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Systemic Lupus Treatment with Stem Cells

As a chronic, inflammatory, autoimmune disease, systemic lupus requires a treatment that would simultaneously correct abnormalities of the immune system while repairing tissue that has been damaged by inflammation. Such a treatment would, in fact, constitute the only truly effective therapy for systemic lupus.

Stem cell therapy accomplishes both objectives.

The treatment of people with systemic lupus by stem cells has already yielded very positive results, some of which are mentioned herein.

Scientists at the Oklahoma Medical Research Foundation (OMRF) have discovered receptors on the surface of bone marrow stem cells that recognize bacteria and viruses and which, when activated, trigger the stem cells to fight foreign pathogens. According to Dr. Paul Kincade, head of the Immunology and Cancer Research Program at the OMRF, and former president of the American Association of Immunologists and the Federation of American Societies for Experimental Biology,

"We have long known that so-called hematopoietic (blood) stem cells create the blood cells that are the front-line soldiers in the body's immune system. But we did not believe that infectious agents played an active role in the process. What we have now discovered is that these stem cells have a sort of antennae that detect bacteria and viruses. And when stem cells receive these distress signals, they spring to action, creating cells the body most needs early in life-threatening situations. Scientists need to study stem cells and leukemia cells in these diseases to determine if they are using this messaging system. It may be possible to boost immunity when necessary and also to shut down inappropriate responses. That could provide a powerful tool to fight cancer, lupus and many other diseases."

This newly discovered "messaging system" efficiently replaces damaged cells but may also be detrimental in certain circumstances. As Dr. Garnett Kelsoe, professor of immunology at Duke University, explains,

"Dr. Kincade's discovery merits widespread attention and will surely be the object of further investigation. The paper requires a new appraisal of just how innate immunity and acquired immunity are intertwined."

Such a discovery could have implications for a variety of diseases, including the various leukemias and a number of autoimmune diseases such as lupus and rheumatoid arthritis. The research was led by Dr. Kincade and Dr. Yoshinori Nagai, in collaboration with the University of Tokyo, Osaka University and Saga University in Japan. Findings were reported in the journal Immunity.

Dr. Ann Traynor, assistant professor of medicine and a researcher in the bone marrow transplantation program at Northwestern Memorial Hospital, along with colleagues from the Feinberg School of Medicine at Northwestern University, has successfully used autologous stem cell transplantation in the treatment of patients with systemic lupus. After an average followup of 2 years, all the patients were found to be in remission while their previously abnormal kidney, heart, lung and immune system functions had returned to normal. Seven patients were chosen who were refractory to standard therapy, including cyclophosphamide. Stem cells were extracted from the bone marrow of each patient, the patients underwent high-dose immunosuppression and then received infusions of the autologous stem cells which had been expanded into T- and B-cells. Circulating white blood cells from before and after treatment were compared. According to Dr. Traynor,

"What is exciting about this observation is that it appears that the immune system can correct its errors if early stem cells are allowed to mature as naive cells in a 'neutral' environment. This new generation of immune cells is not destined to repeat the ruinous errors of the prior generations. Our observation may have implications for the treatment of many immune disorders, including multiple sclerosis, myasthenia gravis, and even some types of cancers."

Five years after the treatment, 50% of 50 patients who participated in the study were still in remission, and the 5-year survival rate was measured at 84%. According to Dr. Richard Burt, chief of the Division of Immunotherapy for Autoimmune Diseases at Northwestern Memorial Hospital in Chicago and associate professor of Medicine at Northwestern University's Feinberg School of Medicine,

"For this study, we enrolled patients who had either life- or organ-threatening lupus and had exhausted all available treatment options. We found that within an experienced center, high-dose chemotherapy and autologous stem cell transplant may be performed safely and result in disease remission and improvement or salvage of residual organ function in the majority of patients. The idea is that if you turn back the clock and let the immune system heal itself, the patient should have a chance of ending up without the disease."

