Sunday, 23 October 2016

laquinimod blocking experimental progression

Varrin-Doyer M, Pekarek KL, Spencer CM, Bernard CC, Sobel RA, Cree BA, Schulze-Topphoff U, Zamvil SS. Treatment of spontaneous EAE by laquinimod reduces Tfh, B cell aggregates, and disease progression. Neurol Neuroimmunol Neuroinflamm. 2016 Sep 21;3(5):e272.

OBJECTIVE:

To evaluate the influence of oral laquinimod, a candidate multiple sclerosis (MS) treatment, on induction of T follicular helper cells, development of meningeal B cell aggregates, and clinical disease in a spontaneous B cell-dependent MS model.

METHODS:

Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by immunization with recombinant myelin oligodendrocyte glycoprotein (rMOG) protein. Spontaneous EAE was evaluated in C57BL/6 MOG p35-55-specific T cell receptor transgenic (2D2) × MOG-specific immunoglobulin (Ig)H-chain knock-in (IgHMOG-ki [Th]) mice. Laquinimod was administered orally. T cell and B cell populations were examined by flow cytometry and immunohistochemistry.

RESULTS:

Oral laquinimod treatment (1) reduced CD11c+CD4+ dendritic cells, (2) inhibited expansion of PD-1+CXCR5+BCL6+ T follicular helper and interleukin (IL)-21-producing activated CD4+CD44+ T cells, (3) suppressed B cell CD40 expression, (4) diminished formation of Fas+GL7+ germinal center B cells, and (5) inhibited development of MOG-specific IgG. Laquinimod treatment not only prevented rMOG-induced EAE, but also inhibited development of spontaneous EAE and the formation of meningeal B cell aggregates. Disability progression was prevented when laquinimod treatment was initiated after mice developed paralysis. Treatment of spontaneous EAE with laquinimod was also associated with increases in CD4+CD25hiFoxp3+ and CD4+CD25+IL-10+ regulatory T cells.

CONCLUSIONS:

Our observations that laquinimod modulates myelin antigen-specific B cell immune responses and suppresses both development of meningeal B cell aggregates and disability progression in spontaneous EAE should provide insight regarding the potential application of laquinimod to MS treatment. Results of this investigation demonstrate how the 2D2 × Th spontaneous EAE model can be used successfully for preclinical evaluation of a candidate MS treatment.

This was lauched by accident yesterday, but as i posted it I suppose I should discuss it. I was not going to do this. Laquinimod has been tested to see if it can block relapsing MS and it was pretty poor, and in the same league as beta interferons. In this study the dose selected completely wipes out the disease in animals, so there is a disparity there. However the big issue in MS is that it appears that laquinimoid improved the loss of nerve content. to a much greater extent than would be predicted by an effect on relapses. So they did a trial and unfortunately a safety issue of the higher doses became apparent and bits of the trials were stopped. Studies on the lower dose continue.


This study was on mice and the drug can wipe the disease out unlike that occuring MS. They use a spontaneous model of MS and the drug is inhibitory, but does this model reflect progressive MS and the answer in my mind is no, it is simply an immune-disease model, Now it has been suggested that progressive MS is mediated by the activity of B cell and B cell follicles but the B cell aggregates seen in the animal models do not appear to have the real structure of a B cell follicle as shown in hte pictures, but laquinmod can sort them out. Does this mean it will block progresive MS. We have to wait and see. You can read the papers as it is open access...also read what the reviewers had to say.

Forsthuber TG, Stuve O.Neurol Neuroimmunol Neuroinflamm. 2016 Sep 21;3(5):e283

There was other animal studies presented at ECTRIMS/ISNI showing a model of nerve loss after dysmyelination that was not dependent on the immune T and B immune system and this wa sblocked by laquinimod , That was much mre impressive

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