Hematopoietic stem cell transplantation for autoimmune diseases.
Autologous hematopoietic stem cell transplantation (HSCT) is the only treatment that can induce long-term, drug-free, symptom-free remission in multiple refractory autoimmune rheumatic diseases. More than 3,000 HSCT interventions have been performed worldwide for severe rheumatic and non-rheumatic autoimmune disorders. Currently, specific conditioning schemes are used to eradicate autoreactive immunological memory from patients. It is controversial. After extensive immunodeficiency in connection with serotherapy and Chemotherapy, HSCT effectively restores the immune system by renewing the CD4+ T cell compartment, specifically the regulatory T cell population. Hematopoietic stem cell transplantation (HSCT) requires careful patient selection based on the autoimmune disease and consideration of therapeutic alternatives, risks and benefits, and the expertise of the transplant team.
Mechanistic aspects of autologous hematopoietic stem cell transplantation
Despite the documented clinical success of HSCT in autoimmune diseases, the precise underlying mechanism of this Treatment remains elusive. A significant amount of autoreactive and inflammatory effector cells are removed by autologous HSCT conditioning. The hope is that the subsequent de novo generation of naïve T cells in the patient will ‘reset’ the immune clock, restoring tolerance. Reinfusion of CD34+ hematopoietic stem cells is considered primarily to shorten the aplasia and is not regarded as therapeutic and supported by studies showing that high-dose cyclophosphamide therapy can still be effective without reinfusion of stem cells for the Treatment of systemic sclerosis.
Clinical data
Multiple sclerosis is the leading indication for autologous HSCT among various autoimmune diseases. A recent review pooled data from 400 patients in 12 studies. Patients had primary relapsing-remitting or progressive disease, and conventional immunosuppression had failed. Approximately 70% had a stable and improved illness for at least three years after transplantation. The timing of HSCT in multiple sclerosis can be critical as there is increasing evidence that neurodegeneration may progress independently of autoreactive processes at a particular stage of the disease.
Most systemic lupus erythematosus patients treated with autologous HSCT had renal or other visceral involvement. About 50% of patients remained disease-free for at least five years. Transplant-related mortality ranged from 4% (US single center experience) to 16 to 12% in a European survey, confirming the importance of center experience.
Prospective clinical trials of autologous hematopoietic stem cell transplantation
Given the mainly positive clinical results and increasing understanding of the mechanisms, one may wonder why there is a delay in conducting phase 3 controlled trials and why recruitment to such problems is slow. There are many reasons:
1- There is no financial interest in this Treatment as it is a complex procedure being studied rather than a single drug.
2- The extensive work to comply with all regulatory aspects within the European Union and sometimes with additional national regulations has to be done by enthusiastic clinicians with limited knowledge. Resources compared to the pharmaceutical industry.
3- Autologous HSCT is considered expensive Therapy and, if it is not carried out for a malignant neoplasm, is not covered by health insurance in many countries.
Mesenchymal stem cells
Mesenchymal stem cells can differentiate into chondrocytes, osteocytes, or fat cells. In addition to their regenerative potential, in vitro results have shown that mesenchymal stem cells also have immunosuppressive properties. These cells suppress the proliferation of T and B lymphocytes when co-cultured with activated lymphocytes by mechanisms that are not yet fully understood. In animal models, mesenchymal stem cells accumulate in inflamed tissue and can reduce inflammation.
