The Promise of ‘Oral Tolerance’ in Combatting Disease

Scientists continue to advance the principle of ‘oral tolerance’ which shows potential in treating everything from multiple sclerosis and arthritis.

Published March 1, 2004

By Vida Foubister
Academy Contributor

A regular diet of quarter-pound hamburgers may not do much for your health. Yet could as little as a microgram of orally ingested proteins prevent or treat devastating disease?

For two-and-a-half days, scientists and clinicians from around the world gathered in Mount Sinai Medical Center’s Stern Auditorium to explore this promising approach to human autoimmune disease: Feeding antigens might inhibit subsequent immune responses. The principle, called oral tolerance, holds out hope for such diseases as multiple sclerosis, diabetes and rheumatoid arthritis.

Oral Tolerance: Mechanisms and Applications, held Oct. 23-26, 2003, was the second conference on this potential therapy sponsored by The New York Academy of Sciences (the Academy). The years in between have brought solid evidence for oral tolerance in animal models, but the path to harnessing it in humans remains unclear. By the conference end, discussion had turned from the future of antigen-specific therapy to a debate on the value of advances since the first meeting, back in 1995.

Putting Principles into Practice

Oral tolerance sounds like an ideal mechanism for manipulating human immune responses, where drug safety is a paramount concern. All it takes is ingesting tiny amounts of proteins. As Howard L. Weiner, the Robert L. Kroc professor of neurology at Harvard Medical School, explained, “It’s nontoxic and can be given on a chronic basis.”

Animal models firmly support the potential therapeutic value of this simple approach. Numerous – and highly reproducible – studies have shown that feeding disease-related proteins can suppress disease. However, it has proven difficult to translate this success to the clinic.

Attempts have still to demonstrate that this approach can be used successfully in humans. Among the failures is a well-designed diabetes trial presented in the meeting’s final session that several speakers cited as a particularly “beautiful” study. Even in the early stages of type 1 diabetes, researchers found that oral insulin did not prevent or delay the development of disease.

“It was a very convincing negative study,” said Warren Strober, acting chief of the Laboratory of Clinical Investigation at the National Institute of Allergy and Infectious Diseases and one of the conference organizers. Results such as these are causing researchers to focus their attention on new findings that support and elucidate the underlying mechanisms.

Control of Immunity

Interest was first triggered when scientists found the same proteins that induce disease when injected can act to suppress disease when administered orally. Because autoimmune diseases such as multiple sclerosis and arthritis are characterized by a lack of suppression, it is believed that oral tolerance might prove useful as a therapeutic for these conditions.

There are two ways to induce a tolerant response in animals. First, small doses of antigen – milligram or even microgram amounts – are believed to act locally in the gut through regulatory T cells. Second, larger doses of antigen might get into the systemic circulation. When the proteins in, for example, a hamburger interact with peripheral organs such as the spleen and lymph nodes, they can result in the deletion of T cells that react to these antigens.

A clinical trial involving multiple sclerosis patients found evidence for the first response in humans. Although the trial failed to demonstrate any clinical difference between patients who were fed an antigen and those who were not, regulatory T cells were identified in the fed group.

“It’s proof that at least one of these mechanisms exists in humans,” said Caroline Whitacre, professor and chair of the Department of Molecular Virology, Immunology, and Medical Genetics at The Ohio State University in Columbus. This finding suggests that much of the research presented is important not only in immunology, but also for the elucidation of oral tolerance pathways in humans.

The first two days of the conference focused on different pieces of these developments. It started with new insights into the control of immunity in the gut. Although the field originated with the oral administration of antigens, it has broadened to include nasal administration as well – what researchers call mucosal tolerance.

The Role of the Mucosal Immune System

The keynote address, by Allan Mowat of the University of Glasgow’s Division of Immunology, Infection and Inflammation, discussed how the mucosal immune system interacts with the body’s broader, systemic immune system. Throughout the conference, speakers continued to compare these alternative routes for antigen delivery.

Dendritic cells, which take up antigens and present them to T cells, were discussed in the second session. It’s thought that enhancing their development could induce more regulatory T cells and thus result in an enhanced tolerant response. “There may be factors that are produced by the epithelium that then subsequently drive dendritic cell maturation,” hypothesized Brian Kelsall, an investigator at the National Institute of Allergy and Infectious Diseases, based on his work with reovirus.

New findings on the role of regulatory T cells also generated significant attention. Andrew Caton, a professor at the University of Pennsylvania’s Wistar Institute, explored “how the diversity of self-antigens affects tolerance induction.” He has found that self-antigens stimulate regulatory T cells through high-affinity interactions with antigen presenting cells in the thymus.

Fiona Powrie, who heads an immunology research group at the Sir William Dunn School of Pathology, University of Oxford, has found that purified populations of CD25 positive regulatory T cells with specificity for self-antigens can cure intestinal inflammation in animals. “That has a lot of traction,” said Strober. “If you could generate these cells as part of oral tolerance, you could turn off inflammation.”

