IL-17 increases in secondary progressive MS

Huber AK, Wang L, Han P, Zhang X, Ekholm S, Srinivasan A, Irani DN, Segal BM. Dysregulation of the IL-23/IL-17 axis and myeloid factors in secondary progressive MS. Neurology. 2014 . pii: 10.1212/WNL.0000000000000908. [Epub ahead of print]

OBJECTIVE:In the current exploratory study, we longitudinally measured immune parameters in the blood of individuals with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), and investigated their relationship to disease duration and clinical and radiologic measures of CNS injury.
METHODS: Peripheral blood mononuclear cells (PBMCs) and plasma were obtained from subjects with RRMS, SPMS, and from healthy controls on a monthly basis over the course of 1 year. MRI and Expanded Disability Status Scale evaluations were performed serially. PBMCs were analyzed by enzyme-linked immunosorbent spot assay to enumerate myelin basic protein-specific interleukin (IL)-17- and interferon (IFN)-γ-producing cells. Plasma concentrations of proinflammatory factors were measured using customized Luminex panels.
RESULTS: Frequencies of myelin basic protein-specific IL-17- and IFN-γ-producing PBMCs were higher in individuals with RRMS and SPMS compared to healthy controls. Patients with SPMS expressed elevated levels of IL-17-inducible chemokines that activate and recruit myeloid cells. In the cohort of patients with SPMS without inflammatory activity, upregulation of myeloid-related factors correlated directly with MRI T2 lesion burden and inversely with brain parenchymal tissue volume.
CONCLUSIONS: The results of this exploratory study raise the possibility that Th17 responses and IL-17-inducible myeloid factors are elevated during SPMS compared with RRMS, and correlate with lesion burden. Our data endorse further investigation of Th17- and myeloid-related factors as candidate therapeutic targets in SPMS.

Th17 what do they do? At one point autoimmunity was caused by Th1 cells andthese were generated by interleukin 12 because the disease in animals could be blocked by antibodies that blocked the Interleukin 12 receptor (p40 molecule). But Oops it was found that it was not interleukin 12 (the receptor is two chains a p40 and p35 molecule) but interleukin 23 (the receptor is a p40 and a p19 molecule). The cells generated by interleukin 23 produce interleukin 17 and (Th17) cells were born. These were then the cells that cause autoimmunity, or are they. Now there is a school showing that you can get Th1 disease in mice and also a Th17-induced disease in mice. This is different from typical EAE and is associated with lots of neutrophils (white blood cell type) rather than  monnuclear (lymphocytes and macrophages). What do they do.

So as soon a interleukin 12 was found clinical trials were initiated anti-IL12/23 stopped animals from getting EAE, however it did nothing to stop spontaneously relapsing EAE (forgotten paper), and it did not stop relapsing MS. So lets inhibit interleukin 17 and see what happens and in most cases not very much in early EAE, but better in late EAE. Studies are ongoing in MS, but where do you target the Th17? 
If you follow the dogma as TH17 being causal then it should be early in MS, but in this study looking at when Th17 responses appear in MS, there is an inference that maybe one should look later and notably in SPMS. Given that to date anti-immunologicals have failed in SPMS would you take the risk of $10,000,000 trial to find out. A case could be made on available data, (e.g. link to B cell follicles etc) will this happen? Will other cytokines be targeted?

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