'Inverse vaccines' could treat autoimmune disease –
from multiple sclerosis to celiac disease
C. Arnold
Nat Med 2024 Vol. 30 Issue 5 Pages 1218-1219
Synthetically glycosylated antigens for the antigen-specific suppression of established immune responses
A. C. Tremain, R. P. Wallace, K. M. Lorentz, T. B. Thornley, J. T. Antane, M. R. Raczy, et al.
Nat Biomed Eng 2023 Vol. 7 Issue 9 Pages 1142-1155
Introduction:
Of the many mysteries associated with multiple sclerosis two are especially relevant: 1) is MS the result of an abnormality in a person’s immune system or is the immune system responding to changes already present in a susceptible person’s central nervous system? and 2) what stimulates the immune system to attack the central nervous system?
We do know that the immune system plays a prominent role in the disease and that persons with MS have prominent immune responses to multiple proteins of myelin, the material that surrounds the nerve fibers (axons) of nerve cells (neurons). It is this immune response that results in myelin destruction, the death of neurons, and of the cells that make myelin, the oligodendrocytes. However, the patterns of response to myelin proteins vary greatly among persons with MS, suggesting different pathways to tissue damage.
Current disease-modifying therapies for relapsing forms of multiple sclerosis exert their beneficial effects by changing a person’s immune system. However, these drugs cause broad effects on the immune system that do not directly relate to changes specific for MS. As a result there are increased risks of significant side effects, such as increased susceptibility to infection and possibly to cancer. To address these issues, the concept of “inverse vaccines” is again being studied.
Key Points:
1. For over 100 years vaccines have been used to induce immune responses to a particular protein or antigen with the intent of preventing infection with specific bacteria, parasites or viruses.
2. In the late 20th century scientists learned that it was also possible to “turn off” the immune system in an antigen-specific fashion via a technique called “immune tolerance.”
3. Immune tolerance can be achieved in multiple ways. One is to overwhelm the immune system with large amounts of antigen (“high dose tolerance”) The other is to induce minimal immunes response with repeated administrations of very low doses of an antigen, gradually “teaching” the immune system to ignore the antigen (“low dose tolerance”). A third way is by the introduction of the antigen to the immune system in a way that results in the production of anti-inflammatory or immune regulatory cells that decrease the activity of the immune system to that antigen. Such an approach has been called “inverse vaccination”.
4. As noted above, persons with MS have increased immune responses to proteins of central nervous system myelin. In particular they have immune responses to the protein myelin basic protein. Such responses are not found in all persons with MS, with responses to multiple other proteins of myelin and to proteins of the Epstein-Barr virus also found.
5. There was great success in treating an animal model of MS, experimental autoimmune encephalomyelitis (EAE) with inverse vaccination-induced immune tolerance. This led to multiple clinical trials of vaccination in persons with MS, despite the diversity of immune responses to proteins of myelin and viruses in such individuals. Summaries of these attempts are presented in these papers. Reduced antibody levels to the inciting antigen were noted in several of these trials, with a reduction in new central nervous system lesions on MRIs, but no clinical effects were observed.
6. As noted above, how an antigen is presented to the immune system determines whether the immune system is stimulated or suppressed (“tolerized”). In the above cited paper by Tremain et al the researchers show that attaching large sugar molecules, such as N-acetylgalactosamine and N-acetylmannosamine, to an antigen “steers” the compound to parts of the immune system, such as the liver and lymph nodes, resulting in suppression of the immune system to that antigen.
7. The researchers tested this approach to treat EAE. It worked. It also worked for other autoimmune diseases. The lead researcher, Dr. Jeffrey Hubbell, founded a company, Anokion, to test this approach in persons with MS. A Phase 1 safety trial involving a small number of individuals has been started. The initiation of this trial is important, but there are multiple issues that constrain enthusiasm for this approach. Some of these are discussed below.
Discussion:
It’s always exciting and hopeful when a new approach to the treatment of MS is proposed. The work of Tremain et al noted above, utilizing a new technique to induce immune tolerance to myelin proteins, could result in a disease-specific therapy, at least in a subgroup of persons with MS that exhibit immune responses to the proteins used to induce tolerance. However, when viewed in the historical context of previous attempts, caution is a reasonable approach.
An animal model of MS, experimental autoimmune encephalomyelitis or EAE, is routinely used to determine whether a drug or procedure has the potential to also treat the human disease. It is induced by immunization with a specific myelin antigen that stimulates the immune system to attack the central nervous system. The initial immune reaction is to the administered antigen but over time another phenomenon occurs, called “epitope spreading” . What that means is that the initial immune response to the administered antigen broadens to involve other proteins as central nervous system tissue is destroyed. These subsequent, diverse immune responses augment and perpetuate the process of tissue destruction even when the response to the original antigen is suppressed or resolves. Epitope spreading occurs both in EAE and in persons with MS. Thus, the key question is whether “reverse vaccination” using a specific antigen to trigger a suppressive response to that specific antigen is also able to suppress immune responses to the broad range of antigens that develop as a result of epitope spreading.
We don’t know the inciting antigen in MS, so inducing immune tolerance to a single myelin protein may not be sufficient to result in suppression of the myriad other immune responses engendered by epitope spreading. Results with EAE suggest this could occur even if the inverse-vaccinating protein is different from the one that triggered the disease, at least in regard to relapses, but not chronic progression. Could this also occur in persons with MS? We don’t know.One approach to possibly mitigate the challenge is consider using multiple myelin proteins as tolerizing antigens. This could result in tolerance to these antigens, possibly also those involved in epitope spreading. I await the results of the new Anokion sponsored clinical trial with cautious optimism.
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