Autoimmunity is the abnormal response of the immune system against host tissue or antigens. The breakdown of the mechanisms of self-tolerance that normally protect an individual from potentially self-reactive lymphocytes results in autoimmune disorders. Until the 1960s it was believed that the immune system possessed a method of eliminating all self-reactive lymphocytes during their development and that failure of the body to rid itself of such self-reactive lymphocytes resulted in autoimmune disorders. Since that time, evidence has suggested that not all self-reactive lymphocytes are destroyed during B-cell and T-cell maturation. Instead these circulating self-reactive cells are regulated through clonal anergy or suppression. Thus, in cases where this regulation goes awry, humoral or cell-mediated responses against self-antigens follow.
Autoimmune diseases can be categorized as organ-specific or systemic. Organ-specific diseases, such as Hashimoto’s thyroiditis, occurs when autoantibodies and sensitized TDTH cells specific for thyroid antigens are produced. In organ-specific diseases, the immune response is directed to a target antigen unique to one organ or gland. For example, Hashimoto’s thyroiditis causes a goiter within the thyroid gland. Unlike organ-specific diseases, systemic autoimmune diseases affect a number of organs and tissues. Two examples of disease in this category are rheumatoid arthritis and multiple sclerosis. Rheumatoid arthritis arises when autoantibodies called rheumatoid factors react with normal immunoglobulin. The disorder manifests itself in connective tissue throughout the body. Similarly, multiple sclerosis affects the central nervous system and is the consequence of autoreactive T cells that participate in the formation of lesions on the myelin sheath of nerve fibers.
Hashimoto's Thyroiditis -- Fas Expression in Inflammation
Kristin Collins
Hashimoto's Thyroiditis (HT) is an autoimmune disorder in which apoptotic cell death of thyroid tissue outweighs its replacement. According to the following experiments performed by Carla Giordano, Giorgio Stassi, Ruggero De Maria and colleagues, apoptosis of thyrocytes is mediated by the interaction of Fas (CD95/APO-1) and its ligand (FasL). Normal thyrocytes do not express Fas. The expression of Fas on the cell surfaces of HT thyrocytes was determined by immunohistochemistry of frozen thyroid sections and two-color flow cytometric analysis of dispersed thyroid follicular cells, obtained by enzymatic digestion.
Suspicious that Fas expression may be a result of the intense inflammatory response in HT glands, normal thyrocytes were exposed to inflammatory cytokines. Only one cytokine, Interleukin 1B (IL-1B), was present in HT glands and possessed the ability to induce Fas expression in normal thyrocytes. IL-1B-induced thyrocyte Fas expression resulted in apoptosis of normal thyrocytes, and could be prevented by cyclohexamide or actinomycin D. This suggests that Fas is functional and requires the synthesis of new RNA and protein.
Unexpectedly, FasL mRNA was present in both autoimmune and nonautoimmune conditions. Because of this, IL-1B-mediated induction of Fas and not Fas/FasL interactions were believed to be the critical limiting factor for thyrocyte destruction. Furthermore, flow cytometry of propidium iodide labeled thyrocytes, ethidium bromide-acridine orange staining and fluorescence microscopy analysis indicate administration of monoclonal antibodies that block Fas on thyrocytes completely suppressed IL-1B-induced apoptotic death. This mechanism may prove useful for preventing apoptosis of thyrocytes and thus deterrence of Hashimoto’s Thyroiditis which leads to clinical hypothyroidism.
Giordano, C., Stassi, G., De Maria, R., et al. (1997). Potential Involvement of Fas and its Ligand in the Pathogenesis of Hashimoto’s Thyroiditis. Science. Feb. 960.
Rheumatoid Arthritis - Cytokine Therapy and Biological Response Modifiers
Gregory Melton and Troilus Plante
Rheumatoid Arthritis is an autoimmune disease that causes a terrible amount of pain and decreases the patient’s life expectancy by an average of over ten years. It is characterized by similar symptoms of osteoarthritis, but is caused by a very different mechanism.
