Oral Antigen Tolerization in Multiple Sclerosis

The myelin sheath is a critical structural constituent of the nervous system. It acts as an electrical insulator for the �wires� (nerve axons) that carry electrical signals from the brain to the body. Multiple Sclerosis (MS) is an inflammatory disease in which the body�s own immune system attacks this protective, insulating tissue. The resulting damage to the myelin appears in the form of �plaques� or �lesions� appear in seemingly random areas in the central nervous system (CNS � the brain and spinal cord).

While no one knows what causes this derangement the immune system, we do know that the autoimmune attack is the fundamental driver of the disease.  The immune system�s infiltrating T-cells somehow mistake myelin basic protein (MBP � the immunologically-active protein which comprises 30% of the polypeptides of CNS myelin) for a foreign invader, and mount a destructive campaign to eradicate it.  This constant inflammatory assault leads to demyelination (the loss of the myelin sheath from the nerves) and sometimes other forms of nerodegeneration.

As the disease progresses, the body�s white matter becomes inflamed, neurons die, and the glial cells that surround and nourish neurons either wither away or multiply pathologically, leading to partial or complete loss of functions controlled by the brain or spinal cord. Initial symptoms commonly include weakness, numbness, tingling, sphincter disturbances, and spastic weakness or paralysis of the legs. Victims suffer frequent relapses and remissions that lead to increasing disability, weakness, visual impairment, spasticity, and urinary incontinence. Approximately 20% of patients with multiple sclerosis experience truly aggressive, debilitating symptoms, while the remainder may live a more or less normal existence.

In the past, treatment for MS was limited to potentially toxic immunosuppressive drugs such as steroids and cyclophosphamides, along with a patchwork of drug �band-aids� for some of the individual symptoms, such as vertigo, fatigue, and depression. There is no specific long-term benefit of these drugs: they may provide symptomatic relief, but they cannot prevent further relapses.  More recently, a new group treatments, known as the �ABCR� (Avonex, Betaseron/Betaferon, Copaxone and Rebif) drugs, have resulted in more meaningful treatment for the disease process. But a cure remains elusive.

Oral Tolerance

When taken orally, many proteins and peptides are not destroyed by the digestive system, but remain intact and immunologically active. As a result, they are able to interact with the gut-associated lymphoid tissue (GALT), which makes up about 70% of the body�s immune reactive cells. This appears to cause the GALT to recognize the antigen as a common constituent of the environment, the constant immunological attack of which would be ruinous to the body � as, indeed, is the case in MS.

The result is a change in the way the immune system as a whole responds to those peptides. At low doses, oral antigens activate regulatory T cells that secrete anti-inflammatory messenger-molecules (cytokines) such as transforming growth factor-beta (TGF-beta) and interleukins 4 and -10 (IL-4 and IL-10). At higher doses, oral antigens initiate a cascade in which the body actually deletes the T-cells specific for the fed antigen. These multiple mechanisms most probably evolved to maintain tolerance to the large variety of proteins in the diet: otherwise, the immune system would be engaged in a neverending war against the food in the intestinal tract and the systemic circulation, leading to secondary malnutrition and pathological chronic inflammation.

Oral tolerization was first demonstrated in by researcher HG Wells in 1911, who showed that feeding guinea pigs egg protein could prevent the sudden, severe, potentially life-threatening allergic reaction to injections of the same proteins. But in recent years, the lessons of oral antigen tolerization have begun to be applied to autoimmune diseases, with successful preliminary studies using type II collagen in rheumatoid arthritis, insulin in type I (autoimmune) diabetes, and retinal soluble antigen (S-Ag) in uveitis.  Among the most promising of these therapies is the use of oral myelin and myelin basic protein as an oral tolerization therapy for MS.

Oral Myelin in Multiple Sclerosis

The specificity of the orally-induced tolerance to MBP has been found to be strikingly species-dependent. For example, feeding rats MBP from the guinea pig or human cadavers is effective in protecting against experimentally-induced MS � yet attempting to orally tolerize rats against their own, rat-type MBP consistently fails. Bovine spinal myelin has been shown to be a good choice for human usage.

