造血干细胞移植与自身免疫病

自身免疫病(autoimmune disease,AID)如系统性红斑狼疮(systemic lupus erythematosus,SLE)、类风湿关节炎(rheumatoid arthritis,RA)、系统性硬化(systemic sclerosis,SSc)等具有较高的致残率和(或)致死率。这些疾病不仅给患者造成极大的负担和伤害,而且造成家庭和社会负担的明显增加。因此,近十年人们更趋于早期和更积极地给予治疗,以防止或延缓患者内脏器官出现明显的不可逆损伤。大剂     

Hematopoietic stem cell transplantation for the treatment of autoimmune diseases

Systemic autoimmune diseases that are resistant to conventional treatment cause considerable morbidity and mortality. Although aggressive new approaches to treating autoimmune diseases have been developed over the past decade, there are still patients with a severe, progressive, and life-threatening course. Based on animal studies and experience in the treatment of hematological disorders with preexisting autoimmune disease, hematopoietic stem cell transplantation has been proposed for the treatment of severe autoimmune diseases. Immunoablation and subsequent autologous peripheral blood stem cell transplantation using CD34⁺ hematopoietic cells with T cell depletion have been used for selected severe autoimmune diseases at many institutes in Australia, Europe, and the United States. However, it is necessary to assess the efficacy and safety of this therapy compared with conventional and other newly emerging therapies.     

Hematopoietic stem cell transplantation in autoimmune diseases. Pros and cons

New therapeutics have clearly advanced our chances of inducing remission in several aggressive autoimmune diseases like rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). Despite this, subgroups of patients with RA or SLE or of other diseases like systemic sclerosis (SSc) or multiple sclerosis (MS) still present a poor response to conventional drugs. In this kind of patients, haematopoietic stem cell transplantation (HSCT) provided important clinical benefits in several studies. This might depend upon several possible mechanisms such as purging of autoreactive T cells during conditioning or changes of the TH1/TH2 biological milieu. An overview of the results obtained so far, the drawbacks and the perspectives in this field are presented.     

Hematopoietic stem cell transplantation in systemic autoimmune diseases. State of the art

The use of stem cell transplantation for severe autoimmune diseases refractory to conventional therapy arose from two discoveries: the excellent results of animal experiments, and serendipitous observations in human coincidental diseases. Experimental data and early phase I-II trials in highly selected patients suggest that highdose chemotherapy followed by autologous hematopoietic stem cell transplantation can arrest progression of severe autoimmune diseases with an acceptable risk/benefit ratio. The present article reviews the phase II-III prospective, multicenter, randomized trials that have been performed in distinct autoimmunediseases. In addition, allogeneic stem cell transplantation for autoimmune diseases is being cautiously explored in current protocols.     

Haematopoietic stem cell transplantation for autoimmune disorders: the American perspective

The hypothesis that haematopoietic stem cell transplantation (HSCT) might be useful in treating refractory autoimmune diseases (AID) was suggested by studies in animal models and by the improvement of concurrent autoimmune diseases in patients who had undergone transplantation for haematological disorders. This concept has now been tested in a substantial number of phase I/II clinical trials of autologous HSCT. These early results are promising, even in patients who have failed on multiple standard therapies for AID. Transplantation-related toxicity has decreased with growing experience in the application of this procedure, better patient selection and the modification of treatment protocols. Randomized trials currently under way or under consideration should clarify the role of HSCT in patients with autoimmune disorders.     

Hematopoietic stem cell transplantation in rheumatic diseases.

The concept of using hematopoietic stem cell transplantation to treat patients with autoimmune disease was first provided by animal studies and anecdotal case reports. Advances over recent years in autologous hematopoietic stem cell transplantation, most notably cytokine-mobilized peripheral blood stem cells, have been followed by its specific use to treat severe autoimmune and inflammatory diseases. Guidelines have been published, and, by March 1999, 150 cases were registered with the International Autoimmune Disease Stem Cell Project Database. This review summarizes the literature published with respect to inflammatory rheumatic disease over the past few years and discusses future directions aimed at refining this intensive approach.     

