Supplement: Fine-Tuning Our Defenses

1 Nonetheless, treatment probably won't involve blocking any one pathway entirely. Instead, the best treatments will make slight modifications in several places. "The future is really novel pathways - to interact with novel pathways that offer the opportunity for different types of responses," says Brian Kotzin, vice president of medical sciences at Amgen in Thousand Oaks, Calif. Billions of Data Points Despite the potential undesirable consequences of shutting down problematic genes, a better understanding of the genetics of autoimmunity will certainly play a key role in developing future therapies. For example, identifying type 1 diabetes (T1D) risk at birth is certainly within reach, says George S. Eisenbarth, executive director of the Barbara Davis Center for Childhood Diabetes at the University of Colorado. "We can now identify a risk that looks like it's going to exceed 80%." Important high-risk genotypes include variants of genes for human leukocyte antigens (HLA). In particular, these include the HLA-DR and HLA-DQ genes, as well as other major histocompatibility complex (MHC) loci, according to Eisenbarth. In part, he found this correlation from the Diabetes Autoimmunity Study in the Young (DAISY). For that study, Eisenbarth and his colleagues used umbilical cord blood from 30,000 newborns to genotype the HLA genes, and then tried to connect those to alleles conferring increased risk. From this work, says Eisenbarth, "Basically, we can identify the risk at birth, and then we follow for the development of autoantibodies."2 Once autoimmunity appears, treatment begins. Moreover, adds Eisenbarth, this treatment begins early enough to prevent the life-threatening buildup of ketones in the blood, which is often the first sign of T1D in young patients. He and his colleagues have found that screening for T1D and treating it early results in a less-severe onset of the disease and a milder clinical course in the first year after diagnosis. The next step will be finding therapies that actually prevent the autoimmune attack from happening in the first place. The genetic basis of other autoimmune diseases is also becoming increasingly clear. For example, Hafler and his colleagues collected eight billion data points from the genomes of thousands of patients with multiple sclerosis (MS) and thousands of controls, and they are already finding genetic links between susceptibility to MS, lupus, and inflammatory-bowel disease.3 "I think the root of the disease is genetic susceptibility, and understanding that is going to be the key to future treatment," says Hafler.4 Restoring Tolerance Regardless of a person's genetic makeup, central and peripheral tolerance play crucial roles in immunity. Briefly, central tolerance removes so-called autoreactive T cells during development in the thymus, and the bone marrow shuts down autoreactive B cells. Peripheral-tolerance mechanisms clean up the escapees, the potentially self-reactive components of the immune system that get into the blood and lymph. Still, some autoreactive cells get away. Failure of central and peripheral tolerance represents a key step in developing autoimmunity. Consequently, scientists seek ways to restore tolerance. If this could be done, autoimmunity could be stopped. Nonetheless, turning tolerance back on fails more than it works. If we got rid of these involved with autoimmunity, then we're exposing ourselves to the risk of other infections. It's a typical yin-yang in medicine and in life. Still, some research lends encouragement. For example, Arnold E. Postlethwaite, associate program director of the Center of Excellence in Connective Tissue Diseases at the University of Tennessee in Memphis, recently completed a study on patients with scleroderma. He and his colleagues gave these patients oral doses of type-I collagen. The results, he says, look promising, at least for patients who have had the disease for 10 years or longer. Part of the benefit of Postlethwaite's study could come from the oral-delivery mechanism. Half of the immune cells in the body are located in the gut-associated lymphoid tissue. So in people with autoimmune disease, giving the right compound orally might turn tolerance back on. In fact, other compounds, such as Cox-2 inhibitors, taken orally can enhance tolerance. These compounds block the Cox-2 enzyme, and that stops the production of prostaglandins, which contribute to the pain and swelling experienced in some autoimmune diseases, such as arthritis. Postlethwaite is also considering a different delivery mechanism. He and his colleagues are developing molecules containing epitopes involved in scleroderma that could be delivered nasally. Some scientists hope that oral and nasal approaches will also trigger tolerance in other autoimmune diseases. For example, researchers funded by the New York City-based Juvenile Diabetes Research Foundation (JDRF) are exploring the use of oral and nasal insulin to induce tolerance for people at high risk for T1D. When it comes to making diseases go away, though, people usually think of vaccines. Lawrence Steinman, chair of the interdepartmental program in immunology at Stanford University, argues that DNA vaccines could wipe out autoimmune disease, just as immunization vanquished polio in the 1950s. Steinman's company, Palo Alto, Calif.-based Bayhill Therapeutics, is running a Phase II clinical trial of a DNA vaccine in patients with MS. The compound being tested consists of DNA engineered from a myelin protein in which cease-fire flags replace the signals that usually cause autoimmunity. Steinman and his colleagues are also launching a trial of a vaccine consisting of engineered-insulin DNA for T1D. In addition, BioMS in Edmonton, Canada, is running a Phase III trial of a vaccine for MS. "That's definitely going to be the future - very specific treatments for autoimmune disease, just as we have very specific vaccines to treat infectious disease," says Steinman. Tackling T cells Many components play a role when an antigen-presenting cell (below) activates a T-cell (above). In autoimmunity, these components serve as potential drug targets. For example, molecules can bind to CD3, which blocks T-cell activation. The autoimmune response offers many potential targets. For example, tumor-necrosis-factor (TNF) blockers wipe out this key inflammation-producing cytokine. Anti-TNFs made a major advance in treating rheumatoid arthritis (RA). Moreover, ever-finer targeting of cell-to-cell signaling molecules is a hot area of investigation. Lloyd F. Mayer, director of the Center of Immunobiology at Mt. Sinai School of Medicine in New York City, argues that such approaches will be the key to future treatments. Still, perhaps the hottest topic in autoimmune therapy these days is regulatory T cells, or Tregs. "Transplantation, treatment of cancer, autoimmunity - they all seem to show that regulatory T cells play a role," says Zoltan Fehervari, a postdoctoral fellow at the University of Cambridge. "Given that, it would seem that there's a huge potential for them."5 Ethan Shevach, chief of the cellular immunology section in the Laboratory of Immunology at the NIH's National Institute of Allergy and Infectious Diseases agrees with the excitement over Tregs, but he and Fehervari both point out some crucial constraints. For one thing, Tregs "don't like to be expanded in culture," says Shevach. For another, the best marker for Tregs, the transcription factor fox p3, is expressed in the nucleus, which makes it basically impossible to see without destroying the cell. Nonetheless, strategies for boosting Treg function are already in clinical trials, and have shown promising results. Other aspects of T cells also provide potential therapeutic targets. For example, the T-cell receptor includes a protein called CD3. Blocking CD3 can prevent activation of autoreactive T cells; this blocking also appears to help boost the function of Tregs. Lucienne Chatenoud of the Hospital for Sick Children in Paris and colleagues gave 80 newly diagnosed T1D patients the anti-CD3 antibody ChAglyCD3, which Herman Waldman and Geoff Hale developed at Oxford University. ChAglyCD3 reduced the patients' needs for insulin for 18 months while preserving residual beta-cell function. "For the first time, one could see something like durable remission or a delay in disease progression. You slowed everything down," says Jeff Browning, senior director of immunobiology at Cambridge, Mass.-based Biogen-IDEC, who was not involved in the research. Such drugs are thought to work by putting CD3 T cells out of circulation for several weeks by clearing them from the pancreas and pushing them into the peripheral lymph nodes. These drugs also induce the generation of new Tregs, explains Teodora Staeva-Vieira, program director for immunology at JDRF, which is funding CD3 research. Other researchers are investigating vaccine-like approaches that take renegade Tregs out of commission. For example, some scientists try this by using small peptides that match a T-cell receptor found at much higher frequency in patients with a particular disease. The Immune Response Corp., based in Carlsbad, Calif., has developed NeuroVax to treat MS using this approach. This drug is in Phase II trials. The list of T-cell approaches goes on. For instance, Treg action might increase by incubating T cells with fox p3, which appears to turn ordinary T cells into Tregs. In addition, drugs based on CTLA4Ig, which modify T-cell activation by acting on the CD28 receptor and are known as selective costimulation modulators, also offer great potential in autoimmune therapy, according to Harvard's Hafler. The Food & Drug Administration approved the first drug of this type, Bristol-Myers Squibb's Orencia (abatacept), in late 2005 for treating RA. The disastrous results of a phase 1 trial...illustrated the risks that always accompany efforts to alter immune system function. In order to further an autoimmune attack, T cells must migrate to the target tissue. Consequently, one new strategy for fighting autoimmune disease involves halting this migration. For instance, Stanford's Steinman invented Tysabri (natalizumab), which is a monoclonal antibody that targets a4b1 integrin. This drug treats MS by blocking the movement of lymphocytes from the bloodstream to inflamed tissue, and it is highly effective. Nonetheless, it was pulled off the market in February 2005 (three months after the FDA approved it) when a handful of patients developed progressive multifocal leukoencephalopathy, an extremely rare but devastating infection of the central nervous system, and some died of the disease. The FDA has since allowed the drug back on the market with stringent safety provisos. Increasing Concerns over Safety Last year, the disastrous results of a Phase I trial of a drug intended to treat B-cell chronic lymphocytic leukemia and RA starkly illustrated the risks that always accompany efforts to alter immune-system function. Wurzburg, Germany-based TeGenero's CD28 "superagonist" TGN1412 was developed to boost Treg function. It might have done so, but it also induced a massive autoimmune attack in Phase I-trial volunteers minutes after they received the injection. Six wound up in the hospital, some with multiple organ failure. Much lower-tech, and safer, approaches should not be ignored, notes Betty Diamond, a professor of medicine and microbiology at Columbia University. For example, she says, evidence is mounting that vitamin D can help reduce autoimmunity while restoring normal protective immune-system function. Statins have also shown promise for treating autoimmune disease. Steinman argues that more effort should be put into understanding drugs with fairly good safety profiles and modest benefits for treating autoimmunity than "highly expensive and potentially dangerous approaches like Tysabri." Nevertheless, Diamond, Steinman, and many of their colleagues are confident that the Holy Grail of autoimmune therapy - an antigen-specific approach that restores tolerance - is achievable. The current period is "an interlude while we get smarter," says Diamond, "which I'm confident that we can and will do." References 1. M. Feldman et al., "Design of effective therapy for human autoimmunity," Nature, 435:612-9, 2005. 2. G. Eisenbarth et al., "Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY)," J Clin Endocrinol Metab, 89:3896-902, 2004. 3. P.L. De Jager et al., "The role of inflammatory bowel disease susceptibility loci in multiple sclerosis and systemic lupus erythematosus," Genes Immunol, 7:327-34, 2006. 4. D.A. Hafler et al., "Applying a new generation of genetic maps to understand human inflammatory disease," Nat Rev Immunol, 5:83-91, 2004. 5. Z. Fehervari et al., "Peacekeepers of the immune system," Sci Am, 295:56-63, October 2006.

Supplement: Fine-Tuning Our Defenses

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