BMT). We report a child who underwent T-cell-depleted BMT. Adenovirus subgenus F serotype 41 was detected antemortem by PCR in cerebrospinal fluid and postmortem in other tissues. Serotypes 40 and 41, associated with gastrointestinal disease, have not previously been implicated in disseminated disease.