Daniel R Getts, Aaron J Martin, Derrick P McCarthy, Rachael L Terry, Zoe N Hunter, Woon Teck Yap, Meghann Teague Getts, Michael Pleiss, Xunrong Luo, Nicholas JC King, Lonnie D Shea & Stephen D Miller. Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis. Nature Biotechnology 18 November 2012 | doi:10.1038/nbt.2434
Aberrant T-cell activation underlies many autoimmune disorders, yet most attempts to induce T-cell tolerance have failed. Building on previous strategies for tolerance induction that exploited natural mechanisms for clearing apoptotic debris, we show that antigen-decorated microparticles (500-nm diameter) induce long-term T-cell tolerance in mice with relapsing experimental autoimmune encephalomyelitis. Specifically, intravenous infusion of either polystyrene or biodegradable poly(lactide-co-glycolide) microparticles bearing encephalitogenic peptides prevents the onset and modifies the course of the disease. These beneficial effects require microparticle uptake by marginal zone macrophages expressing the scavenger receptor MARCO and are mediated in part by the activity of regulatory T cells, abortive T-cell activation and T-cell anergy. Together these data highlight the potential for using microparticles to target natural apoptotic clearance pathways to inactivate pathogenic T cells and halt the disease process in autoimmunity.
This is a picture of MD2's urine after hearing about this article
(apologies for the poor taste, but that was his reaction as it made his p**s boil)
Many, many years ago the group of Stephen Miller showed that if you stuck myelin antigens onto cells with a chemical cross-linker that it could induce immunological unresponsiveness (immune tolerance) to disease induced with myelin antigens. As you may remember, I posted on using this approach as being half-way to a cure in humans when it was posted in ECTRIMS 2012.
The group have realised that sticking peptides to the individuals own white blood cells is a problem, because it has to be individualized and cannot be standardized for every one. They thought that you could replace the cell with a polystrene bead or a microparticle and this NEW bit of biotechnology has turned out to be this weeks "Cure of the week".
They show that if you inject these microparticles into the blood they induce immunological tolerance in an antigen-specific way, via a mechanism that centres on T cell depletion and anergy (unresponsivenes of the T cell to stimulation) and not so much on T regulatory cells or interleukin-10 producing regulatory cells. Furthermre the peptide needs to be stuck on the surface. These microparticles are taken up in the spleen by macrophages expressing a receptor called MARCO, because in some of their past work they show that these cells took up dead (apoptotic) cells.
As such tolerance was not present in MACRO-deficient mice when treated with antigen beads, but this surprisingly had no effect on tolerance induced by dead cells? They did not need polystyrene beads as this could also be done with biodegradable beads, approved for human use, so this could be an approach that could be easily translated into human use as both peptides and beads are available for human use. This is very good news let us hope they develop this, but the problem with this approach is that they are using peptides.
Peptides are easy to manufacture to the standards required for human use, but if you believe the data, it means that they need to know all the antigens that each individual will respond to, as it is very antigen-specific mechanism. The solution to attach a mixture of whole proteins so that you do not need to know which epitopes the individuals will respond to. This is important because each individual will respond to a different set of proteins during disease. Furthermore to get optimal results in established disease they need to transiently deplete the T cells. How do I know this?
Well if you care to read papers Pryce G, O'Neill JK, Croxford JL, Amor S, Hankey DJ, East E, Giovannoni G, Baker D.Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis. J Neuroimmunol. 2005;165:41-52 and notably Smith PA, Morris-Downes M, Heijmans N, Pryce G, Arter E, O'Neill JK, 't Hart B, Baker D, Amor S. Epitope spread is not critical for the relapse and progression of MOG 8-21 induced EAE in Biozzi ABH mice. J. Neuroimmunol. 2005 Jul;164(1-2):76-84 that the Nature journals of the time (Not sure there was Nature Biotechnology then) did not find interesting, then this may be clear.
There you will see that myelin antigens when chemically coupled to polystyrene beads (or microparticles) stop relapsing disease in EAE, not just given before disease ever develops as mainly occurs in this current paper.
Reading these papers and you would know that you didn't need cells to induce tolerance or apoptotic cells for that matter, that it works via depletion and anergy and a little by regulation and that the antigen ends up in macrophages in many different places and not only in the spleen but in the liver and lungs.
So this new technology is really not so new. We are pretty sure that at least some of the authors of the current paper are aware of the original study, so I wonder where the idea really came from?
However, no citation of the original idea by MD2 (.....again). It would show that much of this is not really innovative, which would limit the chances of publication. They have however made some biodegradable beads. These were available 7 years ago but not with the side chains to link proteins to them...we looked. I will not get on the high horse of reporting and refereeing standards, otherwise my wee may boil too.
Labels: autoimmunity, EAE, Tolerance