Monday, December 21, 2015

Spontaneous death of myelin-producing oligodendrocytes could trigger delayed MS-like symptoms

I usually don't check Nature Neuroscience. It does not typically publish immunology-related studies [though MS studies are of interest]. So I was surprised to see such "heavily" packed immunology article there and decided to review it to understand how it ended up there.

It is immediately clear that is not written from immunologist point of view. In general, inter-disciplinary studies are encouraged but if it is not done properly it produces lesser quality research

To this end, the authors have used Plp1-Cre-ERT;ROSA26-eGFP-DTA mouse model where tamoxifen injection releases stop signal from diphtheria toxin A production in oligodendrocytes leading to their death. It appears that this is a rare model of oligodendrocyte deletion where mice actually survive long-term (but it appears this DTA model show late-onset [starting at weeks 26] "leakiness" in absence of tamoxifen injection. This knowledge in itself creates host of issues in data interpretation).  

So, the authors noticed that starting 40 weeks post tamoxifen injection [but not at 10 weeks], spleen and cervical lymph nodes of Plp1-Cre-ERT;ROSA26-eGFP-DTA mice contained MOG-specific effector T cells. These were accompanied with clinical symptoms of EAE.

Similar results were found with 2D2 transgenic CD4 T cells [specific for MOG] transferred into tamoxifen-treated Plp1-Cre-ERT;ROSA26-eGFP-DTA host.  

Now, next experiments were quite surprising. To clearly show the role of T cells in the development of late onset MS-like symptoms in tamoxifen-treated Plp1-Cre-ERT;ROSA26-eGFP-DTA mice the authors tried to cross this DTA model with RAG KO mice. Interestingly, these T/B cell-deficient DTA mice did not survive after tamoxifen injection, implying that recovery from acute oligodendrocyte deletion [following tamoxifen injection] somehow required presence of T or B cells [reminds of studies done by Michal Schwartz lab]. However, the authors neither tried to use CD3KO or B cell KO or simply Ab depletion to test these hypotheses.

Other set of experiments with adoptive transfer of T cells harvested from tamoxifen-treated Plp1-Cre-ERT;ROSA26-eGFP-DTA mice into RAG deficient mice (but not in WT host) produced MS-like symptoms.

In the remaining experiments the authors tried to show that injection of MOG peptide coupled to nanoparticles could tolerize self-reactive T cells.

So what we learned from this study? First, I am surprised that it even get into Nature Neuroscience [it does not belong there]. Now, this could mean few things: (1) this research was rejected from Nature Immunology and ended up in Nature Neuroscience; (2) It was directly sent to Nature Neuroscience but reviewed by non-immunologists; (3) standards for Nature Neuroscience is much lower compared to Nature Immunology, in general.

David Usharauli

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