The holygrail is specific targeting of disease causing immune cells whilst leaving the rest of the immune system intact and over the years I have seen alot of different approaches to the same problem. This is one more approach. We could do this very, very well and showed that depletion followed by tolerogenic antigen administration is the answer. We could take out relapsing disease forever, but the problem was how do you translate the success in animals into humans.
So far attempts to tolerise autoimmunity in MS has failed or in some cases made things worse…In most cases the way they did the study was doomed before it started. This currently approach is to deliver antigen depots in lymph glands with a drug called rapamycin (an immunosuppressive drug), which is sort of the basis of adjuvants made to promote vaccine and disease inducing regimes in animal models. They do this and it forms regulatory T cells (yarn).However they have succeeded in controlling disease and have formed a company and so I wish them well for the future but I have to say MS is the wrong place to start. Why?
Because the question is which antigen do you use. In MS the disease causing antigen is unknown/unproven. For many year alot of people thought it was myelin basic protein and more recently there has been interest in myelin oligodendrocyte glycoprotein…which has been shown to be involved in MOGAD and neuromyelititis optica. This would be a better place to start with no or fewer treatments available and here the antigens are believed to myelin oligodendrocyte glycoprotein or aquaporin-four specific antidodies. In these studies they use a peptide where the the ptide is known to cause disease and so it is simple. This is even easier if you do it before disease is induced…they show details of relapses being inhibited when treatment is done after the attack in the controls 11/16 relapsed verses 4/16 in the controls….you can do much better than this if you look at MD2’s work for 2005…but the key is you know what is the cause of the attack in 2005 MD2 didn’t however, maybe I am missing it but they need to tolerise to a CNS antigen (they can respond to) and cause disease with a different one because this tells you more how it is working and it means if you have to know the antigen, yep you can find evidence that relapses in PLP petide induced relapsing disease in SJL mice is driven by a different response and it it true that the autoantigenic repertoire is expanded with time. If you need the peptide inducing the disease to tolerise the reponse you have to know what is causing the problem. It is all easy with nice soluble peptides but a different mouse strain/individual responses to different peptides and this changes over time and some of these antigens are brick-dust and not easy to work with. So again indicating why MS may is not be the best place to start with the approach…anyway we will see there are other companies tackling the same problem in a different way…the trial results hould be out soon stoney silence and we know what has happened. Is MS a viral disease and not autoimmunity has not been answered but lets see how this is developed.
Kapnick SM, Gosselin EA, Tsai SJ, Oakes RS, Habibabady ZA, Ackun-Farmmer MA, Carey ST, Shah SA, Shen R, Froimchuk E, Eppler HB, Bridgeman CJ, Yanes AA, McIlvaine RA, Noshin M, Tostanoski LH, Black SK, Zeng X, Azimzadeh A, Pierson RN 3rd, Bromberg JS, Jewell CM. Local control of T cell fate in lymph nodes safely and durably reverses myelin-driven autoimmunity. Proc Natl Acad Sci U S A. 2025 ;122(45):e2409563122. doi: 10.1073/pnas.2409563122. Epub 2025 Nov 3. PMID: 41183200.
Development of tolerogenic, antigen-specific immunotherapies could overcome limitations of existing treatments for inflammatory autoimmune diseases by achieving potent, durable remission without impacting healthy immune surveillance. Here, we deliver diffusion-limited polymer depots to lymph nodes to locally guide T cell fates for the treatment of multiple sclerosis (MS), an autoimmune disease that occurs when the immune system mistakenly attacks myelin. In preclinical MS models, depots loaded with myelin self-antigen and tolerizing cues mediate localized retention of activated CD4 T cells, promote myelin-specific regulatory T cells, and reshape inflammation in the central nervous system (CNS) to eliminate lesions. Selective disease reversal is achieved with a single treatment that induces long-lasting remission without hindering healthy responses to vaccine challenge with foreign antigen. Furthermore, depots offer favorable chemistry and manufacturing control features and are well tolerated in non-human primates. This work supports a clinically feasible concept for inducing safe, effective, antigen-specific tolerance without systemic or repeated dosing.
COI None
Disclaimer. My views take them of leave them
Source: multiple-sclerosis-research.org