Resetting the immune system

Short courses with long effects

Cladribine is a tablet taken on a few days in each of two years. It is taken up mainly by lymphocytes and kills them, and their numbers recover slowly over the following months. In the CLARITY trial it reduced relapses compared with placebo over two years.[1]

Alemtuzumab, an antibody against a protein called CD52, removes T and B cells in two courses of infusions a year apart. It reduced relapses more than interferon beta in two phase 3 trials. As the immune system rebuilds, some people develop a new autoimmune disease, most often of the thyroid, which shows that the rebuilt immune system is not always better balanced.[2][3]

Stem-cell transplantation

Autologous haematopoietic stem-cell transplantation (AHSCT) goes furthest. Chemotherapy removes most of the immune system, and the person's own stored blood stem cells are returned to rebuild it. In the MIST trial, people with active relapsing MS who had a transplant were much less likely to worsen than those who stayed on their medicines. In a large retrospective registry study, estimated progression-free survival at five years was 46 per cent, with better results in younger people with relapsing MS than in people with progressive MS. The procedure carries real risks, including a risk of death, and larger trials comparing it with the most effective medicines, including BEAT-MS and the Nordic RAM-MS, are under way.[4][5][7][8]

CAR-T cells

CAR-T therapies, first developed for blood cancers, engineer a person's own immune cells to find and remove B cells, possibly more completely than antibodies can and in tissues that antibodies reach poorly. The first small studies in MS are under way, and the News section reports their early results as they appear.[9]

Teaching the immune system to tolerate myelin

Every treatment in this lesson so far suppresses or removes large parts of the immune system. A long-standing alternative is to switch off only the response against the nervous system and leave the rest of the immune system alone. This is called antigen-specific tolerance, and most attempts use fragments of myelin proteins, called peptides, given in a way meant to calm the immune response rather than provoke it.

The history is sobering. In a phase 2 trial published in 2000, an altered version of a myelin basic protein fragment was poorly tolerated, and three people had relapses, two of which immunological tests linked to the treatment.[10] That trial showed that a treatment aimed at myelin can make MS worse. The largest test so far, MAESTRO-01, gave the myelin basic protein fragment MBP8298, also called dirucotide, or placebo to 612 people with secondary progressive MS for two years, and found no difference in its main or secondary measures.[11]

Newer approaches have reached early trials. ATX-MS-1467, a mixture of four myelin basic protein fragments injected into the skin in slowly rising doses, reduced enhancing MRI lesions in two small open-label trials of 43 and 37 people with relapsing MS, with no safety concerns, but has not been tested against placebo.[12] In the ETIMS approach, a person's own white blood cells are coupled to seven myelin peptides and infused once. The first trial, in nine people, found it safe and saw fewer reactions against the peptides at the higher doses.[13] A version using the person's own red blood cells has completed a phase 1 trial (NCT06430671). Tolerogenic dendritic cells, immune cells grown from a person's blood and loaded with myelin peptides, or with aquaporin-4 peptides for NMOSD, were safe in a phase 1b trial of 12 people and increased regulatory responses in the laboratory.[14] Phase 2 trials are planned.

No tolerance therapy has yet shown a clinical benefit in a controlled trial. The main obstacles are that the immune targets in MS are not fully known and may differ between people, and that the wrong peptide can provoke rather than calm the disease.

Peptides you may hear about. Several other peptides are promoted online as MS treatments, with very different levels of evidence.

GLP-1 medicines such as semaglutide are being studied in small trials in MS, mainly for their effects on weight, metabolism and possibly the nervous system. Results are not yet available.

Cyclotides, stable ring-shaped peptides from plants such as kalata B1, delayed and reduced disease in a mouse model of MS when taken by mouth.[15] They have not been tested in people with MS.

BDNF mimetics and vasoactive intestinal peptide have been studied in laboratory and animal models of MS. The Trial Bank holds no trials of either in people with MS.

BPC-157 has no published research in people with MS and is not approved as a medicine by the US or European regulators.

Ask us to check a claim on the Fact check page if you would like a full answer on any of these.

What they taught researchers

Resetting works best where there is active inflammation to reset. It has done much less for progression without relapses, which is consistent with processes inside the brain that a reset in the blood may not reach.[5][6]