The patient with rheumatoid arthritis presents with severe joint pain with redness and swelling, which at times can be crippling. Patients complain of decreased utility of the limbs, often with the slightest movement causing intense pain. Typically, current pain control measures a relatively ineffective in alleviating the discomfort.
Until recently, little was known about the mechanisms involved with the disease. Researchers were able to aspirate out some of the synovium and found that there were increased numbers of macrophages and fibroblasts in the tissues of patients with rheumatoid. Why they were there was still a mystery.
Another group of researchers discovered that certain cytokines were elevated in these tissues as well. Most markedly, interleukin-1 and tumor necrosis factor alpha (TNF-a). These signaling molecules were believed to be responsible for the chemoattractant effect causing increased levels of macrophages and fibroblasts (Firestein and Zvaifler, 1997). This influx of cells as well as other properties of the cytokines are believed causatory for the inflammation of the joints.
In testing this hypothesis, Moreland and colleagues stated that if this is the case, then decreasing the levels of TNF-a should be beneficial to these patients. Using SCID mice they were able to develop a monoclonal antibody for TNF-a. This antibody was affixed to an IgG1 Fc region to form the treatment TNF-a:Fc antibody. The treatment given to patients involved different dosages of this antibody with soluble TNF-a receptor proteins (Moreland et al., 1997). Binding increased levels of the cytokine in this manner should alleviate some of the symptoms.
As it turns out, this treatment is effective for reducing the inflammation and pain associated with rheumatoid. Seventy-five percent of the patients receiving a certain dosage reported dramatic reductions in inflammation and pain over the three month trial (Moreland et al., 1997). An additional plus to the therapy was that there were relatively few side effects. To date the most effective clinical therapy is a cancer drug called methotrexate. It is effective, however it can have some disturbing side effects, and we are unsure of what long term exposure might cause.
The focus on rheumatoid arthritis has taken a shift toward cytokine therapy. Though treatments are still in the testing phase, they seem to have strong results. The only downside is that we are unsure if they are simply alleviating the symptoms or attacking the cause. However, if we were patients with this condition, the only important factor would be that it works.
A new wave of therapies called biological response modifiers have been created in an attempt to not only alleviate symptoms, but slow or stop the progression of arthritis. One way that scientists are trying to accomplish this is by attempting to treat rheumatoid arthritis with a monoclonal antibody which targets CD4 receptors on T cells. This monoclonal antibody is named IDEC- CD9.1 and is manufactured by IDEC Pharmaceuticals Corp. and SmithKline Beecham. It binds to CD4 receptors on T helper cells, temporarily disabling (but not destroying) them. The inhibition of T helper cells slows down the body's autoimmune response which produces joint destruction.
Another approach to the treatment of rheumatoid arthritis is the development of a recombinant human Interleukin 1 receptor antagonist (rhIL - 1ra) by Amgen, Inc. The rhIL -1ra inhibits Interleukin 1, a cytokine which triggers a cascade of cartilage and bone destruction enzymes, by binding Interleukin 1 cell receptor sites. This interferes with the cytokine’s ability to bind target cells and slows the destructive inflammatory response responsible for bone and cartilage deterioration.
Firestein, G.S., MD and Zvaifler, N., MD. (1997). Anticytokine Therapy in Rheumatoid Arthritis. New England Journal of Medicine. Vol. 37. 195-197.
Moreland, L.W., Baumgartner, S.W., Schiff, M.H., et al. (1997). Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. New England Journal of Medicine. Vol. 337. 141-7.
Skolnick, Andrew, JAMA, January 22/29, 1997 - Vol. 277, No. 4
Multiple Sclerosis - T Cell Vaccination, 4-Aminopyrimidine and
Transplantation
Stephanie Harmon and Stefan Tenzer
As the most common cause of chronic neurological disabilities in young adults (particularly women), multiple sclerosis (MS) affects nearly 250,000 people in the United States alone. It is a dreadful disease that that has eluded scientists for centuries. However, recent advances in the understanding of MS pathophysiology are providing promising new approaches to the treatment of the disease (Perlmutter, 1995). Still, because of its devastating effects and because of the enormous difficulty in successfully attacking such an autoimmune disease, pessimism pervades the community of patients and clinicians who have or treat the disease.
