Experimenting on Human cells

Mice are a commonly used tool to study autoimmunity but it would be better to study human immune cells. 

Enter the NOG mouse.
NOG History.png
The NOD obese diabetic mouse was a mouse strain that was developed in Japan and spontaneously develops diabetes. 

It can be used of EAE studies too but it isrelatively EAE resistant due to genes on chromosome 7.

Baker D, Rosenwasser OA, O’Neill JK, Turk JL Genetic analysis of experimental allergic encephalomyelitis in mice. J Immunol. 1995;155:4046-51.

The SCID severe combined immunodeficient mice has a defective lymphoid system and does not make T or B cells. In humans, SCID is colloquially known as “bubble boy” disease, as victims may require complete clinical isolation to prevent lethal infection from environmental microbes.

In mice the condition is due to a rare recessive mutation on Chromosome 16 responsible for deficient activity of an enzyme involved in DNA repair (Prkdc or “protein kinase, DNA activated, catalytic polypeptide”). Because V(D)J recombination does not occur, the humoral and cellular immune systems fail to mature. SCID mice, therefore, present with impaired ability to make T or B lymphocytes and cannot efficiently fight infections, nor reject tumors and transplants.

By crossing SCID mice with mice carrying mutations in related genes, such as interleukin-2 receptor gamma, more efficient immunocompromised strains can be created to further aid research.

These strains termed NOG mice can be used as an empty mouse to repopulate with human immune cells. The problem here is they react against the mouse tissue and cause lethal graft verses host disease.

However you can take human bone marrow stem cells and transplant these into mice and with time the repopulate the mouse but learn not to reject the mouse tissue. They then have human immune cells in a mouse and now you can use them to investigate the effects of drugs that only work on human cells.
Can we get EAE in these mice? It is only a matter of time before this happens. New versions have been made that have human major histocompatibility complex and so will make immune recognition  even better.

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  • You are a very nice man Prof M, but you need to call it a day with EAE. EAE is not MS and mice are not humans. The fact that your paper highlighted above is 20 years old, says everything about the value of EAE as a research model for MS. Ronald Regan described economists as people who see something working in practice and try and see if it can work theoretically. Treatments for relapses are now highly effective. Treatments for progression could be available in 5 years. Treatments for repair could be around in 10 years. Trials are underway in humans. There is no need for EAE anymore. You have to let it go. If a cure for MS is found, will you still be doing research on EAE? COI: I like mice, I hate waste of time research.

    • The twenty year old paper said neuroimmunological disease is polygenic and non objigate and genes have small influences that you are going to have problems finding and proving any genes impact which is exactly was has happened. Millions has been spent requiring big samples and the development ofa novel mapping technique

    • Treatments for relapses are effective that's true but they are not without side effects…with antigen-specific immunotherapy it is possible to specifically stop relapses without affecting the ability to stop other immune responses.

      Treatments for progression had their origin is in animal studies, treatments for repair have their origins in animal studies.

      If a cure for MS is found will we still be working on EAE….probably not we will move on as will the neuros. We have got cures in mice…will they work in humans?
      Time will tell.

    • "with antigen-specific immunotherapy it is possible to specifically stop relapses without affecting the ability to stop other immune responses."

      Does this require first knowing what the autoantigens are in MS? What are the current best candidates for autoantigens? What's the status of Kir4.1?

    • There is a view by some immunologists that you get an anti-myelin Th2/Th3 response (e.g. after oral tolerance) and this enters the CNS and releases immunosuppressive cytokines in the local environment to suppress autoimmunity. The only problem with this approach is is that it tends not to work even in established EAE let alone MS and it does not factor in what would be the effect on local infections where the anti-infectious immune response is found.

