Introduction and Rationale

Autologous HSCT, although a well-accepted term, is believed to be a misnomer by some, because there is no transplant, only infusion of an autologous blood product (the patient’s own stem cells). These stem cells collected from the patient’s own blood by leukapheresis (or from the bone marrow) are by convention called hematopoietic stem cells (HSCs). HSCs are multipotent stem cells that give rise to blood, immune, and endothelial cells and, for the purpose of autoimmune diseases, are more appropriately viewed as immune stem cells. The therapeutic effect and in particular toxicity from autologous HSCT arises not from the infused autologous stem cells but rather from the immunosuppressive conditioning used to suppress the autoreactive immune system before infusion of HSCs.

The goal of conditioning regimens before HSC infusion in patients with autoimmune diseases is not to use cancer drugs that destroy the entire bone marrow compartment but rather to combine or dose escalate standard immune-suppressive medications to lymphoablate transiently, not myeloablate permanently, the immune system. This lymphoablation allows immune regeneration and a resetting of immune self-tolerance from the multipotent HSCs. For autoimmune diseases nonmyeloablative regimens are safer and less toxic than myeloablative regimens. In particular myeloablative regimens based on total body irradiation (TBI), which are associated with a high rate of growth retardation, infertility, and late cancers, are not indicated for patients with autoimmune disorders. TBI causes approximately a 10% incidence of myelodysplastic syndrome (MDS)/leukemia between 2 and 5 years after transplantation and beginning 8 to 10 years after treatment; the incidence of solid tumors for the remainder of the exposed individual’s life increases linearly.

The most common nonmyeloablative regimen for autoimmune diseases is cyclophosphamide (Cy) combined with rabbit antithymocyte globulin (rATG), a regimen commonly used as a conditioning regimen for patients with aplastic anemia. Another nonmyeloablative regimen used for autologous HSCT of autoimmune diseases is Cy combined with alemtuzumab instead of rATG. However, this regimen is complicated by late autoimmune cytopenias including potentially life-threatening immune thrombocytopenia pupura, autoimmune hemolytic anemia, or immune-mediated neutropenia. Hence, alemtuzumab should not be used in an autologous conditioning regimen for autoimmune diseases. Immune-mediated cytopenias associated with alemtuzumab have generally not been reported when maintenance immunosuppression continues after transplantation, for example, in patients receiving allogeneic HSCT for leukemias or patients receiving immunosuppression following solid organ transplant. Another nonmyeloablative regimen used in autologous HSCT for autoimmune diseases is termed rituximab sandwich, in which 1 dose of rituximab is given before and after the traditional Cy/rATG regimen. The currently preferred conditioning regimen used for juvenile idiopathic arthritis (JIA) is a nonmyeloablative regimen of Cy, rATG, and fludarabine (Flu) (see JIA section).

Special attention should be given to minimize the risk of regimen-related infertility, a side effect that may occur after high-dose Cy, the backbone of nonmyeloablative regimens. In an analysis of 212 patients undergoing allogeneic (not autologous) HSCT for aplastic anemia treated with 200 mg/kg of Cy (the same dose used in HSCT for autoimmune diseases) and ATG, 50% of patients who developed graft-versus-host disease (GVHD) fathered children, versus 62% who did not develop GVHD. This analysis did not document what percentage of patients did not wish to father children. Therefore it could be speculated that the actual fertility rate is higher than 62% because patients receiving an autologous HSCT do not develop GVHD. Although the use of Cy results in significantly less infertility than the use of TBI, a more thorough analysis of pre- and posttransplant fertility (sperm count, motility, morphology, ultrasound-guided antral follicle count, follicle-stimulating hormone, luteinizing hormone, estradiol, testosterone, antimüllerian hormone, inhibin B levels, and referral to reproductive endocrinology) should be considered for patients with an autoimmune disease undergoing HSCT.

It remains unclear whether the collected peripheral blood stem cells (or bone marrow) should be lymphocyte depleted (usually by means of a commercially available instrument that positively selects for CD34+ progenitor cells) before reinfusion of the autograft. T-cell depletion (TCD) of the autograft does increase the risk of late opportunistic infections, especially life-threatening viral infections such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV). The argument in favor of TCD is that it minimizes reinfusion of autoreactive lymphocytes that could lead to early relapse. The argument against taking the increased infectious risk from a TCD graft is that complete lymphoablation may not be necessary. Immune reset occurs from re-establishing the immune regulatory networks and tolerance as a result of conditioning regimen-induced neutropenia/lymphopenia and thymic-derived rebound of nonspecific regulatory cells (CD4+CD25+Foxp3+) and antigen-specific suppressor T cells (discussed in the systemic lupus erythematosus [SLE] section). Whether or not lymphocytes should be depleted from the autograft requires future randomized disease-specific and conditioning regimen-specific protocols. Most autologous HSCT so far reported in children have been T cell depleted, while the center with the largest world-wide experience in HSCT for adult autoimmune diseases, Northwestern University, performs most transplants without ex vivo TCD. Before HSCT, mild in vivo TCD and disease amelioration is obtained by means of mobilization of stem cells with Cy (2.0 g/m ² ) and granulocyte colony-stimulating factor (G-CSF). In patients not heavily pretreated with immune-suppressive medications, the subsequent transplants have been easily tolerated without life-threatening infections.

This article reviews the experience gained with using autologous HSCT in treating the most common childhood autoimmune and rheumatic diseases, primarily JIA, SLE, and diabetes mellitus.