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??Abstract??New drugs such as rituximab had improved the efficacy of patients with non-Hodgkin lymphoma(NHL)significantly??but for high-risk patients or relapsed/refractory patients??hematopoietic stem cell transplantation(HSCT)is still the only way to save their lives.Autologous stem cell transplantation(ASCT)has an important role in the treatment of NHL??especially in the relapse setting.It is also under investigation after first-line therapy??for example??in patients with mantle cell or T cell lymphomas.Chemosensitive is the main prognosis factor.The number of allogeneic stem cell transplantations(allo-HSCT)in NHL patients has increased over the last decade??especially reduced-intensity conditioning stem cell transplantation has been applied more widely because of its graft-versus-lymphoma(GVL)effect with lower transplantrelated mortality.But the role and timing and the best RIC regimen of RIC-allo-HSCT in the treatment of NHL remains unclear??more prospective and random clinical research should ascertain these problems.     

Stem cell transplantation for autoimmune disorders. Preclinical experiments

The clinical use of autologous stem cell transplants for the treatment of refractory severe autoimmune diseases was preceded by convincing proof of its underlying principle in animal models. The various categories of experimental autoimmune disease in laboratory rodents are briefly described here, and the rationale that was used in the selection of suitable experimental autoimmune diseases for translational research is explained. The two models that provided the bulk of the data needed for designing the initial clinical treatment protocols were adjuvant arthritis (AA) and experimental allergic encephalomyelitis (EAE), which were both induced in Buffalo rats. In this strain, AA is manifested as a chronic, progressive, systemic polyarthritis and EAE as a chronic, remitting/relapsing form of encephalomyelitis resembling multiple sclerosis. Both diseases can be cured with autologous stem cell transplantation provided that adequate conditioning is given and that the disease has not yet progressed to the stage of 'scarring'. It is basically the inflammatory stages that respond well to this therapy. The success of treatment depends on how completely the autoantigen-specific activated T-lymphocytes and memory cells are eradicated. Because of a lack of information on the nature of the autoantigens involved in human disease and on the size of those cell populations in the animal models as well as in humans, this aspect of translation is difficult. The experiments have, however, provided important guidelines. High-dose conditioning regimens yield better results than low-dose conditioning, certain conditioning agents perform better than others, and care should be taken not to reintroduce too many T-cells with the autologous graft. The clinical results obtained so far indicate a high predictive power of these two animal models, which are therefore recommended strongly for additional preclinical studies.     

Stem cell transplantation for autoimmune disorders. Immune reconstitution

Lymphocyte recovery is delayed following autologous haematopoietic stem cell transplantation (HSCT). B-cells recover before T-cells and CD8+ before CD4+ T-cells. The initial phase of T-cell recovery is dependent upon the expansion of mature host T-cells that have survived conditioning or are transferred back with the graft. This phase is therefore quicker when the graft is not CD34+ selected. Subsequently, na?ve T-cells appear. Na?ve CD4+ T-cell recovery is thymus dependent and starts at around 6-9 months. Na?ve CD8+ recovery occurs earlier and seems less thymus dependent. Immune function recovers later than lymphocyte number, the former being dependent on a broad repertoire and diversity of effector function. We currently do not know which reconstitution markers are more likely to predict prolonged disease remission as opposed to relapse. Similarly, it is unclear whether disease-specific factors influence reconstitution. A continued, close collaboration between scientists and physicians should both improve the outcomes of HSCT and also provide important pathogenic information about the diseases under treatment.     

