Abstract
With the near-eradication of polio, Guillain-Barré syndrome (GBS) has become the most frequent cause of acute flaccid
paralysis. There are two major forms of GBS, demyelinating and axonal, based on the primary injury to myelin/Schwann
cells or axon of the myelinated nerve fibers, respectively. Current immunomodulatory treatments are only effective in a
proportion of patients. For example, IVIG–a first line treatment modality in GBS–hasten recovery in only ~50% of those
treated with this medication. Despite availability of current of immunotherapies, a significant proportion of patients are left
with severe and permanent neurologic sequelae, including inability to walk independently. There is a dire need for
newer/additional immune treatments that can target relevant pathophysiologic mechanisms and limit the neural injury in
acute phase of the disease. Cellular inflammatory effectors are invoked to play major role in the pathogenesis of
demyelinating GBS, whereas autoantibodies against gangliosides/glycolipids are involved in the pathogenesis of axonal
GBS. Human pathologic studies and data from animal modelling indicate that macrophage lineage cells are final executioner
of nerve injury in demyelinating and axonal GBS. Colony stimulating factor 1 receptor (CSF1R) plays critical role in
proliferation, survival and function of monocytes and fully differentiated macrophages including transmigration in response
to its ligand(s). We hypothesize that blockade of this receptor on macrophage lineage cells can alter the macrophage
recruitment and reduce endoneurial macrophage burden and associated inflammatory nerve injury. This hypothesis will be
tested by the following specific aims: Aim 1 will examine the efficacy of CSF1R blockade (with a neutralizing antibody
and a small molecule inhibitor) in: a) anti-ganglioside antibody-mediated model of axonal GBS; and b) transgenic T-
lymphocyte mediated inflammatory demyelinating model of GBS. Studies under Aim 1 will also compare IVIG to CSF1R
antagonists in axonal and demyelinating GBS models. Synergy between CSF1R inhibitors and IVIG will also be examined
in this Aim. Aim 2 will examine the role of CSF1R signaling in infiltration of circulating monocytes/macrophages in the
injured nerves by generating bone marrow chimeras and bone marrow derived-macrophage and peripheral nerve tissue co-
culture model. These studies will use wild type, CSF1 mutant osteopetrotic, and transgenic CSF1R deficient mice. Aim 3
will validate the expression of CSF1 and CSF1R in nerves obtained from GBS and related chronic inflammatory
demyelinating polyradiculoneuropathy (CIDP) patients and compared to diseased and nondiseased controls. The
proposal
inflammation
tests a unifying hypothesis that
and injury in demyelinating and axonal models of GBS.
the CSF1R on circulating macrophage lineage cells are
current
central to endoneurial
CSF1R blocking stratgies in this project are
translatable as the small molecuel inhibitor proposed for these studies is already in a clinical trial and a number of
monoclonal CSF1R neutralizing antibodies are in clinincal development for cancer. This project may help in developing a
new treatment strategy that has relevance not only to GBS but other immune neuropathies including CIDP.