WPI research update - developing a mouse model for ME/CFS

J

jaded

Senior Member (Voting Rights)
Shared recently on the WPI Facebook site:

https://www.facebook.com/share/p/LqnDkLQRGktPubRD/?mibextid=WC7FNe

“Vincent Lombardi, Ph.D., to develop first double humanized fecal transplant mouse model to study ME/CFS

Vincent Lombardi, Ph.D.
Vincent Lombardi, Ph.D., associate professor of Microbiology and Immunology at UNR Med, has been awarded an R21 grant from the National Institute of Allergy and Infectious Diseases to conduct research on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In this collaborative effort between the University and the Bateman Horne Center in Salt Lake City, humanized mice, produced by engrafting immunodeficient mice with human stem cells, will undergo a fecal transplant and receive purified antibodies from individuals with ME/CFS or healthy controls.

The mice will then be evaluated for physiological changes, as well as exercise intolerance, neurocognitive dysfunction, sleep disturbances and behavioral alterations, symptoms consistently observed in those with ME/CFS. This approach holds promise for providing valuable mechanistic insight into the underpinnings of ME/CFS, improving our understanding of this debilitating condition and potentially leading to targeted therapies”.


Does this mean they think it’s antibody driven/autoimmune given that they’re using purified antibodies from ME/CFS patients to create the mouse model? Would they likely have pilot data to support a grant application?
 
Jonathan Edwards said:
Hard to know from the above but I don't understand why the mice are having feral transplants as well as patient IgG.
Click to expand...

I think their prior research hypothesised that antibodies were potentially reacting to bacterial antigens. Could this be tested for if the mouse model was given a certain bacterial composition of faecal matter?
 
jaded said:
I think their prior research hypothesised that antibodies were potentially reacting to bacterial antigens. Could this be tested for if the mouse model was given a certain bacterial composition of faecal matter?
Click to expand...

Well, if the animals made antibodies to the bacteria in the transplant, why would you need antibodies from patients as well?

It doesn't make any sense at all to me.

Maybe the idea is that the patients' antibodies bind to the bacteria in the gut. But if the bacteria are in the gut then binding of antibodies will do nothing to them because there is no complement to induce killing. If the bacteria are in the circulation then having some antibodies would normally be considered a very good thing - to clear the bacteria.

As far as I know there is nothing to support any sort of mechanism - whatever it is supposed to be.
 
Jonathan Edwards said:
Well, if the animals made antibodies to the bacteria in the transplant, why would you need antibodies from patients as well?

It doesn't make any sense at all to me.

Maybe the idea is that the patients' antibodies bind to the bacteria in the gut. But if the bacteria are in the gut then binding of antibodies will do nothing to them because there is no complement to induce killing. If the bacteria are in the circulation then having some antibodies would normally be considered a very good thing - to clear the bacteria.

As far as I know there is nothing to support any sort of mechanism - whatever it is supposed to be.
Click to expand...

Thanks for your comments. I’ve found the grant information:

https://reporter.nih.gov/project-details/10869779

Development of humanized microbiota mouse models of ME/CFS
Project Number1R21AI183042-01
Contact PI/Project LeaderLOMBARDI, VINCENT C
Awardee OrganizationUNIVERSITY OF NEVADA RENO

Our preliminary data, as well as our previous published studies, show that ME/CFS cases have alterations in gastrointestinal mucosal immunity and mitochondrial homeostasis. Several other studies have described significant alterations in the composition of the gut microbiome in ME/CFS cases, when compared to age and gender-matched controls, potentially implicating a pathological role for a dysbiotic microbiota in the progression of ME/CFS through the gut-microbiota-brain axis.

We hypothesize that by conducting a fecal microbiota transplantation (FMT) with stool from ME/CFS cases into mice that are engrafted with a functional human immune system, we can develop an animal model that will replicate ME/CFS-associated pathology. We further hypothesize that this model can be used to conduct ME/CFS research that is not practical or possible when working with human subjects.

In Specific Aim 1, we will characterize and transplant stool from ME/CFS cases and healthy controls into common C57BL/6J laboratory mice, which have a normal murine immune system, as well as mice that are engrafted with a functional human immune system. We will then evaluate these mice for exercise intolerance, neurocognitive dysfunction, and sleep disturbances; behavioral alterations consistent with those observed in human cases.

In Aim 2, we will pathologically evaluate these mice to identify changes in the gut and the brain that potentially implicate the altered microbiota in ME/CFS pathophysiology. These studies will lay the foundation for a larger research focus to identify ways to target the gut-microbiota brain axis in the prevention and treatment of ME/CFS. ME/CFS is a multisystemic, debilitating, and neglected illness for which no accepted efficacious treatments are currently available.

Population-based epidemiologic studies suggest that ME/CFS may affect as many as 2.5 million people in the United States alone. Moreover, ME/CFS produces an annual economic burden of at least $17 billion 4. Although ME/CFS represents a serious public health concern, after almost four decades of research, the pathophysiology of this illness is still largely unknown.


Public Health Relevance Statement
Project Narrative Several lines of evidence suggest that a gut-microbiota-brain axis connection is involved in the pathophysiology of ME/CFS.

Mice that received fecal transplants from human donors with other neuroimmune diseases present with behavioral alterations consistent with these diseases, suggesting that fecal transplants may be used to create humanized mouse models of ME/CFS.

Therefore, we propose to develop humanized mouse models of ME/CFS by using stool from ME/CFS subjects and healthy controls. Fecal transplants will be made using C57BL/6J mice and Hu-CD34+ NSG-SGM3 transgenic mice engrafted with a human immune system. We will then evaluate these mice for behavioral alterations and mucosal and neuroimmune alterations consistent with ME/CFS.


Project Start Date
07-May-2024
Project End Date
31-March-2026


Project Funding Information for 2024
Total Funding
$196,965
Direct Costs
$135,000
Indirect Costs
$61,965
 
That doesn't say anything about transferring purified antibodies.
The whole thing sounds like nonsense to me as an immunologist, but I have been wrong in the past now and again.

It might make some sense if people with ME/CFS had gut bacteria that normal people do not have but as far as I know nothing like that has ever been found - just maybe some differences in proportions of types. Thos proportions are not going to stay the same in mice so it seems pretty hopeless from that angle.
 
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