Stem-cell mobilization is an immunosuppressive process, especially if cyclophosphamide is used. More profound immunosuppression is subsequently achieved through conditioning before HSCT. Conditioning means that an immunosuppressive regimen causes an at least transient bone marrow insufficiency, leading to a pancytopenia. The aim of conditioning is to eliminate to the greatest extent possible autoreactive cells, mostly T or B cells. The dose-limiting factor for such an intense immunosuppression is the hematotoxicity. However, hematotoxicity is reduced by retransfusion of autologous hematopoetic stem cells after conditioning. In any case, a transient pancytopenia occurs with a nadir around day 10 after HSCT. Transfusion of red cells or platelets may be necessary. Prophylactic antibiotic, antifungal, and antiviral therapy are given depending on the intensity of leuco- or lymphopenia. For conditioning chemotherapy, cyclophosphamide, busulfan or radiotherapy, or antibodies against components of the immune system have been used alone or in combination.
Explore This IssueNovember 2008
Allogeneic HSCT is associated with GvHD that carries significant morbidity and mortality. Theoretically, allogeneic HSCT offers the replacement of an autoreactive immune system with one that is putatively normal, but, in practice, this has yet to be proven. In fact, there are case reports of allogeneic HSCT being performed in patients with rheumatoid arthritis (RA) suffering from drug-induced aplastic anemia and, despite four years of remission, relapse occurred with all immune competent cells being of donor origin. On the other hand, similar cases have had up to 20 years clinical and serological remission.
Although hematopoetic reconstitution occurs within two weeks after HSCT, complete regeneration of the adaptive immune system, in contrast, is delayed up to years. It is thought that as the immune system returns in the presence of the inciting autoantigen, tolerance occurs.
HSCT is associated with substantial morbidity and mortality. In the beginning, transplant-related mortality for patients with systemic sclerosis (SSc) undergoing HSCT was higher than 10% in retrospective database analyses. In the last years, transplant-related mortality seems to be reduced after patients with advanced organ damage have been excluded from transplantation. Currently, active prospective trials recruit patients with a high risk of an adverse outcome of their autoimmune disease but with a still preserved organ function.
Toxicity of HSCT comes from the induction regimen itself. For example, cyclophosphamide or melphalan are potentially cardiotoxic, especially if used in patients with preexisting heart disease; this can be the case in autoimmune diseases such as SSc. G-CSF used to mobilize stem cells and to shorten engraftment after transplantation has been shown to induce a flare of the autoimmune disease in single cases. Antithymocyte globulin (ATG) used in the conditioning regimen is associated with hypersensitivity reactions.