Stem cell transplantation for autoimmune diseases

Much progress has been made in the field of haemopoietic stem cell transplants (HSCTs) for severe autoimmune disorders. Theoretical considerations, animal data and anecdotal evidence suggested some time ago that intensive immunoablation followed by autologous HSCT could restore normal immune reactivity in patients with severe autoimmune disorders. Based on a concept statement issued in 1995, two European societies, the European League Against Rheumatism (EULAR) and the European Group for Blood and Marrow Transplantation (EBMT) began collecting phase I/II trial data in an international collaborative network. Sufficient information from more than 350 patients allows a preliminary assessment with level three evidence. Autologous HSCTs can induce remissions in all disease categories tested so far. Remissions can be transient or durable. HSCTs are associated with significant morbidity and mortality. Treatment-related mortality (TRM) is near 10% at 1 year and is associated with the intensity of the conditioning and the stage of the disease at the time of transplant. Marked interdisease differences exist. There are few data available in haematological autoimmune diseases, more in systemic sclerosis (SSc), systemic lupus erythematosus (SLE), juvenile idiopathic arthritis (JIA) and multiple sclerosis (MS). Patient selection has been recognized as a crucial element from the phase I-II trials. Patients with advanced disease, severely compromised organ function or irreversible organ damage should not be considered as candidates for HSCT. Prospective randomized studies should now determine the value of HSCT compared to standard therapy. Such trials are ongoing for patients with systemic sclerosis (ASTIS trial--Autologous Stem Cell Transplantation International Scleroderma Trial) or are planned for patients with multiple sclerosis (ASTIMS trial--Autologous Stem Cell Transplantation International Multiple Sclerosis Trial) and rheumatoid arthritis (ASTIRA trial--Autologous Stem Cell Transplantation International Rheumatoid Arthritis Trial). More phase II data are needed for other indications such as SLE and JIA.     

Stem cell transplantation for autoimmune disorders. Coincidental autoimmune disease in patients transplanted for conventional indications

The practice of stem cell transplantation for severe autoimmune diseases refractory to conventional therapy originated from two landmark discoveries: the excellent results of animal experiments, and serendipitous observations in human coincidental diseases. The latter include patients with an often long-standing autoimmune disease who have developed a haematological condition (aplasia, leukaemia, lymphoma) requiring stem cell transplantation (from marrow as well as from blood). Allogeneic and autologous transplants have been performed. The initial information deriving from both procedures is their feasibility, even more convincing since the patients were affected by two simultaneous severe diseases. The information derived from autologous transplants has, however, now been superseded by the considerable and increasing number of those transplants performed for primary autoimmune diseases. On the other hand, allogeneic stem cell transplantation for very severe autoimmune diseases is being cautiously explored in current protocols. Allogeneic transplants in coincidental disease have also suggested a graft-versus-autoimmunity effect, which may become relevant in conjunction with non-myeloablative, less toxic condition regimens.     

Stem cell transplantation: progress in Asia

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multiorgan involvement and high mortality, which was reduced because of the most widely and classically used immunosuppressive therapies. However, some patients continue to have significant mortality. So a shift in the approach to the treatment of SLE is needed. In the past decade, most transplants have been performed in the treatment of SLE with allogeneic or autologous hematopoietic stem cells and currently emerging mesenchymal stem cells. There are some important differences between the two procedures.     

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.     

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. 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 Crohn's disease

There is much interest in the possibility that haematopoietic stem cell transplantation might benefit patients with inflammatory bowel disease, with an emphasis on Crohn's disease. Case reports of patients with Crohn's disease undergoing stem cell transplantation for other reasons, or specifically for Crohn's disease, support the view that major improvements can be achieved, with even the possibility of a cure in a small number of, but certainly not all, cases. The development of Crohn's disease in a previously normal patient receiving an allogeneic transplant from an individual with the NOD2 mutation illustrates the importance of the genotype of the immune system. Population of the lamina propria by myofibroblasts with the donor's phenotype shows that non-immune mechanisms make also play a part. A clinical trial to determine the value of stem cell transplantation in Crohn's disease has been set up under the supervision of the European Group for Blood and Marrow Transplantation.     

Stem cell transplantation for autoimmune disorders. Refractory juvenile idiopathic arthritis

Since 1997, haematopoietic stem cell transplantation (HSCT) has been applied as an experimental procedure in more than 50 children with refractory juvenile idiopathic arthritis. We describe here follow-up data on 34 children with juvenile idiopathic arthritis, treated with HSCT in order to evaluate its feasibility, safety and efficacy. Data were collected on immunological reconstitution, complications and key rheumatological parameters. The clinical follow-up of the children ranged from 12 to 48 months. Eighteen of the 34 patients achieved a drug-free complete remission. Seven of these patients had previously failed treatment with anti-tumour necrosis factor-alpha. Six of the 34 patients showed a partial response (ranging from 30 to 70%), and 7 of the 34 patients showed a complete relapse of disease. Infectious complications were frequently seen. There were three cases of transplant-related mortality and two cases of disease-related mortality. It is still unclear why especially patients with systemic juvenile idiopathic arthritis are at risk of episodes of reactive haemophagocytosis.     

