Making MS worse more evidence for a T cell origin

Lisa Ann Gerdes, Kathrin Held, Eduardo Beltrán, Carola Berking, Jörg C. Prinz, Andreas Junker, Julia K. Tietze, Birgit Ertl-Wagner, Andreas Straube, Tania Kümpfel, Klaus Dornmair and Reinhard Hohlfeld CTLA4 as Immunological Checkpoint in the Development of Multiple Sclerosis Anals Neurol 2016 | DOI: 10.1002/ana.24715

We investigated a patient who developed multiple sclerosis (MS) during treatment with the CTLA4-blocking antibody ipilimumab for metastatic melanoma. Initially he showed subclinical magnetic resonance imaging (MRI) changes (radiologically isolated syndrome). Two courses of ipilimumab were each followed by a clinical episode of MS, 1 of which was accompanied by a massive increase of MRI activity. Brain biopsy confirmed active, T-cell type MS. Quantitative next generation sequencing of T-cell receptor genes revealed distinct oligoclonal CD4+ and CD8+ T-cell repertoires in the primary melanoma and cerebrospinal fluid. Our results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint and therapeutic target in MS.

CTLA4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 is a protein receptor that, functioning as an immune checkpoint, downregulates immune responses. CTLA4 is constitutively expressed in Tregs but only upregulated in conventional T cells after activation. It acts as an “off” switch when bound to CD80 or CD86 on the surface of antigen-presenting cells.. In this study when CTLA was blocked with an antibody MS flared

They suggest that CTLA4 is an immunological checkpoint in the development of MS, that is, transition from subclinical RIS to CDMS as observed here.. This interpretation is further supported by 2 additional recent case reports.The first report describes a patient with pre-existing multiple sclerosis who had 2 clinical exacerbations and increased MRI activity shortly after initiation of ipilimumab for metastatic melanoma.The second report describes a 76-year-old patient who developed apparently de novo inflammatory CNS demyelination after treatment with ipilimumab for metastatic melanoma A third report describes a patient whose MS seemed to remain stable after treatment with ipilimumab for melanoma, but the tumor did not respond to ipilimumab, and the patient died due to melanoma progression.

In more general terms, the observations support the autoimmune pathogenesis of MS, and specifically, underline the central importance of autoreactive T cells in the pathogenesis of MS.

However if the CD28 molecule is blocked which is the “on” switch then not much appears to happen in terms of therapy of MS.

Why does it not work in MS when it appears to work in animals?
It is not clear but the T cell activation step may be occurring in the CNS and the infused antibody can’t get into the CNS.

However the antibody may not have to get into the brain in all cases.

Macrez R, Ortega MC, Bardou I, Mehra A, Fournier A, Van der Pol SM, Haelewyn B, Maubert E, Lesept F, Chevilley A, de Castro F, De Vries HE, Vivien D, Clemente D, Docagne F. Neuroendothelial NMDA receptors as therapeutic targets in experimental autoimmune encephalomyelitis. Brain. 2016. pii: aww172. [Epub ahead of print]

Multiple sclerosis is among the most common causes of neurological disability in young adults. Here we provide the preclinical proof of concept of the benefit of a novel strategy of treatment for multiple sclerosis targeting neuroendothelial N-methyl-D-aspartate glutamate receptors. We designed a monoclonal antibody against N-methyl-D-aspartate receptors, which targets a regulatory site of the GluN1 subunit of N-methyl-D-aspartate receptor sensitive to the protease tissue plasminogen activator. This antibody reverted the effect of tissue plasminogen activator on N-methyl-D-aspartate receptor function without affecting basal N-methyl-D-aspartate receptor activity (n = 21, P < 0.01). This antibody bound N-methyl-D-aspartate receptors on the luminal surface of neurovascular endothelium in human tissues and in mouse, at the vicinity of tight junctions of the blood-spinal cord barrier. Noteworthy, it reduced human leucocyte transmigration in an in vitro model of the blood-brain barrier (n = 12, P < 0.05). When injected during the effector phase of MOG-induced experimental autoimmune encephalomyelitis (n = 24), it blocked the progression of neurological impairments, reducing cumulative clinical score (P < 0.001) and mean peak score (P < 0.001). This effect was observed in wild-type animals but not in tissue plasminogen activator knock-out animals (n = 10). This therapeutic effect was associated to a preservation of the blood-spinal cord barrier (n = 6, P < 0.001), leading to reduced leucocyte infiltration (n = 6, P < 0.001). Overall, this study unveils a critical function of endothelial N-methyl-D-aspartate receptor in multiple sclerosis, and highlights the therapeutic potential of strategies targeting the protease-regulated site of N-methyl-D-aspartate receptor.

In this study they blocked a receptor function on the blood vessels and it stopped white blood cell migrating into the CNS. However we know what happens when you block white blood cells getting into the brain, would this be the same?

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