Brain Vessels near Muscle Autografts Are Sites for Entry of Isogeneic Macrophages into Brain

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An autograft of skeletal muscle on rat dorsal medulla is a permanent opening in the blood-brain barrier to solutes. Is the graft also a site for the entry of exogenous, isogeneic leukocytes? Five weeks after inserting the graft, peritoneal macrophages (Mφ) from inbred Fischer rats were activated by phorbol myristate acetate, labeled with a fluorescent dye, and infused as a bolus of about 2 × 106 cells into the axillary artery of Fischer hosts. The cells circulated for 2 h. The brains were then fixed, frozen, and sectioned. Only when Mφ had been activated and a muscle autograft inserted did appreciable numbers of Mφ enter the medulla. Nonactivated Mφ invaded the grafts but very few entered the brain at 2 h. In rats with gel foam grafts, only a few activated Mφ invaded gel and brain. Before entering tissues, Mφ must adhere to the lumenal face of vessels. Cell adhesion molecules, e.g., I-CAM-1 and its ligand adhesion molecule, leukocyte function antigen (LFA-1), are known to mediate adhesion. I-CAM-1, detected immunohistochemically, increased in graft vessels and in nearby brain vessels. The rise may have been mediated by cytokines, interleukin-6, and tumor necrosis factor-β, found in the grafts. LFA-1, however, assayed by fluorescence-activated cell sorting, was on both activated and nonactivated, exogenous Mφ. Thus, Mφ-endothelial attachment may have involved other adhesion molecules, e.g., selections. The autograft also induced major histocompatability complex class I on microglia and classes I and II on brain vessels near the graft. These vessels, by expressing adhesion molecules, are entry routes into brain for activated, isogeneic leukocytes that can then migrate for a limited distance of 1-2 mm in an otherwise intact brain.