Therapeutic Antibody Targeting of Indoleamine-2,3-Dioxygenase (IDO2) Inhibits Autoimmune Arthritis, Merlo et al 2017

J

Jaybee00

Senior Member (Voting Rights)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466478/

Rheumatoid arthritis (RA) is a debilitating inflammatory autoimmune disease with no known cure. Recently, we identified the immunomodulatory enzyme indoleamine-2,3-dioxygenase 2 (IDO2) as an essential mediator of autoreactive B and T cell responses driving RA. However, therapeutically targeting IDO2 has been challenging given the lack of small molecules that specifically inhibit IDO2 without also affecting the closely related IDO1. In this study, we develop a novel monoclonal antibody (mAb)-based approach to therapeutically target IDO2. Treatment with IDO2-specific mAb alleviated arthritis in two independent preclinical arthritis models, reducing autoreactive T and B cell activation and recapitulating the strong anti-arthritic effect of genetic IDO2 deficiency. Mechanistic investigations identified FcγRIIb as necessary for mAb internalization, allowing targeting of an intracellular antigen traditionally considered inaccessible to mAb therapy. Taken together, our results offer preclinical proof of concept for antibody-mediated targeting of IDO2 as a new therapeutic strategy to treat RA and other autoantibody-mediated diseases.
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Highlights
  • IDO2-specific Ig treatment alleviates arthritis in two preclinical arthritis models

  • IDO2 Ig inhibits autoreactive T and B cells, recapitulating genetic IDO2 deficiency

  • IDO2 Ig uses FcγRIIb to internalize and access its intracellular target

  • FcγRIIb on B cells is necessary for IDO2 Ig function in vivo
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@Jonathan Edwards Given that people with MECFS apparently have mutations in IDO2--do you think using IDO2-specific mAb will work for MECFS as it apparently does for RA? Did this pan out for RA?
 
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Jaybee00 said:
@Jonathan Edwards Given that people with MECFS apparently have mutations in IDO2--do you think using IDO2-specific mAb will work for MECFS as it apparently does for RA? Did this pan out for RA?
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This is not rheumatoid arthritis. It is some sort of animal disease.
Thousands of drugs improve models like this are useless in humans.
There are no auto reactive T cellist RA so the theory is wrong.
I am afraid this looks like what we used to call the yak dung effect. If you throw yak dung at an experimental animal disease it tends to get better because the immune system is distracted by the yak dung. Doesn't really matter what sort of dung either!

Presumably IDO2 is trendy at the moment so someone has found a way to show targeting it cures arthritis.

If you give a monoclonal like this to a human they will become immune to it within weeks - and what then?
 
I am not sure what this would have to do with ME. And I am not aware of any data showing IDO2 mutations being raised in ME? I thought so far we had no gene linkages.
 
Thanks. IDO2 mutation data from Ron Davis/Robert Phair group--"all 77 patients tested have a mutation in the IDO2 gene, this is "unusual"." I believe this a report of new data.

From the livestream of ME Action (US) for ME Awareness Day, 34:00 to 42:00


- Nanoneedle: the assay shows a signal for 50 ME/CFS patients but none of the healthy controls. Rahim Esfandyapour contacted 2 labs, one in the US and the other in China, for developing a prototype of the nanoneedle chip but that is on hold due to the COVID19 lockdown of labs.

- Metabolic trap theory: all 77 patients tested have a mutation in the IDO2 gene, this is "unusual". They are now using cultured cells for experiments, which makes testing easier, faster and cheaper because it provides "an abundance of material": they don't need a mass spectrometer anymore. They have the equipment available at Stanford with someone who knows how to use it, so they can run tests on a daily basis.

- Post-COVID19 study: the plan is to spot when the conversion from viral infection to ME/CFS occurs by gathering a massive amount of data from biological samples over time. Ron Davis thinks this conversion occurs very early on after the infection.
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The entire metabolic trap hypothesis by Robert Phair builds on the idea of damaging IDO2 mutations being a necessary prerequisite to the disease. According to this hypothesis, IDO2 is actually not working and due the peculiar enzyme kinetics of IDO1, patients' cells may get "stuck" with too high tryptophan concentrations and no way to clear it out (due to bistability that makes IDO2 mostly effective at high tryptophan concentrations and IDO1 at lower ones). So targeting IDO2 would do absolutely nothing as a treatment for ME/CFS if it's true that patients already have mutations in IDO2, which make it broken.
 
- Metabolic trap theory: all 77 patients tested have a mutation in the IDO2 gene, this is "unusual".


That does not amount to scientific data in my mind. Just a throw away statement with no background on controls or methodology.
 
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