Monday, 14 December 2015

Neuroinflammation in animal models in rats

Kurosawa K, Misu T, Takai Y, Sato DK, Takahashi T, Abe Y, Iwanari H, Ogawa R, Nakashima I, Fujihara K, Hamakubo T, Yasui M, Aoki M. Severely exacerbated neuromyelitis optica rat model with extensive astrocytopathy by high affinity anti-aquaporin-4 monoclonal antibody. Acta Neuropathol Commun. 2015;3(1):82. 

INTRODUCTION:Neuromyelitis optica (NMO), an autoimmune astrocytopathic disease associated with anti-aquaporin-4 (AQP4) antibody, is characterized by extensive necrotic lesions preferentially involving the optic nerves and spinal cord. However, previous in-vivo experimental models injecting human anti-AQP4 antibodies only resulted in mild spinal cord lesions compared to NMO autopsied cases. Here, we investigated whether the formation of severe NMO-like lesions occurs in Lewis rats in the context of experimental autoimmune encephalomyelitis (EAE), intraperitoneally injecting incremental doses of purified human immunoglobulin-G from a NMO patient (hIgGNMO) or a high affinity anti-AQP4 monoclonal antibody (E5415A), recognizing extracellular domain of AQP4 made by baculovirus display method.
RESULTS:NMO-like lesions were observed in the spinal cord, brainstem, and optic chiasm of EAE-rats with injection of pathogenic IgG (hIgGNMO and E5415A), but not in control EAE. Only in higher dose E5415A rats, there were acute and significantly severer clinical exacerbations (tetraparesis or moribund) compared with controls, within half day after the injection of pathogenic IgG. Loss of AQP4 was observed both in EAE rats receiving hIgGNMO and E5415A in a dose dependent manner, but the ratio of AQP4 loss in spinal sections became significantly larger in those receiving high dose E5415A up to about 50 % than those receiving low-dose E5415A or hIgGNMO less than 3 %. These lesions were also characterized by extensive loss of glial fibrillary acidic protein but relatively preserved myelin sheaths with perivascular deposition of IgG and C5b-9, which is compatible with post mortem NMO pathology. In high dose E5415A rats, massive neutrophil infiltration was observed especially at the lesion edge, and such lesions were highly vacuolated with partial demyelination and axonal damage. In contrast, such changes were absent in EAE rats receiving low-dose E5415A and hIgGNMO.
CONCLUSIONS: In the present study, we established a severe experimental NMO rat model with highly clinical exacerbation and extensive tissue destructive lesions typically observed in NMO patients, which has not adequately been realized in in-vivo rodent models. Our data suggest that the pathogenic antibodies could induce immune mediated astrocytopathy with mobilized neutrophils, resulted in early lesion expansion of NMO lesion with vacuolation and other tissue damages.


In humans with Devics MS (NMO) a large group of peple make antibodies to a water channel called aquaporin 4. So how do you know they cause a problem.  You can remove they and the person with NMO gets better. You can injecte them into animals and they show signs of disease. this was done here, You can do the same with  antidoies from MS also and in contrast to what some people have been saying about no autoimmunity. It is clear that some of these antibodies cause problems. Another way to show pathogenic antibodies against an autoimmune targetm is to try treat the autoimmunitiy using antigen-specific mechanisms.

In MS this has failed to date. Does this surprose me?..No. ProfG may say this is obvious because MS is not an autoimmune disease and I will say this may be but that is not a good enough reason to explain the failure of the antigen-specific therapies in MS.

(A) The targets in MS are unlikely to be myelin basic protein because if it was there would be alot more peripheral nerve involvment.

(B) The methods to induce tolerance as used in MS are simply not good enough, yet people try over and over again and they fail over and over again. We have shown that to get optimum immunological tolerance, you do not use the subcutaneous route to deliver target autoantigens as the intravenous route is much more robust and importantly you have to deplete the CD4 T cells first to optimise. This is not going to be done because it would mean having to own two drugs the depleter and the tolerogenic antigen approach. So people plough on and fail.

Only last we week we heard about alpha B crystallin and its intravenous application and did it stop relapsing MS...The answer was no but did they deplete T cells first..the answer was no and so maybe we have thrown away the best opportunity to find an autoantigen in MS. Why? Because essentially all people respond to this protein as do healthy people, but in MS the target gets expressed in the brain. So then you have a system that could be targeted.

However once you get primary damage you can get release of proteins because of  the damage and this can set up an autoimmune responses.

4 comments:

  1. "However once you get primary damage you can get release of proteins because of the damage and this can set-up an autoimmune responses." For there in lies the question ... What leads to the first attack? Would be MS immune-mediated and not autoimmune, or is it really autoimmune? What makes us MSers negative return answer to alpha B crystalline protein? A viral infection do all this, or would the response of harmful interaction of genes, or both together? ... There are many more questions than answers ...

    ReplyDelete
    Replies
    1. Johnny nash summed it up well back in the day. Enjoy.
      https://www.youtube.com/watch?v=GEstgTAXyec

      Delete
    2. Good music ... As we say here in Brazil, "lights a back and feel the vibe..."

      Delete
  2. But at least we are asking the right questions. We're getting closer to the answer.

    ReplyDelete

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