Stem cell transplantation for autoimmune disorders. Multiple sclerosis

Autologous transplants for severe and refractory multiple sclerosis (MS) were proposed in 1997 and have been performed on about 200 selected patients worldwide. Phase I/II clinical studies have shown that high-dose immunosuppressive therapy suppresses inflammation in the CNS and may delay the progression of clinical disease. The procedure is associated with toxicity from the high-dose cytotoxic therapy and a risk of serious infections. There is a transplant-related mortality risk of 1-5%, requiring careful patient selection before transplantation. Treatment should be reserved for patients who have a significant chance of response, i.e. young patients with low disability scores but rapidly progressing disease who have inflammatory rather than neurodegenerative changes in the CNS. The long term effect of high-dose immunosuppression after transplantation on the frequency of relapse or progression of MS is unclear, but the initial concept of immune ablation by high-dose therapy and the reconstitution of normal immunity and tolerance from transplant-derived lymphocyte progenitors has given way to the concept of 'resetting' the immune system. The clinical effect of transplantation remains to be demonstrated in comparative studies.     

Stem cell transplantation for autoimmune disorders. Rheumatoid arthritis

Haematopoietic stem cell transplantation (HSCT) is now being investigated as a potential therapy for patients with severe refractory rheumatoid arthritis unresponsive to conventional therapies, including tumour necrosis factor-alpha blockade. Pilot studies and an analysis of worldwide cases included in the European Group for Blood and Marrow Transplantation/Autologous Blood and Marrow Transplant Registry registry have enabled the progression of the technique. HSCT is well tolerated in patients with rheumatoid arthritis, and there has been no transplant-related mortality. Although HSCT is not a cure, an improved response to previously ineffective therapies is often seen. Further research is, however, required, and this procedure is still considered appropriate only for those patients for whom there is no reasonable therapeutic alternative. This paper reviews all the previous data relating to HSCT in rheumatoid arthritis, outlines the current stand and discusses future protocol options and research.     

Hematopoietic stem cell transplantation in Oman

Hematopoietic SCT (HSCT) is an integral part of the management of patients with hematologic disorders. The Sultanate of Oman, with a population of 2.3 million, has an HSCT program based in the Sultan Qaboos University (SQU) hospital. Initiated in 1995, this two-bed unit continues to be the only program in the country. Between June 1995 and August 2006, a total of 128 patients underwent HSCT in this center, averaging about 10-12 transplants per year. The median age of these patients was 11 years (2 months to 45 years). Hematologic malignancies (49%) and inherited disorders (42%) constituted the major transplant indications, whereas BM failure accounted for the remaining. The majority of transplants carried out so far have been HLA-matched sibling-donor allogeneic HSCTs. Among the inherited disorders, homozygous beta-thalassemia and primary immunodeficiency are important transplant indications in this center. The approximate cost of an uncomplicated transplant in this center is US$50,000. The success of this program has now led to the initiation of a new and larger HSCT complex to provide the opportunity for more patients to benefit from this treatment modality within the country.     

Hematopoietic stem cell transplantation in Thailand

Hematopoietic SCT was first performed in Thailand in 1986. At present, there are FOUR active centers: Siriraj, Ramathibodi, Chulalongkorn and Pramongkutklao Hospitals. The annual number of transplants varies from 120 to 150 cases. Although the number of eligible patients is high, only a proportion of the patients can undergo hematopoietic SCT due to the high cost of the procedure. The overall results are comparable to those reported in the Western countries. The incidence of acute GVHD is low, whereas chronic GVHD is high, especially in those who receive PBSC.     

Hematopoietic stem cell transplantation in thalassemia

SCT still remains the only cure currently available for patients with thalassemia. Results of transplants in this disease have steadily improved over the last two decades due to improvements in preventive strategies, effective control of transplant-related complications and development of new preparative regimens. Currently, high-resolution HLA typing has enabled physicians to perform transplants from unrelated volunteer donors for thalassemia with results comparable with those obtained employing an HLA-identical sibling. The probabilities for obtaining thalassemia-free survival after transplant in thalassemia from an HLA-identical donor, family member or MUD are between 85 and 87%. Therefore, when an HLA-identical donor is present, the transplant of allogeneic stem cell should be performed as allogeneic gene therapy. In the light of advances in transplantation for thalassemia, patients with an HLA-identical donor should be offered SCT.