Tolerance-inducing therapies: A how-to guide for vaccinating against autoimmunity

Many of us may know someone who has taken allergy shots. These shots work on the concept of tolerance—that small doses of an antigen in the context of no inflammation or illness leads to the body learning that antigen is safe. When the body is exposed to that antigen again, no inflammation happens because the immune system has built up a tolerance to it. All of this happens while the rest of the immune system stays at full strength.

In Multiple Sclerosis (MS), the patient’s T cells attack structural proteins within the myelin sheaths that protect nerve cells in the brain and spinal cord, leading to inflammation, pain, and loss of motility and cognition. In a recent review article, Willekens and Cools describe multiple tolerance-inducing vaccinations that are in development for the suppression of the antigen-specific T cell response in MS—some as far as phase II clinical trials. If this targeted vaccination therapy works, it would be a vast improvement over current MS therapies that typically cause more general immune suppression and make infections or cancer more likely.

Figure 1. MS Vaccination Strategies. Strategy #1: introduction of peptides induces tolerance via peptide uptake by resident innate cells; Strategy #2: cell-treatment reduces autoimmunity by inactivating T cells directly; Strategy #3: cell-treatment suppresses T cells by tolerizing dendritic cells

Three basic classes of vaccinations have been generated. In the first technique, antigens from the myelin sheath, or short portions of the antigens called peptides, are injected into the skin or muscle with no adjuvant. This technique is thought to lead to peptide uptake by resident innate cells that are known to induce tolerance when no inflammation is present. Some of the trials that use this method have been incredibly effective, leading to a roughly 80% decrease in lesions that occur in MS. Others have lead to an (~60%) increase in lesion, suggesting the composition of the peptide that is given to patients is incredibly important. A variation on this technique is the injection of DNA encoding for the peptide, which is transcribed then translated into the peptide itself, with moderate clinical success. This technique doesn’t directly change the patient’s immune system, but instead assumes the normal mechanisms of tolerance are intact.

In the second method, the patient’s T cells are isolated from a blood draw, then treated before being transferred back into the patient. One potential outcome of cell-treatment is to make the cells less likely to attack the patient’s own body. For example, in several similar trials, autoimmune T cells are isolated and irradiated, then put back into the body. The patient’s immune system sees these now-inactive T cells as pathogenic and kills them, and in that process is taught that similar autoimmune T cells should be eliminated as well.

In the final class of current vaccinations strategies, cell treatment is also employed—in this case, to make the cells suppressive. Innate cells known to be tolerizing, called tolerogenic dendritic cells (tolDCs), are isolated or generated from the patient’s own cells. These tolDCs are then cultured with peptides present in the myelin sheath. Once educated on these peptides, the tolDCs are given back to the patient, where they can suppress T cells within the patient that react to those same peptides.

Two important caveats must be noted. First, this type of therapy has been most effective in relapsing-remitting MS; like essentially all other current therapies for MS, this vaccination strategy shows little success for the treatment of late-stage, progressive MS. Second, some MS patients don’t react to the proteins tested here, so patients need to be tested for which antigens their systems reacts against before treatment. Even with these caveats, vaccination strategies show that treatment for autoimmunity is becoming more personalized, more targeted, and less likely to cause unintended side-effects.


Willeksen, B and Cools, N. Beyond the Magic Bullet: Current Progress of Therapeutic Vaccination in Multiple Sclerosis. CNS Drugs. 2018 May 14; 32(5): 401–410. doi: 10.1007/s40263-018-0518-4

Featured image adapted from user Dr. Jana on the Wikemedia Commons under CC BY 4.0.

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