Use of Genetically Engineered Molecules

Lupus is characterized by overactive B lymphocytes that circulate in the blood and most body tissues. Contact between autoreactive B and T cells, which is mediated by proteins on the surface of both cell types, is required for pathogenic autoantibody production. The new treatments focus on B and T lymphocytes and their interactions in an effort to prevent production of antinuclear antibodies.

Researchers reported on a broad array of findings at a recent conference at the National Institutes of Health in Bethesda, Maryland. One strategy for treating SLE involves altering the activity of molecules on the surface of T cells that determine how the cells respond when they are stimulated. David Wofsy, MD, of the University of California, San Francisco, reported that his research has focused on two molecules, designated CD28 and gp39, that provide the signals by which T cells distinguish between normal molecules and foreign material.

Genetically engineered molecules that block the functioning of CD28 or gp39 in a mouse model of lupus effectively inhibit the disease, but long-term treatment is required. In a recent advance, Wofsy and his colleagues found that a combined blockade of both molecules produced sustained benefits that persist even after treatment is stopped. Ten months after the 2-week course of therapy that blocked the functioning of both molecules, 70% of the mice were alive. The control groups received treatment that blocked only CD28 or gp39 and had survival rates of 0% and 18%, respectively. Wofsy hopes to begin phase I clinical trials of the new drug soon.

Immunosuppression

Current therapies for SLE are generally directed toward modulating T- and B-cell activity by using immunosuppressive agents (such as corticosteroids) and cytotoxic drugs (such as cyclophosphamide and azathioprine). Joseph E. Craft, MD, of the Yale University School of Medicine, said that newer therapeutic agents under development may have fewer side effects. This would allow treatment of SLE without compromising the immune responses that are normally required to resist infection.

The new agents are expected to be more selective. They would down-regulate autoreactive T or B cells or interrupt the ongoing autoreactive T- and B-cell co-stimulation required for pathogenic autoantibody production. Interruption of co-stimulatory pathways in mouse models largely abrogates both autoantibody production and end-organ disease, such as kidney inflammation.

Regulation of the Self-Destruction Process

Arthur M. Krieg, MD, of the University of Iowa College of Medicine, reported on research into the triggers of antibody production in SLE. Recent findings indicate that abnormal B cells capable of producing autoantibodies may arise in healthy persons but normally self-destruct before causing harm. Mice with SLE have a defect in this self-destruction process. Some of their defective B cells survive and produce autoantibodies. Several mechanisms that can initiate this process have been identified.

One such mechanism is an intrinsic abnormality of the B cells that prevents self-destruction. In other cases, some environmental stimuli may activate otherwise normal B cells to produce autoantibodies. In still other cases, T cells, which normally regulate antibody production by B cells, may stimulate the B cells that can produce autoantibodies instead of causing these cells to self-destruct. Several genes that regulate the self-destruction process have been identified.

Genetic Analysis

Edward Wakeland, PhD, reported on work done while he was with the University of Florida College of Medicine involving a search for the genes responsible for the development of SLE. The studies focused on the analysis of families in which many members have SLE and on the genetic analysis of the mouse models.

Wakeland and colleagues identified the positions of several genes contributing to SLE in mice. They produced a collection of mouse strains, each of which carried one of these genes, and were able to characterize the functional effects that each of the genes has on the immune system. More recently, they identified genes that suppress SLE.

Bone Marrow Transplantation

In a different but related approach, autologous and allogeneic bone marrow transplantation is in the early stages of clinical investigation as therapy for SLE and several other diseases suspected of having an autoimmune pathogenesis. Patients with SLE in whom conventional therapy has failed are potential candidates for this procedure. Several centers in the United States and elsewhere have treated a few patients, and other such programs are in the planning stages. The goal of this treatment is to eliminate disease-causing B and T lymphocytes from the body and reconstitute the bone marrow with cells that are free of disease and function normally.

In autologous bone marrow transplantation, undifferentiated marrow stem cells that are presumed to be free of disease are harvested from the patient's peripheral blood after conditioning with growth factors. The patient is then treated with total-body irradiation or a combination of cytotoxic drugs and antithymocyte globulin aimed at ablating bone marrow and peripheral lymphoid cells. The bone marrow is then reconstituted by reinfusion of the patient's stored stem cells and conditioned with growth factors.

Some researchers believe that the immune abnormalities causing SLE may also extend back to stem cells (at least in some patients) and that allogeneic bone marrow transplantation, although technically more difficult and hazardous than autologous transplantation, eventually may prove to be the favored technique. With this method, stem cells are harvested from a normal, HLA-matched person. After ablation, the cells are transfused into the patient to reconstitute the patient's bone marrow.

At a recent workshop sponsored by the Lurie Cancer Center at Northwestern University in Chicago, Richard Burt, MD, and others reviewed experience with bone marrow transplantation to date in U.S. and European adults and children. The International Bone Marrow Transplant Registry/Autologous Bone Marrow Transplant Registry has served as a data resource center for these efforts. Transplantation has been done in more than 100 patients with nonmalignant disease, including at least 10 patients with SLE. Although it is too early to assess the outcome, some patients have clearly improved and have discontinued therapy with all medications.

Immunoablative Therapy

Robert Brodsky, MD, and his colleagues from Johns Hopkins University are exploring an alternative approach to immune modulation in patients with lupus or other autoimmune diseases, one that they believe will be at least as effective as but less toxic than bone marrow transplantation. Reasoning from an earlier observation that some of the patients with autoimmune aplastic anemia who did well after allogeneic bone marrow transplantation had repopulated their marrow with their own stem cells rather than those of the donor, these researchers and others came to two important conclusions. First, stem cells seem capable of surviving high-dose "ablative" pretreatment with cyclophosphamide. Second, disease remission may be caused by the cyclophosphamide-induced immunoablation itself, with or without marrow transplantation.

Applying this reasoning, several groups now treat autoimmune aplastic anemia by using an immunoablative course of high-dose cyclophosphamide alone. According to Brodsky, many now consider this approach as primary therapy for this disease. More recently, the Johns Hopkins group has extended the use of immunoablative cyclophosphamide therapy to a small number of patients with severe autoimmune diseases, including SLE, with promising results (Ann Intern Med. 1998; 128:1031-5).

Summary

Top Summary

Each of the new approaches to treating SLE offers some hope in the ongoing effort to respond effectively to the challenges of this debilitating and often lethal condition. Research is extremely active and promises to accelerate as more is learned.