Stem cell transplantation for treatment of severe autoimmune diseases: current status and future perspectives

Autoimmune diseases include a heterogeneous group of disorders with variable presentation and severity. Immunosuppressive and immunomodulatory therapies are often used for treatment with considerable success in some cases. These diseases may also be severe and refractory to conventional treatment. Thus more aggressive intervention might be indicated in a subset of patients. Animal studies suggest that high-dose therapy supported by stem cell transplantation may lead to remissions in experimental autoimmune disease models. Anecdotal case reports suggest that the same may be the case in some human autoimmune diseases as well. This review attempts to summarise some current concepts and future perspectives on stem cell transplantation in the treatment of severe autoimmune diseases.     

Haematopoietic stem cell transplantation for autoimmune disease: limits and future potential

Stem cell transplantation (SCT) for autoimmune disease is handicapped by a lack of definitive clinical trials able to demonstrate an overall benefit. This deficiency will become more problematic as the impetus grows to introduce and evaluate additional technologies intended to improve the safety and efficacy of the procedure. The development of effective surrogate analyses to predict outcome by measuring resurgent autoimmune clones or by genomic- and proteomic-based technologies to detect early disease recurrence may be of value in assessing the benefits of these modifications without the need for full-scale, long-term, randomized trials. The introduction of safer allogeneic transplantation techniques may increase the effectiveness of the procedure, while work on marrow stem cell plasticity and/or fusion suggests that SCT may serve not simply to halt the autoimmune process, but also to contribute cells capable of healing or regenerating diseased organs. Finally, the introduction of therapeutic transgenes into transplanted cells may further increase the effectiveness of SCT, although the regulatory complexities of gene therapy trials will probably delay this process. All these innovations will ensure that the next decade will see major changes in the practice and purpose of SCT for autoimmune disease.     

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     

Stem cell transplantation for the treatment of end-stage liver disease

The past two decades have witnessed an explosion of research and clinical application of stem cells, transforming the field of regenerative medicine. Stem cell transplantation has already been performed to treat patients with cancer,liver diseases, and various types of chronic diseases. Indeed, stem cell-based therapies are effective in many diseases, and provide novel insights into the treatment of end-stage liver disease. Several clinical trials have indicated the efficacy profiles of stem cell transplantation in patients with end-stage liver disease, including liver cirrhosis, liver failure, and liver tumors. Animal models of acute liver failure have also provided important insights into the safety,mechanisms, and efficacy of stem cell therapies. Nevertheless, excitement due to this promising field must be tempered with careful and calculated research. In particular, studies on the quality, safety, and efficacy of stem cell transplantation are needed to ensure that qualified products are tested in well-designed clinical trials and approved by governments. Therefore, further investigations are required to effectively balance the safety with the innovation of stem cell transplantation research toward the effective treatment of end-stage liver disease.     

Stem cell transplantation for thalassemia

Thalassemia, one of the most common genetic disorders, is considered to be a global problem. Several millions of the patients suffer from severe thalassemic diseases. Stem cell transplantation is currently the only curative therapy. Bone marrow transplantation offers a high probability of cure when performed in young children. There is a higher risk as the patient becomes older, especially the high incidence of graft rejection. Modified conditioning regimens live been developed to overcome graft rejection in patients with class III or full blown manifestations. The alternative use of stem cell from cord blood makes possible earlier transplant with better chance of cure, although the engraftment is slower compared to bone marrow transplantation. More experiences with regard to stem cell transplantation in adult patients, the use of stem cell transplantation from related donors as well as matched unrelated donors are necessary.     

Stem cell transplantation for neuroblastoma

High-risk neuroblastoma is a childhood malignancy with a poor prognosis. Gradual improvements in survival have correlated with therapeutic intensity, and the ability to harvest, process and store autologous hematopoietic stem cells has allowed for dose intensification beyond marrow tolerance. The use of high-dose chemotherapy with autologous hematopoietic stem cell rescue in consolidation has resulted in improvements in survival, although further advances are still needed. Newer approaches to SCT and supportive care, most notably the transition to PBSC, have resulted in further improvement in survival and decreases in treatment-related mortality. Research into experimental approaches to hematopoietic SCT is ongoing.