One of the more perplexing questions in biomedical research is why does the body’s protective shield against infections, the immune system, attack its own vital cells, organs, and tissues The answer to this question is central to understanding an array of autoimmune diseases, such as rheumatoid arthritis, type 1 diabetes, systemic lupus erythematosus, and Sjogren’s syndrome. When some of the body’s cellular proteins are recognized as “foreign” by immune cells called T lymphocytes, a destructive cascade of inflammation is set in place. Current therapies to combat these cases of cellular mistaken identity dampen the body’s immune response and leave patients vulnerable to life-threatening infections. Research on stem cells is now providing new approaches to strategically remove the misguided immune cells and restore normal immune cells to the body.
Autoimmune diseases arise when this intricate system for the induction and maintenance of immune tolerance fails. These diseases result in cell and tissue destruction by antigen-specific CD8 cytotoxic T cells or autoantibodies (antibodies to self-proteins) and the accompanying inflammatory process. These mechanisms can lead to the destruction of the joints in rheumatoid arthritis, the destruction of the insulin-producing beta cells of the pancreas in type 1 diabetes, or damage to the kidneys in lupus. The reasons for the failure to induce or maintain tolerance are enigmatic. However, genetic factors, along with environmental and hormonal influences and certain infections, may contribute to tolerance and the development of autoimmune disease
The current treatments for many autoimmune diseases include the systemic use of anti-inflammatory drugs and potent immunosuppressive and immunomodulatory agents. In recent years, researchers have contemplated the use of stem cells to treat autoimmune disorders. The immune-mediated injury in autoimmune diseases can be organ-specific, such as type 1 diabetes which is the consequence of the destruction of the pancreatic beta islet cells or multiple sclerosis which results from the breakdown of the myelin covering of nerves. These autoimmune diseases are amenable to treatments involving the repair or replacement of damaged or destroyed cells or tissue. In contrast, non-organ-specific autoimmune diseases, such as lupus, are characterized by widespread injury due to immune reactions against many different organs and tissues. This is a severe disease affecting multiple organs in the body including muscles, skin, joints, and kidneys as well as the brain and nerves.
The objective of hematopoietic stem cell therapy for lupus is to destroy the mature, long-lived, and auto-reactive immune cells and to generate a new, properly functioning immune system. In most of the clinical trials, the patient’s own stem cells have been used in a procedure known as autologous hematopoietic stem cell transplantation. Nonetheless, the recovery phase, until the immune system is reconstituted represents a period of dramatically increased susceptibility to bacterial, fungal, and viral infection, making this a high-risk therapy. Recent reports suggest that this replacement therapy may fundamentally alter the patient’s immune system. Following hematopoietic stem cell transplantation, levels of T cell diversity were restored to those of healthy individuals. This finding provides evidence that stem cell replacement may be beneficial in reestablishing tolerance in T cells, thereby decreasing the likelihood of disease reoccurrence.
The ability to generate and propagate unlimited numbers of hematopoietic stem cells outside the body whether from adult, umbilical cord blood, fetal, or embryonic sources would have a major impact on the safety, cost, and availability of stem cells for transplantation. The current approach of isolating hematopoietic stem cells from a patient’s own peripheral blood places the patient at risk for a flare-up of their autoimmune disease. This is a potential consequence of repeated administration of the stem cell growth factors needed to mobilize hematopoietic stem cells from the bone marrow to the blood stream in numbers sufficient for transplantation. In addition, contamination of the purified hematopoietic stem cells with the patient’s mature autoreactive T and B cells could affect the success of the treatment in some patients. Propagation of pure cell lines in the laboratory would avoid these potential drawbacks. Whether embryonic stem cells will provide advantages over stem cells derived from cord blood or adult bone marrow hematopoietic stem cells remains to be determined
Currently, there is an extensive amount of stem cell gene therapy research being conducted in animal models of autoimmune disease. The goal is to modify the aberrant, inflammatory immune response that is characteristic of autoimmune diseases. Researchers most often use one of two general strategies to modulate the immune system. The first strategy is to block the actions of an inflammatory cytokine (secreted by certain activated immune cells and inflamed tissues) by transferring a gene into cells that encodes a “decoy” receptor for that cytokine. Alternatively, a gene is transferred that encodes an anti-inflammatory cytokine, redirecting the auto-inflammatory immune response to a more “tolerant” state. Embryonic stem cells are substantially more permissive to gene transfer compared with adult stem cells, and embryonic cells sustain protein expression during extensive self-renewal. Ultimately, stem cell gene therapy should allow the development of novel methods for immune modulation in autoimmune diseases. One example is the genetic modification of hematopoietic stem cells or differentiated tissue cells with a “decoy” receptor for the inflammatory cytokine interferon gamma to treat lupus. Theoretically, embryonic stem cells or adult stem cells could be genetically modified before or during differentiation into pancreatic beta islet cells to be used for transplantation. The resulting immune-modulating islet cells might diminish the occurrence of ongoing autoimmunity, increase the likelihood of long-term function of the transplanted cells, and eliminate the need for immunosuppressive therapy following transplantation. Researchers are exploring similar genetic approaches to prevent progressive joint destruction and loss of cartilage and to repair damaged joints in animal models of rheumatoid arthritis. Chondrocytes, cells that build cartilage in joints, may provide another avenue for stem cell-based treatment of rheumatoid arthritis. These cells have been derived from human bone marrow stromal stem cells derived from human bone marrow