Translating to Humans

A later session turned again to animal studies. It “focused on mechanisms: what cell is presenting the orally or nasally fed antigen, what happens to the cell it is presented to, what are the important molecules for those presentations to take place, what are the homing molecules to take cell populations where they need to go, what are some of the enzymes that are important for promoting tolerance versus immunity,” summarized Whitacre.

The effort to prove oral tolerance in humans has generated considerable interest beyond scientific circles. One story, published in May 2002, drew particular attention. Human Trials: Scientists, Investors, and Patients in the Quest for a Cure features Weiner himself as the field’s unwavering champion. In this book, Susan Quinn chronicles the efforts of the company Weiner founded, AutoImmune, Inc., to develop the concept of oral tolerance into a drug.

AutoImmune’s efforts, however, have not succeeded thus far. Despite the depth of the new findings into the mechanisms of oral tolerance, therefore, the conference’s closing session returned to the challenge of demonstrating success in the clinic. “It’s a testament to people’s tenacity that we’re all here today believing that we might be able to make something of it,” remarked Norman A. Staines, a professor in the Infection and Immunity Research Group at King’s College London.

Promise, Tenacity, and Uncertainty

Often during the conference, the sheer drama of promise, tenacity and uncertainty could be felt. One such moment came during the concluding presentation, by Charles O. Elson, a professor of medicine at the University of Alabama at Birmingham. “As far as getting insight into the fundamental processes that are involved” in oral tolerance, Elson said, “I don’t believe we’ve advanced an awful lot.”

“I can’t disagree more,” Strober hurried to say after the meeting. “We have made enormous progress.” As more is learned about regulatory T cells, it is inevitable that scientists will learn how to induce oral tolerance in a way that allows therapeutic effects, he continued. With each new study, researchers are learning more about how these T cells are generated, expanded and maintained. “The ‘big news’ from this conference is that we are well on our way to this goal.”

Or was uncertainty itself the big news? In the final session, Lloyd Mayer, also one of the conference organizers, addressed those who had presented data from clinical trials in humans. Mayer, professor and chairman of the Immunobiology Center at Mount Sinai, asked “how each one of you decided on the dosing regimen and the scheduling of your oral feeding.” His question pointed to the difficulty of translating doses from animals to man. As he argued, “if we move forward doing human trials with doses that are generated by hand waving, we’re going to wind up with conflicting and variable results.”

Understanding the Mechanisms

How did the field get to this point? Oral tolerance, strictly defined as the active non-response to a foreign protein administered through the mucosal route, was initially described in the early 1900s. The field experienced resurgence in the late 1970s, and studies over the next decade suggested that there are “cells acting to suppress immune responses both locally and systemically,” explains Mayer. At the time of the Academy’s first conference in 1995, the field was exploding. “When we began working on oral tolerance, we thought that it would be as simple as feeding an antigen and getting positive results in people,” said Weiner, one of the conference organizers. “As we all know, that hasn’t happened.”

What has been learned since the promise in animals was first reported? Essentially, everything reported at the conference about the mechanisms underlying oral tolerance in animals was unknown nine years ago. This includes basic information about the mucosal environment in the gut, the processing of antigens by dendritic cells, and the generation and role of regulatory T cells, as well as advances in animal models of oral tolerance.

It is now known, for example, that regulatory cells can work in what’s called a bystander fashion. This means that “they don’t have to be responsive to precisely the right protein. If it’s a protein in the same organ it’s probably good enough,” explains Whitacre.

Some of the cytokines that are involved in shutting down inflammatory responses have been defined, elucidating the mechanism by which regulatory cells might work. “What you have in oral tolerance is the induction of T cells that produce transforming growth factor beta (TGFß), which then induces other regulatory cells to produce interleukin 10 (IL-10),” said Strober, summarizing the current thinking on regulatory T cell function. “These cells could downregulate inflammatory processes.”

More Work Needed

The final conference session focused on the results of several clinical trials. Apart from positive results in smaller phase I and phase II studies, “everybody had data that showed it did not work, which basically we knew, but it was sobering to see it in black and white,” said Mayer, referring to the large-scale phase III studies that were presented. “It was depressing. Oral tolerance is not ready for prime time in humans.”

“At first I was really disappointed,” Whitacre admits. “I wanted one of these trials to be overwhelmingly positive and it just wasn’t.” But, she adds, “it’s really important to know what doesn’t work.”

One common theme was that antigen feeding might be a good adjunct therapy, in combination with other drugs or treatments. In addition, some form of mucosal adjuvant might be required. “I’m convinced that, with careful work, we’ll ultimately get mucosal tolerance to be effective in human diseases,” said Weiner.

So what needs to be done for oral tolerance to succeed? Mayer would like to see all the mechanistic studies that have been done in animals duplicated in humans. Ultimately, the goal is to identify the cells that are involved in tolerance induction and determine the antigen form, regimen and dose required for suppression to occur. This work still lies ahead.

Also read: Promising Immunotherapies over Toxic Chemotherapies