Following numerous successful animal experiments, phase I/II clinical trials conducted in humans throughout the 1990s provided exciting evidence for the effectiveness of oral antigen therapy in MS. In the first of these trials, Weiner et al administered either a 300 milligram bovine myelin supplement or a placebo protein to 30 relapsing-remitting MS victims for one year. Users of oral myelin suffered only half the rate of major attacks of the controls. 

In open-label continuation of this study, 16 patients either took up, or continued to take, oral bovine myelin supplements for up to three years, being examined every three months for their flareup rate and their functionality. While using the bovine myelin supplement, MS victims� flareup rate was cut by more than two thirds, from an average of 1.6 flareups over each of the two years before taking the supplement to just 0.5 flareups per annum while taking it.

In a series of related studies, researchers were able to show the immunological basis of these results. These trials confirm that, when you take an oral myelin supplement, intact MBP appears in the your circulation. More importantly, people suffering with MS who take bovine myelin supplements experience the production of protective T-suppressor cells that specifically recognize MBP. These T-suppressor cells secrete the anti-inflammatory TGF-beta 1. These responses are consistent with what�s seen in animal models of MS, where oral myelin tolerization  successfully treats the disease.  No such changes are seen the group not taking myelin. Related approaches, using vaccination with the autoimmune T-cells themselves, T-cell receptor peptides, or Cop-1 (a synthetic analog of MBP), have also been shown to be effective, and support the oral tolerization approach.

Unfortunately, the clinical trials came to an end in the late 1990s, after the placebo group in a large, double-blind, controlled trial showed such remarkable progress that it became impossible to statistically evaluate the value of the oral myelin supplement. Still, the raw data from the trial revealed some remarkable findings.  For one thing, the fall in attack rate in patients taking the myelin supplement was as or more impressive than that seen with any of the �ABC� drugs. The study also showed that MS sufferers who added oral myelin to Betaseron therapy had fewer attacks than those taking Betaseron and placebo.

Meanwhile, drug manufacturers seem to have realized that their ability to profit from oral myelin therapy would be limited, because as a dietary supplement they would never be able to impose restrictive patent protection on its use. Instead, pharmaceutical companies have funded subsequent trials using synthetic, patentable analogs or fragments of bovine myelin, such as epitope P85 VVHFFKNIVTP96 and MBP8298.

Additionally, the outbreak of the bovine spongiform encephalopathy (BSE � �mad cow disease�) epidemic in Europe in the 1990s led to reluctance to use nervous tissues as part of a therapy. Now that the nature of the disease is better understood, however, all risk of BSE can be eliminated through the use of supplements derived from lyophylized spinal extract from free-range, pasture-fed, New Zealand or Australian livestock, which can be absolutely guaranteed to be free of the infectious prions that cause the disease.

The relentless drive of the pharmaceutical giants for exclusive control over their products means that the large-scale trials required for oral myelin tolerization to be approved by national medical authorities are unlikely to ever be completed. But the choice to pursue this option is available to individuals in consultation with their doctors now, in the form high-quality bovine myelin supplements.

References

Weiner HL. Oral tolerance for the treatment of autoimmune diseases. Annu Rev Med. 1997; 48: 341-51.

Fukaura H, Kent SC, Pietrusewicz MJ, Khoury SJ, Weiner HL, Hafler DA. Induction of circulating myelin basic protein and proteolipid protein-specific transforming growth factor-beta1-secreting Th3 T cells by oral administration of myelin in multiple sclerosis patients. J Clin Invest. 1996 Jul 1; 98(1): 70-7.

Hohol MJ, Khoury SJ, Cook SL, Orav EJ, Hafler DA, Weiner HL. Three-year open protocol continuation study of oral tolerization with myelin antigens in multiple sclerosis and design of a phase III pivotal trial. Ann N Y Acad Sci. 1996 Feb 13; 778: 243-50.

Whitacre CC, Gienapp IE, Meyer A, Cox KL, Javed N. Treatment of autoimmune disease by oral tolerance to autoantigens. Clin Immunol Immunopathol. 1996 Sep; 80(3 Pt 2): S31-9.

Weiner HL, Mackin GA, Matsui M, Orav EJ, Khoury SJ, Dawson DM, Hafler DA. Double-blind pilot trial of oral tolerization with myelin antigens in multiple sclerosis. Science. 1993 Feb 26; 259(5099): 1321-4.