      The most robust way of getting antigen specific tolerance is with the intravenous delivery of antigen..even one can get this to work. It works by anergy, deletion and active suppression but is very antigen specific and means that you have to know what the target antigen is. In addition we believe for it to work property in established disease you need to deplete the T cells first and tolerise them as they regenerate. This approach is very effective in animals and works so well it cures the animals if started early enough. We believe this approach works in humans also and have eliminated some ones immune response problem is it was n=1.

      Simply injecting the antigen intravenously without the depletion is not good enough on its own and so I have doubts this approach will truly work in MS, although it is being tried in Chicago.

      Next problem is you need to know the antigen and the simple answer here is that everyone's targets antigens are different and they change over time.This is obvious if you take three mice strains.

      So in humans one approach is to pick a selection that many humans respond to, the problem is you have to define these and many are based on what human T cells proliferate to. However in animals it is often not these antigens that are pathologically important. The pathological ones do not cause good proliferation.

      Our approach has been give the individual all the proteins in myelin/oligodendrocyte (delivered in a tolerogenic way) and let the immune system select what it is interested in. If you remove responses to the dominant ones you can have impact

      It is clear that Kir 4.1 is not a major target and the early studies pointing at 50% pwMS responding to them is way off the mark.

    • "Our approach has been give the individual all the proteins in myelin/oligodendrocyte (delivered in a tolerogenic way) and let the immune system select what it is interested in."

      That makes sense, thanks for this response!

  • Interesting discovery concerning MS by using the wrong mice for research


    An innocent mistake made by a graduate student in a Northwestern Medicine lab (she accidentally used male mice instead of female mice during an experiment) has led scientists to a novel discovery that offers new insight into why women are more likely than men to develop autoimmune diseases such as multiple sclerosis (MS).

    The finding, detailed in a paper published in The Journal of Immunology, focuses on a type of white blood cell, the innate lymphoid cell, that exhibits different immune activities in males versus females.

    • There is a Harvard and North Western Fanclub in the blog and so I am not allowed to say anything other than positive things:-).

      Cutting edge: c-Kit signaling differentially regulates type 2 innate lymphoid cell accumulation and susceptibility to central nervous system demyelination in male and female SJL mice. Russi AE, Walker-Caulfield ME, Ebel ME, Brown MA.
      J Immunol. 2015 Jun 15;194(12):5609-13. doi: 10.4049/jimmunol.1500068. Epub 2015 May 13.http://www.jimmunol.org/content/194/12/5609.long

      Many people use female mice because you can group house them, whereas with male animals they fight like crazy, if they are not weaned properly. Even if they are they can often fight and this is particularly the case with male SJL mice who will pick fights with females rather than mate with them.

      Therefore in any group housing you have to establish a social heirachy (pecking order to work out who is top dog) and this can be stressful and this can be particularly the case with males and so in many cases male mice get less disease than female mice.

      In this study a graduate student gets the blame for not following protocol..Iis it good to be blamed for this in public I wonder?. Maybe better to say that they were being inquisitive to know how males responded with the knockout, especially as there are so many papers reporting sexual dimorphism in relation to sex and susceptibility to EAE.

      In this paper they report that C-kit is the factor that is the difference between males and females which influences how the immune response develops. Maybe it is.

      However, the difference between males and females have been put down to so many different things. Maybe when it is shown to be a factor in humans them we will report it

      We have seen similar things in one strain there is a big sexual dimorphism of GPR55 in another genetic background the sexual effect disappears.

      Genetic background can result in a marked or minimal effect of gene knockout (GPR55 and CB2 receptor) in experimental autoimmune encephalomyelitis models of multiple sclerosis. Sisay S, Pryce G, Jackson SJ, Tanner C, Ross RA, Michael GJ, Selwood DL, Giovannoni G, Baker D. PLoS One. 2013 Oct 9;8(10):e76907.

      If we look at the historical records the sex ratio of male to female was about 1:1 around 1900 not it is 2-3:1. Has the influence of c-kit changed. Did c-kit make you more likely to get killed in world war one and two?

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