The study was begun in 1997 when Dr. Burt performed the first stem cell transplant in the U.S. to treat lupus. It involved 50 patients from 20 states and continued through 2005. Results were so positive that the next step is planned in which autologous stem cell transplantation will be compared with standard therapies in a randomized trial.

The procedure is similar to that used to treat some types of cancer. Stem cells are extracted from the patient's bone marrow and high-dose chemotherapy is employed to ablate the immune system, after which the harvested and expanded stem cells are reinfused to the patient for the purpose of repopulating the bone marrow. Similar success was reported by researchers who conducted a European multicenter trial in 2004, which carried a 13% treatment-related mortality rate, as opposed to 2% in this study. According to Dr. Yu Oyama, an autoimmune disease specialist at Northwestern Memorial Hospital and an assistant professor within the Division of Immunotherapy for Autoimmune Diseases at the Feinberg School of Medicine,

"It is doubtful our lower treatment mortality rate was due to patient selection, as our patients were very ill."

Dr. Burt adds,

"A center effect on survival has also been reported for stem cell transplantation in malignancies. However, it's important to note that the patients in this study are not comparable to those with malignancies. The patients in this study had organ dysfunction and were immunocompromised for a long time, conditions which often rule out stem cell transplant for cancer patients because it would be too dangerous. This highlights the importance for a medical center to have experience when treating lupus patients with high-dose chemotherapy and stem cell transplant."

According to Dr. Walter Barr, a rheumatologist at Northwestern Memorial Hospital and professor of Medicine in the Division of Rheumatology at the Feinberg School of Medicine at Northwestern University,

"Fortunately, the majority of patients with lupus can be successfully managed with our available medical therapies. However, for the very severely ill subset of lupus patients who have failed conventional therapies, stem cell transplantation provides a promising new alternative."

Researchers in the Division of Rheumatology, the Division of Nephrology, the Department of Preventive Medicine, and the Department of Medicine at Northwestern University in Chicago collaborated in the study and in the transplantation of hematopoietic stem cells for active SLE. As reported in the Journal of the American Medical Association in 2006, in an article entitled, "Nonmyeoablative hematopoietic stem cell transplantation for systemic lupus erythematosus", Drs. Richard Burt and Ann Traynor at Northwestern University described one particular patient in their study as follows:

"The first patient enrolled in this study was in the midst of a lupus flare manifest by nephritis and rapidly declining renal function, uncontrolled hypertension, immune-mediated cytopenias, and serositis characterized by a large pericardial effusion and abdominal pain. Antinuclear antibody (ANA), anti-double-stranded (ds) DNA and complement were normal. This patient is now more than 1 year post-stem cell transplant and is taking no immunosuppressive medication. Her serologies are normal, effusions have resolved, blood pressure is normal and renal function is markedly improved. This is the first autologous T-cell-depleted hematopoietic cell transplantation performed to treat lupus in an active flare. This patient has, for the first time since disease onset 13 years ago, entered a complete clinical and serological remission which persists at > 1 year of followup."

The cost of the treatment is approximately $100,000 per patient, but some insurance companies may pay for part of this expense. Findings were published in the Journal of the American Medical Association and in The Lancet.

Scientists at the University of Texas Southwestern Medical Center have discovered a link between a family of genes and abnormalities of the immune system that are associated with SLE in an animal model. Variations in the structure and expression of a subset of genes belonging to the SLAM/CD2 family have been found to play a role in autoimmunity in mice with lupus. These genes were already known to contribute to the regulation of immunity, and now it is further discovered that altered genes in this family may be responsible for abnormal lymphocyte responses. In mice with lupus, the Ly108 gene is expressed in elevated levels in lymphocytes and is thought to act in combination with additional genes and signaling molecules in the mice. According to Dr. Edward Wakeland,

"Given our association of variations in the SLAM/CD2 cluster with lupus susceptibility in mice, further work on the relationship of polymorphisms in the SLAM/CD2 cluster to SLE in humans is clearly warranted."

