Work in my laboratory is divided into two main research areas: 1) chemokines and chemokine receptors in defense and disease following microbial infection and 2) mouse/human neural progenitor cells (NPCs) and remyelination following viral-induced demyelination. Below, I highlight funded research ongoing within the laboratory.
1. Chemokines and chemokine receptors in defense and disease following viral infection of the CNS.
My laboratory has a long-standing interest in understanding events that initiate and maintain inflammation within the CNS in response to viral infection. To this end, we have set forth on a directed path to determine the functional significance of chemokines and chemokine receptors in both host defense as well as disease development following instillation of a positive-strand RNA virus (mouse hepatitis virus – MHV) into the CNS of susceptible mice. Indeed, we were the first laboratory to show that blocking chemokine function via both antibody neutralization and genetic silencing in virally-infected mice resulted in increased mortality accompanied by reduced immune cell infiltration into the CNS.
Subsequently, we have shown that unique chemokine/chemokine receptor signaling pathways are critical for interrelated events required for optimal host defense following viral infection including linking innate and adaptive immune responses, regulating antiviral effector functions e.g. cytokine secretion/cytolytic activity by effector T cells, and promoting the directional migration of antigen-sensitized lymphocytes into the CNS. We have also focused on how chemokine signaling influences the biology of oligodendroglia with regards to protection from inflammatory cytokine-induced apoptosis.
2. Mouse/human neural progenitor cells (NPCs) and remyelination following viral-induced demyelination.
MHV infection of the CNS results in viral persistence in white matter tracts leading to chronic infiltration of activated lymphocytes and macrophages that contribute to demyelination. Importantly, generation of autoreactive T lymphocytes specific for myelin proteins e.g. myelin basic protein (MBP) and proteolipid protein (PLP) is not prevalent therefore epitope-spreading is not a relevant aspect in this model system. Additionally, MHV-induced demyelination results in moderate-to-severe clinical disease characterized by hind-limb paralysis. Similar to the human demyelinating disease multiple sclerosis (MS), remyelination failure is also observed in MHV-infected mice. Therefore, an important and clinically-relevant question related to demyelinating diseases is to design therapies that promote remyelination of demyelinated axons.
We have previously shown that surgical engraftment of syngeneic neural progenitor cells (NPCs) into mice persistently-infected with MHV results in survival and migration of engrafted NPCs accompanied by extensive remyelination. We are the only group, to my knowledge, examining the therapeutic potential of cell replacement strategies using a viral model of demyelination. This is important in that the etiology of MS remains enigmatic and viruses have long been considered important as a potential triggering agent in inducing demyelinating diseases such as MS. Moreover, numerous viruses are capable of persisting within the CNS therefore understanding if NPCs are capable of promoting repair within this environment is critical.
We have determined that transplanted cells migrate to areas of demyelination by responding to the specific chemokines expressed within areas of demyelination. We have now moved forward with our studies on NPC-mediated clinical/histological recovery to address whether allogeneic NPCs are antigenic and subject to immune-mediated rejection. We are also investigating the therapeutic potential of human NPCs (hNPCs) in mediating functional recovery following transplantation into MHV-infected mice. We have determined that intraspinal transplantation of hNPCs into MHV-infected mice results in rapid rejection. Therefore, we are now interrogating mechanisms by which to prolong hNPC survival. More importantly, we have shown that transplantation of hNPCs results in sustained clinical recovery lasting out to six months post-transplant (p.t.). Our data indicates that hNPCs are immunosuppressive as evidenced by dramatic reduction in neuroinflammation accompanied by remyelination within the spinal cords of transplanted animals. These findings are provocative and indicate that hNPCs are indeed therapeutic although rapidly rejected.