Wednesday, 6 January 2016

Hunting for Targets

The search for the target antigens of multiple sclerosis, part 1: autoreactive CD4+ T lymphocytes as pathogenic effectors and therapeutic targets.Hohlfeld R, Dornmair K, Meinl E, Wekerle H.
Lancet Neurol. 2015 Dec 23. pii: S1474-4422(15)00334-8.

Identification of the target antigens of pathogenic antibodies and T cells is of fundamental importance for understanding the pathogenesis of multiple sclerosis, and for the development of personalised treatments for the disease. Myelin-specific CD4+ T cells emerged long ago as a key player in animal models of multiple sclerosis. Taking a forward-translational approach, autoreactive CD4+ T cells have been studied extensively in patients with multiple sclerosis, and there is evidence, but as yet no direct proof, that autoreactive CD4+ T cells are a key player in the pathogenesis of the disorder. Several therapies that selectively target myelin-specific CD4+ T cells have been investigated in clinical trials up to phase 3. So far, however, none of these (mostly underpowered) therapeutic trials have provided definitive evidence of clinical efficacy. One major obstacle to personalised, highly selective immunotherapy is the absence of standardised and reliable assays to assess antigen-specific human T-cell responses. Such assays would be essential for stratification of patients with multiple sclerosis according to their individual target antigens.

The search for the target antigens of multiple sclerosis, part 2: CD8+ T cells, B cells, and antibodies in the focus of reverse-translational research.Hohlfeld R, Dornmair K, Meinl E, Wekerle H. Lancet Neurol. 2015 Dec 23. pii: S1474-4422(15)00313-0.

Interest in CD8+ T cells and B cells was initially inspired by observations in multiple sclerosis rather than in animal models: CD8+ T cells predominate in multiple sclerosis lesions, oligoclonal immunoglobulin bands in CSF have long been recognised as diagnostic and prognostic markers, and anti-B-cell therapies showed considerable efficacy in multiple sclerosis. Taking a reverse-translational approach, findings from human T-cell receptor (TCR) and B-cell receptor (BCR) repertoire studies provided strong evidence for antigen-driven clonal expansion in the brain and CSF. New methods allow the reconstruction of human TCRs and antibodies from tissue-infiltrating immune cells, which can be used for the unbiased screening of antigen libraries. Myelin oligodendrocyte glycoprotein (MOG) has received renewed attention as an antibody target in childhood multiple sclerosis and in a small subgroup of adult patients with multiple sclerosis. Furthermore, there is growing evidence that a separate condition in adults exists, tentatively called MOG-antibody-associated encephalomyelitis, which has clinical features that overlap with neuromyelitis optica spectrum disorder and multiple sclerosis. Although CD8+ T cells and B cells are thought to have a pathogenic role in some subgroups of patients, their target antigens have yet to be identified.

The techology is available to get at the antigen-specific receptors of T and B cells, but what is the target in MS? 

Will this be a "fishing trip" or focused work that finds the answer but if the answer is "myelin basic protein" what will be the question?


  1. Is autoimmunity to MBP the cause of MS or a consequence of damage in the CNS? Also, how would personalised, highly effective immunotherapies be developed if the auto antigen is recognized? Could tolerance be restored by introducing peptides on nanoparticles as is being tested by the researchers in Chicago?

    1. You could restore tolerance (as we have done many many times in the lab) in MS by using peptide nanoparticles, we've done the same thing many years back (the first to do so I think)using plastic beads coupled to antigen in our mice. But, importantly we ned to know what the candidate antigens are for MS and there's still much doubt about that. Also for it to work effectively, there has to be a transient depletion of T cells before the tolerogen is introduced for a robust tolerance to be re-established. I think the Chicago researchers are also looking at this strategy in type I diabetes, where at least the antigens are better identified but as they don't seem to hinclude a depletion step, I have some doubts as to whether it will work robustly.

    2. "Is autoimmunity to MBP the cause of MS or a consequence of damage in the CNS?"
      I doubt its solely MBP but that is the multi-million dollar question.

    3. Does Autoimunity to MBP exist is one other question also.

      Time will tell if the Chicago approach works, but as MD2 indicates they are stacking the cards against themselves because without the transient depletion step the approach is inefficient as was shown with alpha B crystalin-induced tolerance

      In their (Chicago) phase I the response on depressing immune cells was only seen at the highest dose and there were relapses in this group suggesting that higher doses will be needed. Worryingly 2 people (albeit highly active before treatment) relapsed 2-3 weeks afer treatment.

      We have an approach that means you don't need to know the antigen, but need to make it more human friendly.

  2. If I'm talking nonsense please correct me, but if this strategy really sure that glatiramer acetate "solve" partially the problem of MS, since it is based on four amino acids of MBP, and it's not what you see, it is low efficiency. Now maybe if tolerance therapy is applied after the exhaustion of the immune system or after Alemtuzumab works out, as MD said...

  3. There are only 20 amino acids so those 4 will look like many things?


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