The majority of autoimmune endocrine diseases are characterized by immune destruction of endocrine tissue leading to glandular dysfunction and hormonal imbalance. Endocrine autoimmune diseases include: hypophysitis, Graves' disease, thyroiditis, autoimmune disease of the adrenal gland (Addison's disease), hypoparathyroidism, autoimmune type 1 diabetes mellitus, and autoimmune polyendocrine syndromes. These diseases have complex etiologies, which are unique to each disease, and, to some extent, unique to each patient. With the exception of autoimmune polyendocrine syndrome type I, genetic susceptibility to the development of endocrine autoimmune diseases is associated with multiple polymorphisms in the major histocompatibility complex genes (11). Genetic susceptibility alone, however, is insufficient to elicit autoimmune disease. Studies of autoimmune disease manifestation in identical twins show a lack of concordance, suggesting that specific (environmental or stochastic) immune triggering events are essential to pathogenesis of autoimmune disorders in patients with genetic susceptibility (12).
The potential of HSCT for treatment of autoimmune diseases is dependent on both the pathogenesis and severity of the underlying disorder. For example, hormone replacement therapy is both effective and well tolerated in patients with thyroiditis and (after destruction or removal of the thyroid gland) Graves' disease. Prognosis for these diseases is excellent, and complications related to hormone therapy are minimal; therefore, HSCT for these diseases cannot be justified. Moreover, HSCT is effective only for diseases in which the primary defect is expressed through hematopoietic stem cells. For example, autoimmune polyendocrine syndrome type 1 results from a defect in central (thymic) toler ance, which allows for the clonal expansion of self-reactive T cells (13). HSCT in patients with autoimmune polyendocrine syndrome type 1, whether autologous or allogeneic, might restore immunologic tolerance to autologous tissue antigens; however, in the absence of therapy to correct the defect in central tolerance mechanisms, autoimmune pathology will recur. Nevertheless, therapies to cure autoimmune polyendocrine syndrome type 1 must also address existing immunologic reactivity toward auto-antigens, and thus HSCT might be used as supportive therapy to thymic transplantation.
Stem cell therapies should be considered, however, for autoimmune type 1 diabetes mellitus, Addison's disease, and autoimmune polyendocrine syndromes types II and III, because these diseases are both clinically severe and potentially amenable to HSCT. Autoimmune type 1 diabetes mellitus is strongly associated with both types II and III autoimmune polyendocrine syndromes (14). Moreover, autoimmune type 1 diabetes is representative of the difficulties associated with HSCT for endocrine autoimmune diseases. The remainder of this chapter, therefore, will focus on the potential therapeutic benefit of HSCT for autoimmune type 1 diabetes mellitus as a model for the potential of HSCT in the treatment of endocrine autoimmune diseases.
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