The role of macrophages, perivascular cells, and microglial cells in the pathogenesis of experimental autoimmune encephalomyelitis.

Clinical signs of experimental autoimmune encephalomyelitis (EAE) in rats can be suppressed by treatment with liposomes containing dichloromethylene diphosphonate (Cl2MDP liposomes). Here we investigated whether besides the blood-borne macrophages also ED2+ perivascular cells and microglia are affected by this treatment. For this purpose we examined the central nervous system of bone marrow chimeras in which EAE was induced with encephalitogenic T cells. Quantification of cell numbers of various cell types in inflammatory lesions in the spinal cord showed that after treatment with Cl2MDP liposomes more than 95% of the bone marrow derived (I1-69+) macrophages were eliminated. In addition the number of ED2+ perivascular cells were seen to be decreased by 68% as compared to ED2+ cells in control liposome treated animals. However the number of these perivascular cells in Cl2MDP liposome treated animals did not differ from the number of perivascular cells in naive animals, indicating that only newly recruited, inflammation associated, ED2+ macrophages were eliminated. Moreover, detection of degenerating nuclei by in situ nick translation (ISNT) in combination with staining for ED1 or ED2 showed that in the perivascular space no degenerating cells were present. Cl2MDP liposome treatment furthermore decreased the numbers of T cells infiltrating the parenchyma by more than 50%. Instead T cells were found in large numbers in the perivascular space. Microglia did not seem to be eliminated by Cl2MDP liposome treatment as shown by the absence of ED1+/ISNT+ cells in the CNS parenchyma. However the number of ED1+ (I1-69-) microglial cells decreased by more than 80%, indicating that the activation of this cell type was impaired. It is concluded that bone marrow derived macrophages play an important role in the pathogenesis of EAE via interactions with lymphocytes and the activation of resident microglia.