Systemic immunodepression after stroke (central nervous system [CNS] injury induced immunodepression syndrome, CIDS) increases the susceptibility towards infections that have detrimental effects on neurological outcome. Here, I have investigated whether immunodepression after stroke represents an adaptive mechanism for reducing the likelihood of developing CNS antigen specific immune responses and consequences of suppressing this mechanism.
A murine model of middle cerebral artery occlusion (MCAo) and pharmacological blocking of the effects regarding CIDS mediated by sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis were applied. Propranolol and mifepristone, respectively, were applied to wild-type C57Bl/6J and 2D2 transgenic mice, whose CD4+ T cells have been described to exert detrimental effects against CNS-antigen myelin oligodendrocyte glycoprotein (MOG). The role of β2-adrenoreceptor in SNS mediated CIDS was investigated in β2-adrenoreceptor knockout mice. To elucidate the CD4+ T-cell aggressiveness induced by stroke these cells were harvested from a group of 2D2 mice that received MCAo and treatment with propranolol and mifepristone, and were adoptively transferred to lymphocyte deficient Rag-1KO mice after MCAo.
Blocking SNS mediated CIDS decreased the rate of bronchopulmonary infections, increased MOG-specific type 1 T helper (Th1) cell responses in the ischemic brains of 2D2 mice but did not worsen the long-term neurological outcome in these mice.
Blocking simultaneously SNS with propranolol and HPA axis with mifepristone resulted in a stably two thirds smaller infarct volume, decreased infection rate, improved health status and long-term survival of 2D2 and C57Bl/6J mice. It increased MOG-specific Th1 cell responses in the ischemic brains of 2D2 mice. This was not accompanied by worse functional neurological outcome in these mice based on EAE like disease development and locomotor deficits. After stroke, 2D2 mice developed polyradiculitis-like phenotype, the symptoms of which were diminished by blocking SNS and HPA axis illustrated by normalization of stroke-induced elongated F-wave latencies upon sciatic nerve stimulation and diminished T cell and macrophage infiltration into spinal nerve roots after MCAo. CD4+ T cells from treated 2D2 mice did not worsen long-term neurological outcome in RAG-1KO mice following adoptive transfer.
In conclusion, pharmacological blocking of SNS and HPA axis with propranolol and mifepristone resulted in infarct volumes sustainably smaller by two thirds in 2D2 as well as in C57Bl/6J mice, increased MOG-specific Th1-type immune responses in the ischemic brains of 2D2 mice but did not worsen long-term neurological outcome.
PDF-Datei von FUDISS_thesis_000000098339
Falls Ihr Browser eine Datei nicht öffnen kann, die Datei zuerst herunterladen und dann öffnen.