Stem cell transplantation for rheumatic autoimmune diseases

Abstract

Immunoablative therapy and hematopoietic stem cell transplantation (HSCT) is an intensive treatment modality aimed at 'resetting' the dysregulated immune system of a patient with immunoablative therapy and allow outgrowth of a nonautogressive immune system from reinfused hematopoietic stem cells, either from the patient (autologous HSCT) or a healthy donor (allogeneic HSCT). HSCT has been shown to induce profound alterations of the immune system affecting B and T cells, monocytes, and natural killer and dendritic cells, resulting in elimination of autoantibodyproducing plasma cells and in induction of regulatory T cells. Most of the available data have been collected through retrospective cohort analyses of autologous HSCT, case series, and translational studies in patients with refractory autoimmune diseases. Long-term and marked improvements of disease activity have been observed, notably in systemic sclerosis, systemic lupus erythematosus, and juvenile idiopathic arthritis, and treatment-related morbidity and mortality have improved due to better patient selection and modifications of transplant regimens. Treatment-related mortality has decreased to approximately 7%. Prospective, randomised, controlled clinical trials are ongoing or planned in systemic sclerosis, systemic lupus erythematosus, and several nonrheumatological conditions. IntroductionData from nearly 1,000 patients with refractory autoimmune disease (AD) treated with hematopoietic stem cell transplantation (HSCT) have been collected by the European Group for Blood and Marrow Transplantation/European League Against Rheumatism (EBMT/EULAR) Working Party for Autoimmune Diseases in the past 10 years (Tables 1 and 2; Riccardo Saccardi, chair of the EBMT/EULAR Working Party, personal communication) [1][2][3][4]. The advent of this multistep treatment modality ( Figure 1) followed clinical observations of remissions of AD in patients who were transplanted for concomitant hemato-oncological conditions [5]. The immunological principles were subsequently confirmed through mechanistic studies in animal models of AD [6]. HSCT in AD was widely pioneered in the 1990s at a time when few biologicals were available to treat AD and when refractory progressive disease posed a major challenge. The introduction of effective biologicals for the treatment of rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), ankylosing spondylitis, and systemic lupus erythematosus (SLE) has reduced the demand for intensive and toxic treatments such as HSCT. Nevertheless, clinicians still face cases of severe and life-threatening AD such as progressive systemic sclerosis (SSc), vasculitis, or SLE, refractory to conventional medication and biologicals, for whom HSCT may be a therapeutic option. Whereas biologics target one cell type or soluble cytokine only, HSCT affects all immune effector cells involved in AD, notably B and T lymphocytes, monocytes, natural killer (NK) cells, and dendritic cells (DCs). In contrast to conventional immunosuppressive medication and b...

Transplantation of Genetically Modified Haematopoietic Stem Cells to Induce Antigen-Specific Tolerance as a Cure for Autoimmune Diseases

“…In general, there is a positive short term benefit with reduced relapses, reduced disease progression and/or activity, and in some cases, complete remission. However with time, the incidence of relapses increases [26][27][28][29][30][31].…”

Reply

“…In ASCT, conditioning with high-dose cyclophosphamide, antithymocyte globulin, and/or total-body irradiation nullifies the majority of autoreactive effector cells involved in the adaptive and innate immune response, including B and T lymphocytes, monocytes, natural killer cells, and dendritic cells. 1 Thus, the immunosuppressive effect of ASCT may be regarded as the key factor in autoimmune diseases. A favorable response of the underlying disease to ASCT will logically lead to the resolution of all accompanying symptoms, including skin calcification.…”

Dexamethasone Preconditioning Improves the Response of Collagen-Induced Arthritis to Treatment with Short-Term Lipopolysaccharide-Stimulated Collagen-Loaded Dendritic Cells

“…This goal could be achieved if a transient immunosuppression is induced in the recipient just before receiving an injection with tolerogenic DCs. Data from animal models of autoimmunity and patients affected by autoimmune diseases has shown that nonmyeloablative immunosuppression followed by hematopoietic stem cell transplantation led to a reset of the dysregulated immune system of the recipient, which in some cases, reach complete remission of the disease [9]. …”