CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis

@article{citeulike:3139318, abstract = {10.1073/pnas.0800898105 The migration of lymphocytes into the CNS during viral encephalitis is hindered by the blood–brain barrier (BBB) such that most infiltrating cells remain localized to perivascular spaces. This sequestration of leukocytes away from the parenchyma is believed to protect the CNS from immunopathologic injury. Infections of the CNS with highly cytopathic neurotropic viruses, such as West Nile virus (WNV), however, require the parenchymal penetration of T lymphocytes for virus clearance and survival, suggesting that perivascular localization might hinder antiviral immune responses during WNV encephalitis. Using human and murine brain specimens from individuals with WNV encephalitis, we evaluated the expression of CXCL12 and its receptor, CXCR4, at the BBB and tested the hypothesis that inhibition of CXCR4 would promote T lymphocyte entry into the CNS parenchyma and increase viral clearance. Antagonism of CXCR4 significantly improved survival from lethal infection through enhanced intraparenchymal migration of WNV-specific CD8 T cells within the brain, leading to reduced viral loads and, surprisingly, decreased immunopathology at this site. The benefits of enhanced CD8 T cell infiltration suggest that pharmacologic targeting of CXCR4 may have therapeutic utility for the treatment of acute viral infections of the CNS.}, author = {Mccandless, Erin E. and Zhang, Bo and Diamond, Michael S. and Klein, Robyn S. }, citeulike-article-id = {3139318}, doi = {http://dx.doi.org/10.1073/pnas.0800898105}, journal = {Proceedings of the National Academy of Sciences}, keywords = {flavivirus, pathogenesis}, number = {32}, pages = {11270--11275}, posted-at = {2008-08-20 10:34:22}, priority = {2}, title = {CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis}, url = {http://dx.doi.org/10.1073/pnas.0800898105}, volume = {105}, year = {2008} }

TY - JOUR ID - citeulike:3139318 L3 - citeulike-article-id:3139318 N2 - 10.1073/pnas.0800898105 The migration of lymphocytes into the CNS during viral encephalitis is hindered by the blood–brain barrier (BBB) such that most infiltrating cells remain localized to perivascular spaces. This sequestration of leukocytes away from the parenchyma is believed to protect the CNS from immunopathologic injury. Infections of the CNS with highly cytopathic neurotropic viruses, such as West Nile virus (WNV), however, require the parenchymal penetration of T lymphocytes for virus clearance and survival, suggesting that perivascular localization might hinder antiviral immune responses during WNV encephalitis. Using human and murine brain specimens from individuals with WNV encephalitis, we evaluated the expression of CXCL12 and its receptor, CXCR4, at the BBB and tested the hypothesis that inhibition of CXCR4 would promote T lymphocyte entry into the CNS parenchyma and increase viral clearance. Antagonism of CXCR4 significantly improved survival from lethal infection through enhanced intraparenchymal migration of WNV-specific CD8 T cells within the brain, leading to reduced viral loads and, surprisingly, decreased immunopathology at this site. The benefits of enhanced CD8 T cell infiltration suggest that pharmacologic targeting of CXCR4 may have therapeutic utility for the treatment of acute viral infections of the CNS. IS - 32 JF - Proceedings of the National Academy of Sciences EP - 11275 TI - CXCR4 antagonism increases T cell trafficking in the central nervous system and improves survival from West Nile virus encephalitis VL - 105 SP - 11270 KW - flavivirus KW - pathogenesis AU - Mccandless, Erin AU - Zhang, Bo AU - Diamond, Michael AU - Klein, Robyn PY - 2008//12/ UR - http://dx.doi.org/10.1073/pnas.0800898105 ER -