T H E   N I H    C A T A L Y S T     M A Y  –  J U N E   2005




by Karen Ross

A meeting of the minds: (left to right) NCI’s Steven Pavletic, NIDCR’s Gabor Illei, NCI’s Fran Hakim, and NIAMS’ John Hardin bring their expertise to bear in a protocol using autologous stem-cell transplantation for patients with severe systemic lupus erythematosus

In a bold attempt to control or perhaps even cure their disease, two patients with intractable systemic lupus erythematosus underwent bone marrow stem-cell transplantation at the Clinical Center. They are participating in a clinical protocol organized by rheumatologists, immunologists, and stem-cell transplantation experts from NIAMS, NIDCR, NCI, NIDDK, NINDS, and the CC Department of Transfusion Medicine.

Since the transplants were done only a few months ago, it is too soon to say what the long-term benefits will be, but the initial results are encouraging, says NCI’s Steven Pavletic, the principal investigator.

The patients tolerated the transplant procedure well, Pavletic says, and are being weaned off the medications they currently use to keep their symptoms in check. Ultimately, the team plans to do transplants on 14 patients and follow them for up to five years.

Lupus at a Glance

Like multiple sclerosis and rheumatoid arthritis, lupus is an autoimmune disease—a disorder in which the immune system turns against its own host.

The immune system, says NIAMS rheumatologist John Hardin, is capable of generating millions of responses. Most of the time, these responses are protective, killing off viruses, bacteria, and even incipient cancer cells before they have a chance to cause harm. But in autoimmune disease, the system mounts an inappropriate response against some part of the patient’s own body.

Lupus patients have an immune reaction to components of the cell nucleus, primarily DNA-protein complexes, which are released during the normal process of cell death. Antibodies bind to the nuclear material and form clumps that are deposited in organs throughout the body, causing kidney damage, arthritis, skin rashes, and numerous other symptoms.

Lupus, which often strikes in early adulthood and has no known cure, is a debilitating and sometimes fatal disease—approximately 10 percent of lupus patients die from their disease in an average five-year period, and the mortality rate is higher in those with major organ involvement.

Immunosuppressive drugs are the current standard treatment for severe lupus. Side effects arise because these drugs quash both helpful and disease-causing immune responses. Moreover, for many patients, the medication becomes less effective over time.

Stem-Cell Transplantation Rationale

Bone marrow stem-cell transplantation is a promising new avenue of treatment for lupus. Developed to treat cancers of the immune system like leukemia and lymphoma, hematopoietic stem-cell transplants involve destroying a patient’s diseased immune system with radiation or chemicals and then injecting stem cells that will develop into a new, healthy immune system. Ideally, after transplant, lupus patients would be free of the self-reactive immune cells that caused their disease.

Transplants can be done with either donor stem cells (an allogeneic transplant) or the patient’s own stem cells (an autologous transplant). Although allogeneic transplants using donor cells from individuals who are not genetically predisposed to lupus may reduce the chances of recurrence, the NIH team opted initially for autologous transplants.

Eliminating the risk of graft vs. host disease, a serious complication of allogeneic transplants, was one reason, says Pavletic. In addition, there is some evidence from animal models of autoimmune disease that autologous transplants are effective.

Finally, approximately 100 lupus patients have been treated with autologous transplants with some success in clinical trials at other institutions. They were not cured—many still required immunosuppressive medications or had lingering symptoms of their disease—but about half of the patients continued to benefit from their transplants after two to four years.

"The main message," says Pavletic, "is that patients who have failed all other treatments can experience durable remissions with transplantation."

The NIH Protocol

Several aspects of the NIH transplant protocol fuel the investigators’ hope for improved outcomes:

The regimen of drugs used to deplete the patient’s original immune system is not only less drastic than that used in other protocols but also may have a better chance of eliminating all of the immune cells that contribute to lupus.

The criteria used to enter patients into the trial and to measure their responses have been carefully defined to point more precisely to why the transplant does or does not work in specific patients.

But the most significant new feature, the investigators agree, is the intensive collaboration among lupus experts and experts in both the clinical and laboratory aspects of stem-cell transplantation. "The level of collaboration is totally unprecedented," says Gabor Illei, chief of the Sjögrens Syndrome Clinic at NIDCR, who is involved with the protocol.

The work of the bench scientists not only guides the transplant team in the clinic, but also contributes to the basic understanding of lupus.

Frances Hakim, of the NCI Experimental Transplantation and Immunology Branch, analyzes patients’ T cells before, during, and after transplant. She examines the T cells that persist after the depletion procedure, focusing particularly on whether any of these are the "bad actors" that cause lupus symptoms, and she studies how T cell populations recover after transplant. Amrie Grammer, of the NIAMS Autoimmunity Branch, conducts similar studies on B cells.

This in-depth exploration of each patient’s immune system, says Hakim, "should give some insight into the pathogenesis of lupus and the generation of the next level of immune therapy."


There are some possible downsides to treating lupus with autologous stem- cell transplantation. As with stem-cell transplants in general, the procedure itself is somewhat risky, and there is always the chance that some of the disease-causing cells will escape eradication and trigger a recurrence of the disease after transplant.

Lupus presents a particular problem, however, because it has a strong genetic component, says Hardin. Studies of identical twins have shown that if one twin has lupus, the other has a 40 percent chance of developing the disease. This genetic propensity may be retained in an autologus transplant.

On the positive side, lupus doesn’t usually appear until after age 20, so there is some hope that the disease would take as long to develop the second time as it did the first time—decades. And if the disease did recur, Hardin noted, it would be like a "new" case of lupus for which conventional treatment could be offered.

Ideally, says Hardin, the meticulous study built into the protocol will suggest stem-cell transplantation strategies to eliminate the disease-causing immune cells and leave the rest of the immune system intact. n

For more information about the trial, contact Steve Pavletic at 301-435-4000 or by e-mail.

A description of the trial can be found at this website.



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