Treatment of Multiple Sclerosis can be divided into three categories: primary treatment to arrest the underlying disease process, secondary treatment to ameliorate the symptoms, and tertiary treatment to prevent long-term complications. A few current research strategies aimed at arresting the disease process and relieving MS symptoms include T cell vaccination, the use of 4-aminopyrimidine, and myelin-producing cell transplantation.
T cell vaccination is a relatively new treatment that is at the forefront of clinical interest. It has been used successfully in laboratories to treat MS-like disease. The principle of the vaccination is derived from traditional microbial vaccination, treating the myelin-attacking cells as pathogens (i.e. like viruses or bacteria). The cells are isolated from the blood, inactivated by irradiation, and injected as vaccine to sensitize the immune system. In one of the pilot clinical trials, conducted by the Dr. L. Willems Institute, Belgium, a cell vaccine was prepared from a person’s own myelin-attacking cells. The results of this trial indicated that the procedure was safe and had no adverse effects. Also, a three year evaluation pointed to significantly reduced relapse rates compared to rates in control patients. Some of the patients were relapse-free over the three years. Presently, Baylor College of Medicine is using this new form of immunotherapy for its phase I study and is preparing for a phase II study in 1998. And although the effectiveness of this treatment will need to be proven to a greater degree of statistical importance, T cell vaccination appears to be quite promising (Baylor College of Medicine, Neurology Research, 1997).
Another area of research into MS is examining the effectiveness of 4-aminopyrimidine (4-AP) in improving MS symptoms. 4-Aminopyrimidine is a potassium channel blocker which has been demonstrated to increase nerve conduction and prolong the duration of nerve action potentials in demyelinated axons (Perlmutter, 1995; Haverkamp, Appel, and Wong, 1997). Recently, Dutch investigators have studied the competence of 4-AP in ameliorating symptoms. Their results clearly confirm that patients show improvement with the chemical compared to control patients (Perlmutter, 1995). Until now, the main emphasis in developing new treatment strategies for MS have been mostly anti-inflammatory, designed to reduce exacerbations or extent of acute attack. 4-Aminopyrimidine attempts to reestablish function in demyelinated nerve pathways whose conduction abilities are compromised.
Finally, other research groups are investigating the possibility of transplanting myelin-producing cells in animals. Researchers at the University of Wisconsin and the University of Lund, Sweden, are trying to develop an immortal cell line of human oligodendrocyte precursors (OP), the equivalent of rat CG4 cells, that have been proven effective in remyelinating animal central nervous systems. So far they have been successful in growing human glial cells in culture. If from these glial cultures they can develop pure OPs, the OPs will facilitate integration into the central nervous system with less likelihood of rejection, as well as ensure that transplanted cells are pathogen-free. Hopefully the researchers will reach the stage of transplantation so that they can test the cells for remyelinating and migratory capabilities (The Myelin Project, 1997).
Baylor College of Medicine. (1997). T Cell Vaccination: New Treatment
for Multiple Sclerosis.
http://www.bcm.tmc.edu/neurol/research/ms/ms14.html.
Haverkamp, L.J., Appel, V. and Wong, E. (1997). 4-Aminopyrimidine in
Multiple Sclerosis.
http://www.bcm.tmc.edu/neurol/research/ms/ms9.html.
The Myelin Project. (1997).
http://www.myelin.org .
Perlmutter, D. MD. (1995). Fatigue in Multiple Sclerosis. Townsend Letter for Doctors and Patients. Nov. 2-6.
Weinreb, H.J. MD. (1997). Treatment of MS.
http://aspin.asu.edu/msnews/weinrebg.html.
Zhang, J. MD., Ph.D. (1997) Autoreactive T cells in Multiple Sclerosis:
Pathologic Relevance and Therapudic Application.
http://www.bcm.tmc.edu/neurol/research/ms/ms12.html.