7/27/2019 New Drug Target for MS

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Multiple sclerosis (MS) is an autoim-

mune inflammatory disease causedby myelin-specific T cells that inducean immune response against the

white matter of the brain and spinalcord. The current therapeutic optionsare limited. Reporting inNature

Medicine, Yamashita and colleaguesnow show that repulsive guidancemolecule A (RGMa), a membrane-

bound axon guidance molecule,constitutes a promising new targetfor the treatment of MS.

RGMa was originally identifiedin the visual system, and is knownto have a crucial role in the nervous

system. The authors carried outan expression analysis in mice thatrevealed the presence of RGMa in

dendritic cells, which promptedan investigation of its role in theimmune system. In vitroexperiments

showed that RGMa expression canbe induced by stimulating dendriticcells with lipopolysaccharide. RGMa

was found to bind to neogenin, animmunoglobulin superfamily recep-tor that is expressed on CD4+T cells.

Stimulation of CD4+T cells withRGMa results in the activation ofRAP1, a small GTPase that promotes

T cell adhesion by activating theintegrin LFA1.

The relevance of these interac-

tions to the development of MS wasdemonstrated in mice with experi-

mental autoimmune encephalitis(EAE) a model system for MS.Here, it was found that induction

of the disease by vaccination with

MOG, a myelin-derived antigen, wasparalleled by an increase in RGMaexpression on CD11c+dendritic

cells. Immunohistochemical analysisshowed neogenin expression onCD4+T cells, and elevated RAP1

activation in the cervical spinal cordsof mice with EAE, but not in controlmice. In humans, RGMa expression

on dendritic cells was detected insamples of brain and spinal cordfrom patients with MS, but not in

control samples.To test whether RGMa can be

therapeutically targeted, EAE mice

were treated with RGMa-specificantibodies by intraperitonealinjection. This reduced the inva-

sion of inflammatory cells to thecentral nervous system (CNS) andattenuated clinical signs of disease.

Adoptive transfer experiments

in mice in which the disease wasinduced with MOG-pulsed bonemarrow-derived dendritic cells

(BMDCs) confirmed the criticalrole of RGMa on dendritic cellsfor disease induction; BMDCs in

which RGMa was silenced withsmall interfering RNA had a reducedcapacity to induce EAE. Further

experiments indicated that RGMaexpressed on dendritic cells activatesT cells in peripheral tissues and the

CNS, and that RGMa-specific treat-ment reduces T cell proliferation andcytokine responses. Importantly, the

anti-RGMa antibody also showedeffectiveness in a model of relapsingremitting MS, in which administra-

tion of the antibody at the late stageof the first paralytic incident reducedthe clinical severity of relapses.

In humans, it was shown thatthe RGMa-specific antibodycan modulate T cell proliferative

responses and cytokine expression inperipheral blood mononuclear cellsisolated from patients with relapsing

remitting MS. Interestingly, RGMapolymorphisms have been associatedwith MS in humans. These findings

suggest that RGMa is a promisingnew target for the treatment of MS.

Alexandra Flemming

ORIGINAL RESEARCH PAPERMuramatsu, R.

et al.RGMa modulates T cell responses and is

involved in autoimmune encephalomyelitis.

Nature Med. 17, 488494 (2011)

AUTOIMMUNE DISEASE

New drug target for MS?

R E S E A R C H H I G H L I G H T S

NATURE REVIEWS |DRUG DISCOVERY VOLUME 10 |MAY 2011

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