Historically, HSCT was used to rescue hematopoiesis after myeloablative therapy for the treatment of nonresectable tumors and malignancies. Subsequently, improvements in induction and immunosuppressive therapies have allowed the use of myeloablative therapy as a supportive platform for replacement of defective hematopoietic stem cells in patients with congenital diseases. In the context of HSCT therapies, autoimmune diseases share aspects of both congenital diseases and malignancies, in that both immunosuppressive therapy and replacement of defective hematopoietic stem cells may be directly therapeutic. Recently, observed therapeutic resolution of coincidental autoimmune diseases in patients receiving HSCT for primary malignancies or hematopoietic failure suggested the possible application of HSCT in the treatment of primary autoimmune diseases (reviewed in ref. 1).
Autoimmune diseases encompass a broad range of diseases with unique pathogeneses and manifestations. Criteria for classification of a disease as autoimmune include: (1) direct evidence of adoptive transfer of disease by immune cells or antibodies, (2) indirect evidence by reproduction of autoimmune disease in animal models, or (3) circumstantial evidence by clinical response to immunosuppressive therapy (2). These criteria are functional, however, and do not implicate a specific mechanism in the pathogenesis of autoimmunity. To cure autoimmune disease, the mechanisms that promote autoimmunity must be altered; consequently, the potential of HSCT for treatment of these diseases differs with respect to the disease.
Allogeneic HSCT has the potential to cure autoimmune diseases in which genetic susceptibility to autoimmunity is expressed through hematopoietic stem cells. For example, allogeneic HSCT elicited durable disease remission in patients suffering from rheumatic autoimmune diseases coincidental to malig nancy or marrow failure as indication for HSCT (1). These observations led to the initiation of phase I/II clinical trials of HSCT for primary autoimmune diseases, and therapeutic resolution (durable remission) of autoimmune disease after allogeneic HSCT was observed (reviewed in ref. 3). As a result, phase III clinical trials of HSCT for treatment of systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and systemic sclerosis are in development (4).
Allogeneic HSCT is associated with significant morbidity and mortality from toxic conditioning therapies, graft-vs-host disease, graft loss, and infection secondary to chronic immunosuppressive therapies; therefore, allogeneic HSCT is limited to patients with life-threatening disease. Although the toxicity of conditioning regimens and the possibility of graft failure are limitations to the widespread application of allogeneic HSCT for the treatment of autoimmune diseases, recent research in animal models suggests that nonmyeloablative HSCT may cure autoimmune diseases (5,6). In patients receiving HSCT for primary malignancies, donor immune cells preferentially target malignant cells, a phenomenon known as the "graft-vs-leukemia" effect (7). Reduced toxicity of conditioning therapy often leads to the establishment of mixed hematopoietic chimerism after allogeneic HSCT, thus promoting therapeutic destruction of malignant cells while reducing the risks associated with graft loss and toxic conditioning therapies (reviewed in ref. 8). In HSCT for primary autoimmune diseases, a similar phenomenon, that of "graft-vs-autoimmunity," led to resolution of autoimmune manifestations (9). Therefore, allogeneic HSCT may cure autoimmune disease without the necessity for myeloablative conditioning, which reduces the risk of mortality resulting from severity of HSCT conditioning regimens and graft loss.
Autologous HSCT likewise may restore immunologic tolerance to self-antigens, thereby inducing autoimmune disease remission. Autologous HSCT for the treatment of autoimmune disease is based on the principle that dose escalation of immunosuppressive therapies may be necessary to fully ablate autoimmune-reactive cells, and hematopoietic stem cells necessary to restore hematopoiesis after immunosuppressive (or ablative) therapies. Autologous HSCT minimizes risks associated with allogeneic HSCT such as graft loss, graft-vs-host disease, and chronic immunosuppression; nevertheless, autologous HSCT carries increased risk of disease relapse or recurrence when compared with allogeneic HSCT because of both preexisting immunity to tissue antigens and genetic susceptibility to the (re)development of autoimmune reactivity to these antigens (reviewed in ref. 3).
In general, diseases that are responsive to immunosuppressive therapy are candidates for dose escalation of immunosuppressive therapy followed by autologous hematopoietic stem cell rescue. For example, systemic lupus erythematosus and juvenile idiopathic arthritis respond to immunosuppressive therapy, and, in phase I/II clinical trials, long-term remission (>4 years) was induced in patients receiving autologous HSCT for these diseases (10). Relapse was frequent after autologous HSCT for systemic lupus erythematosus and multiple sclerosis; nevertheless, patient sensitivity to standard clinical therapies was restored.
Although HSCT has the potential to cure or ameliorate symptoms of autoimmune diseases, the potential therapeutic benefit of HSCT in the treatment of autoimmune disease must not only justify the risks associated with transplant, but also must clearly demonstrate improved quality of life for patients when compared with available supportive therapies. HSCT has successfully induced disease remission in patients suffering from rheumatic autoimmune diseases, providing patients relief from debilitating illness. The success of HSCT in inducing remission of rheumatic autoimmune diseases has encouraged interest in the possible application of HSCT therapy to the treatment of endocrine autoimmune diseases.
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