Differences in sequence and expression levels in a subset of SLAM/CD2 genes are being further elucidated. Findings were published in the journal Immunity in an article entitled, "Association of Extensive Polymorphisms in the SLAM/CD2 Gene Cluster with Murine Lupus."

In light of such positive results, scientists at the National Institutes of Health (NIH), an agency of the U.S. Department of Health and Human Services, have launched a five-year study to examine autologous hematopoietic stem cells in the treatment of refractory SLE during which B- and T-cells will also be examined for their roles in triggering the symptoms of the disease. Stem cells will be extracted from the bone marrow of 14 patients between the ages of 15 and 40, and readministered to each patient after immunosuppressive drugs have ablated the immune system. As previously described herein, the stem cells are then known to repopulate the bone marrow to establish a more properly functioning immune system. The treatment requires a 2-week hospital stay and several outpatient visits, followed by monthly medical checkups for 6 months, quarterly visits for 2 years and annual visits for the remainder of the study. The researchers are hoping to find a minimum of 24 months of remission without relapse in the patients. According to Stephen Katz, M.D., Ph.D., director of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a division of NIH,

"Many patients with severe forms of lupus have limited treatment options that may offer only temporary relief of symptoms and no disease regression. For these patients, stem cell transplantation therapy may offer hope for a normally functioning immune system."

Patients admitted to the study have proven to be refractory to immunosuppressant drugs. As Dr. Andrew von Eschenbach, director of the National Cancer Institute (NCI), a division of NIH, explains,

"Advances in cancer therapy can yield advances in the treatment of autoimmune diseases. Cyclophosphamide, when used as a cancer therapy, suppresses the immune system. This discovery led to improvements for lupus patients. Similarly, altering the immune system through progenitor cell transplantation, which is a cancer treatment, may also benefit lupus patients. Lupus is different from cancer. However, we have found that both diseases can benefit from treatment that modulates the immune system."

In previous studies, dysfunctional T-cells and overactive B-cells have been found to contribute to the destructive autoimmune process that characterizes lupus. T- and B-cell activity from before and after the transplantation will be compared in the study. Researchers at NIAMS will conduct the B-cell studies, while researchers at NCI will conduct the T-cell studies. Other divisions of NIH will also be involved, namely, the National Institute of Neurological Disorders and Stroke (NINDS) which will investigate the role of the central nervous system in the disease, and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) which will examine the extent of involvement of the kidneys.

Adult stem cells offer the same pluripotency of embryonic stem cells, but without the danger of forming teratomas (tumors), which remains a serious risk from embryonic stem cells. It is neither necessary nor desirable to use embryonic stem cells in the treatment of systemic lupus or other disorders, since a growing number of studies are showing increasing success with adult stem cells. In fact, the only stem cell studies that have ever shown success in the treatment of any human disease have involved adult stem cells, since no study has ever been conducted in which a disease was successfully treated with human embryonic stem cells, although this fact is not generally reported by the media. Ever since researchers first isolated human embryonic stem cells in 1998, there has never been a successful treatment for any human disease in a human being by embryonic stem cells. Embryonic stem cells have in fact proven to be very problematic, whereas stem cells from bone marrow, by contrast, have been safely used by doctors for over 40 years. Human umbilical cord blood in particular is now known to be a rich source of growth factors and cytokines, both of which are necessary for the regeneration of tissue, and stem cells that are derived from human umbilical cord blood have been shown to be more effective at tissue regeneration than are other types of stem cells that lack such additional factors. Ethics and politics aside, adult stem cells are highly preferable to embryonic stem cells purely for scientific reasons. (Please see the section entitled "Stem Cell Primer" for an explanation of the different properties of the different types of stem cells).

Adult stem cell therapy offers a potentially effective treatment of a chronic disease which previously has been considered incurable.


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