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DURHAM, N.C. -- In a bold attempt to control a disabling and often fatal immune disease called scleroderma, physicians at Duke University Medical Center are leading a national study to test whether stem cell transplants can reconstruct defective immune systems. If successful, the therapy would represent the first therapy ever to treat and potentially reverse the disease itself, not just alleviate its symptoms, said the Duke researchers.

Scleroderma is an "autoimmune" disease in which the body's immune system mistakenly attacks connective tissues that support the skin and internal organs. Patients with scleroderma experience varying degrees of pain, inflammation, hardened skin and organ failure. The disease affects up to 100,000 Americans and strikes three to four times as many women as men.

What causes the disease is unclear, but scientists believe a combination of genetic susceptibility and exposure to infections or environmental toxins may trigger its onset. Abnormal immune regulation perpetuates the self destruction of tissue.

The predominant therapy for scleroderma is cyclophosphamide, a chemotherapy drug that suppresses the immune system and alleviates the symptoms of disease. Still, about 50 percent of patients with severe organ involvement die within five years of diagnosis, despite standard therapy.

"Current therapies treat the disease symptoms but they don't alter the course of the disease," said Keith Sullivan, M.D., a Duke oncologist in the division of cellular therapy and the study's lead investigator. "We are hoping that transplantation will actually lessen or eradicate the defective immune response that initiates and perpetuates the disease."

The Duke-led study will increase the dose and duration of cyclophosphamide and compare this regimen against stem cell transplants, using purified stem cells derived from a patient's own blood.

The study -- Scleroderma Cyclophosphamide or Transplantion (SCOT) -- is being funded by a $20 million grant from the National Institute of Allergy and Infectious Diseases (NIAID). Led by the Duke Rheumatology Division and Adult Bone Marrow Transplant Program, the study will enroll 226 patients at 36 institutions nationwide.

"Our hope is to apply the benefits of stem cell transplantation to a chronic disease that can be severely disabling to some patients and fatal for others," said Sullivan. "If the therapy is successful, we could potentially extend its application to other severe autoimmune diseases."

Autoimmune diseases are caused by defects in the immune system that prompt its fighter T-cells to attack various parts of the body that are mistakenly perceived as foreign. Transplants using stem cells from bone marrow or blood are considered a viable treatment for scleroderma because they replace the blood-forming and immune systems that give rise to these self -destructive abnormalities.

Stem cell transplants are traditionally used to cure aggressive and recurrent cancers or inborn errors of the immune system. But physicians had anecdotally observed that patients with autoimmune disorders improved after receiving transplants for other diseases. In 1997, a pilot study of 35 patients with severe scleroderma confirmed these anecdotal reports. The study was initiated by Sullivan and Dr. Dan Furst of UCLA and was led by investigators at the Fred Hutchinson Cancer Research Center in Seattle.

The SCOT study will compare the effects of stem cell transplantation versus twelve monthly doses of high-dose cyclophosphamide. The seven-year, randomized clinical trial will evaluate differences in the death rates and significant organ damage between the two treatment groups. Researchers at 36 collaborating university sites will conduct the trial while analyzing the molecular basis of the disease and how treatments impact immune and cellular function, gene expression, and vascular abnormalities.

"One of the primary questions we want to answer is whether we can chronically suppress the immune system for one year and subdue the disease, or whether we need to completely repopulate the immune system with purified stem cells," said Joseph Shanahan, MD, a Duke rheumatologist and co-investigator of the study.

Patients undergoing transplants will receive their own, purified blood stem cells through a process called an "autologous" transplant. Patients are first given drugs that stimulate the release of stem cells into their bloodstream. The stem cells are then extracted from the blood, separated to remove lymphocytes, and stored for future use. Only the primordial stem cells – those which have not yet begun to commit to be a specific cell type – will be extracted.

The patient's immune system is then destroyed using high doses of chemotherapy and radiation: the goal is to eradicate the immune cells responsible for attacking the body. Following the immune destruction, the stored blood stem cells are re-infused into the patient and begin to repopulate the blood-forming and immune system. Using the patient's own stem cells reduces the potential for complications that often arise when non-self donor blood or marrow are used.

Immune cell function will be measured pre- and post-transplant to determine the effects of the transplant upon the patient's immune system.

The Duke clinical team is collaborating with basic scientists at Duke to study how the disease and its treatments impact the immune system; blood vessel function, size and flow; gene expression; and cellular signaling. Major research projects include:

• Duke cardiologist Chunming Dong, M.D., will assess the loss of small blood vessels caused by scleroderma and will measure the effects of treatment on vascular "progenitor" cells that sustain proper blood vessel function. In addition, he will profile changes in gene expression caused by the disease and its treatments. He will also transplant cells from scleroderma patients into immune-deficient mice to determine how the defective "endothelial" cells that line blood vessels react before and after treatment.
• Duke researcher Greg Sempowski, Ph.D., and colleagues will monitor recovery of the thymus – where T-cells are manufactured -- following treatment. In other studies, his team is developing ways to speed recovery of the immune system after transplant to reduce the duration of immune suppression that patients experience.
• Shanahan and Duke biomedical engineer Joseph Izatt, Ph.D., will examine the microvascular density, structure and function of blood vessels after treatment. Using a series of advanced imaging techniques such as optical coherence tomography, laser Doppler imaging, and orthogonal polarization spectral imaging, they will assess changes and repairs in very small blood vessels commonly affected by scleroderma.
• Michael Colvin, M.D., and David Adams, Ph.D., will monitor the pharmacologic kinetics of the drug cyclophosphamide to determine its toxicity and therapeutic impact on patients.

For more information about the SCOT trial, including a list of participating sites, visit the study's website at www.sclerodermatrial.org or call the hotline at 866-909-SCOT.