Mouse modeling, immune function and autism

Contrary to the title of this post and any images that it may conjure up of mice parading down a runway in this season's 'hottest looks' whilst pouting to the clicks and flashes of multiple cameras, I'm back to mouse models and autism again(!) and an interesting piece of research by Hsiao and colleagues*.

I am kinda standing on the shoulders of giants with this paper given that it comes from the laboratory of Paul Patterson who has already run with a short description about it on his blog (see here). Whilst not pinning my colours to any mast, Prof. Patterson's blog is one I enjoy reading, not least because of the various links being made between the immune system and the brain (at least in mice). I assume most people would recognise by now that the brain does not run independent of the rest of the body despite our implicit need to compartmentalise anything and everything (see this post on labels).

Drawing heavily on Prof. Patterson's latest blog entry and the paper in question - hopefully without plagiarising - a few factoids:

• The Patterson team have previously published results based on a mouse model of stimulated immune activation during pregnancy and the resultant behavioural effects on offspring which seemed to overlap with the core symptoms of autism (see this paper by Malkova and colleagues**).
• In the latest study* the authors report on the profile of immune function in offspring mice of immune-stimulated mothers, suggesting some interesting effects in the area of T regulatory cells and cytokine production. I have recently talked about T-cells in this post on pristine cysteine so will perhaps put that to one side for now. Of just as much interest are elevations in that old favourite IL-6 and similar suggestions for IL-17, again the source of some interest recently on the topic of autoimmunity and autism (here). Roads toward inflammation seemed to be a key part of their findings.
• Coincidental to these findings is the report of "altered myeloid lineage potential and differentiation" in offspring. I'm not even going to profess to begin to know what this actually means, aside from referring you to quite a nice overview of hematopoietic stem cells (here) showing the distinction between myeloid and lymphoid progenitors. 
• Then to the big findings and please don't shoot the messenger: irradiating and transplanting "immunologically normal" bone marrow from both affected and non-affected control mice offspring into the offspring of immune stimulated mother mice seemed to correct some of the autism-type behaviours that were exhibited. So repetitive- and anxiety-like behaviours seemed to be reduced bearing in mind that anxiety is not (yet) a core symptom of autism (see here).
• That and some suggestion that timing might be everything when it comes to programming for immune dysfunction as a result of very few effects being seen when transplanting bone marrow from affected offspring to non-affected offspring over being born into a stimulated maternal immune system environment.

I note that on quite a few sites analysing these latest results, the authors have gone to great lengths to stress that (a) these were mouse findings - I'll say again, these were mouse findings, and (b) at the moment, no-one is suggesting that a bone marrow / stem cell transplant is any kind of 'treatment' for autism given questions for example, about whether the 'irradiation' bit of the procedure might have shown any effect alongside the actual bone marrow transplant. I would most definitely support these statements given both the preliminary nature of this research and also the complications and risks attached to bone marrow transplants (see here).

Having said that this is not the first time that bone marrow transplants and conditions like autism have appeared in the research literature. This paper by Akaho and colleagues*** talks about such transplants in cases of autism (and schizophrenia) occurring alongside leukaemia with a specific focus on maintaining treatment regimes and the anxiety related to the treatment process. Sharma and colleagues**** discussed some rather more direct observations following administration of "autologous bone marrow-derived mononuclear cells" in their quite varied patient group including cases of autism, bearing in mind one tree does not a forest make.

Indeed the concept of stem cell therapy, words which still seem to create quite an emotional response in many people, seems to be occurring more and more often in the research literature on autism as per this review by Siniscalco and colleagues***** (full-text) including a familiar name (Anna Sapone). I know many people might read 'stem cells and autism' and think back to those pop-up ads that seem to appear on various search engines offering some kind of James Bond style 'Die Another Day' rearrangement. Again, no endorsement is intended or given but perhaps what the Patterson lab study is suggesting is that a little more focused research is required in this area just before the door is entirely slammed shut. 

The Hsiao findings do represent another very important preliminary step into the immune-behaviour relationship with conditions like autism in mind. Assuming that the whole is greater than the sum of its parts, these moves towards a more whole body analysis of conditions like autism, where immune function, gut and gut bacterial function and brain function are examined in unison, offer the promise of some truly tantalising insights into autism.

And finally... just in case you are not convinced on the potential for an immune-behaviour link, cast your eye over this recent preliminary report on Alzheimer's disease and the use of IVIg as another area ripe for further inquiry.

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* Hsaio EY. et al. Modeling an autism risk factor in mice leads to permanent immune dysregulation. PNAS. July 2012.
DOI: 10.1073/pnas.1202556109

** Malkova NV. et al. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism. Brain, Behavior & Immunity. 2012; 26: 607-616.

*** Akaho R. et al. Bone marrow transplantation in subjects with mental disorders. Psychiatry & Clinical Neurosciences. 2003; 57: 311-315.

**** Sharma A. et al. Administration of autologous bone marrow-derived mononuclear cells in children with incurable neurological disorders and injury is safe and improves their quality of life. Cell Transplantation. 2012; 21: Suppl 1: S79-S90.

***** Siniscalco D. et al. Autism spectrum disorders: is mesenchymal stem cell personalized therapy the future? Journal of Biomedicine & Biotechnology. 2012; 480289.

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Hsiao EY, McBride SW, Chow J, Mazmanian SK, & Patterson PH (2012). Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proceedings of the National Academy of Sciences of the United States of America PMID: 22802640