Thursday, 4 September 2014

Profiling Antigen Specific Therapy

Burton BR et al. Sequential transcriptional changes dictate safe and effective antigen-specific immunotherapy NATURE COMMUNICATIONS | 5:4741 | DOI: 10.1038/ncomms5741

Antigen-specific immunotherapy combats autoimmunity or allergy by reinstating immunological tolerance to target antigens without compromising immune function. Optimization of dosing strategy is critical for effective modulation of pathogenic CD4 T-cell activity. Here we report that dose escalation is imperative for safe, subcutaneous delivery of the high self-antigen doses required for effective tolerance induction and elicits anergic, interleukin (IL)-10 secreting regulatory CD4 T cells. Analysis of the CD4 T-cell transcriptome, at consecutive stages of escalating dose immunotherapy, reveals progressive suppression of transcripts positively regulating inflammatory effector function and repression of cell cycle pathways. We identify transcription factors, c-Maf and NFIL3, and negative co-stimulatory molecules, LAG-3, TIGIT, PD-1 and TIM-3, which characterize this regulatory CD4+ T-cell
population and whose expression correlates with the immunoregulatory cytokine IL-10. These results provide a rationale for dose escalation in T-cell-directed immunotherapy and reveal novel immunological and transcriptional signatures as surrogate markers of successful immunotherapy.

Antigen-specific therapy is the only way to control autoimmunity, whilst limiting the effects on generalised immunosuppression,that can lead to infections, in some instances cancer. At present we are using a "hammer to crack a nut" and most immune modulating drugs take out large parts of the immune system and can result in things such as PML, which is sometimes a lethal infection caused by lack of immune monitoring of the brain by the immune system.

If you deliver myelin antigens by the blood (intravenous route) or sometimes the nose (intra nasal route) you can inhibit the development of experimental myelin autoimmunity induced by sensitizing animals through the skin with adjuvants that boost the immune response. This idea was developed towards the clinic but perhaps fear of inducing allergic reactions following delivery of the antigens through the blood prompted a change in direction for a number of groups and they started to inject the myelin into the skin. 

In some instances this can work and it stops autoimmunity from being induced and appears to work by the generation of a suppressor cell that produces interleukin 10. This cytokine can inhibit autoimmune T cells.

This is great, but there is a problem with this route, in that injecting things into the skin is a sensitizing route and can make disease worse rather than better. This has happened both in animals and worryingly also in multiple sclerosis. Whilst this would scare many people off, companies have been set up to develop this approach one such drug is called ATX-MS-1467 is in trial at the moment.

The difference between whether an antigen delivered into the skin induces sensitization of immune tolerance where the immune system no longer responds may be a product of the dose administered.

Dose-escalation (increasing the dose of antigen) strategies may reduce the risk of immunotherapy-associated adverse effects, which may range from mild symptoms to anaphylaxis (extreme allergic response that may stop you exhaling due to swelling of the airways). Dose-escalation permits administration of larger antigen doses and, when successful, the reinstatement of immunological tolerance towards the administered antigen.

In this current study in mice they increased the dose of myelin antigens under the skin  before giving mice EAE, an MS-like disease. However the myelin antigen was not identical to that found in real myelin, but an engineered myelin antigen that gives superstimulating capabilities and turns the immune system off rather than on, which I call the "weed killer effect". You give weedkiller to a plant and it can make it grow itself to death. This engineered myelin antigen makes the cell grow to inactivity(anergy) or death.

In this study they increased the dose of the "weedkiller" and found that at low doses it did nothing with higher doses it caused unresponsiveness, but at higher doses it caused adverse effects.However if they escalated the dose this adverse event was not seen and animals got "high dose tolerance"/ desensitized and produced less inflammatory molecules. They then did a screen to see what proteins were produced by these during the formation and establishment of these "tolerant cells". 

They found clusters of genes sharing this expression pattern were related to cell division processes. Other cluster of proteins are associated with unpregulation of IL-10 production and negative stimulatory molecules. They then showed that as IL-10 was turned on this associated with the production of some of the molecules identified in the screen.  With increasing number of stimulations certain proteins became more upregulated such as LAG-3.

Is this a breakthrough that is going to cure you tomorrow, as the media may hype...Well the simple answer is this another "cure of the week", but it could be translated sooner rather than later. 

This study suggests that there are sets of molecules that could be looked for and should be increased if the antigen specific tolerance is working (assuming that you can look at the disease causing cells which may be a needle in a haystack as they will occur at low numbers in the blood). You could maybe then correlate this with people who respond to the treatment and those that may not and if they are not responding should you up the dose? Therefore, they could be biomarkers for activity and you could look how to increase this type of regulatory cell

The other way this can be translated is to increase the dose over time. It looks like this is occurring to some extent in the trials that are ongoing The authors of this study are involved in the commercial development of this approach and aims to deliver myelin peptides to MSers. Hope this information was available and informed the current trials.

Let's hope that the basic science doesn't get messed up in the trials and that it proves to turn off the myelin response in humans. Then we can see if the MS goes away....Let's hope so.

However, some people think that MS is not autoimmune or that myelin is not the target and others think that, even if MS were autoimmune, delivering myelin peptides via the skin is going to be a problem. 

Time will tell. The studies are already ongoing..

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