ACTIVATION OF INTRAVASCULAR MACROPHAGES WITHIN MYOCARDIAL SMALL VESSELS IS A FEATURE OF ACUTE VASCULAR REJECTION IN HUMAN HEART-TRANSPLANTS

Background: We investigated the pathogenesis of acute vascular rejecti on by performing immunofluorescent screening on frozen sections for C1 q, C3c, and immunoglobulin M in endomyocardial biopsy specimens from a ll new heart transplants. Methods: Immunofluorescence for C4c, C5, imm unoglobulin G, and immunoglobulin A was performed on all positive endo myocardial biopsy specimens. Twenty-eight positive endomyocardial biop sy specimens from six patients were identified, and 22 of those were s tudied with transmission electron microscopy. Results: Endothelial hyp erplasia and myocyte necrosis were prominent in the five female patien ts with positive immunofluorescence. In addition, macrophages with ult rastructural cytologic features of activation were seen filling capill aries and venules in intimate contact with endothelium and exiting tho se vessels. Activated macrophages were large cells with abundant cytop lasm and ruffled borders and contained numerous lysosomes, rough endop lasmic reticulum, and mitochondria. Intravascular activated macrophage s were identified in five of six patients with positive immunofluoresc ence but were not seen in any of the endomyocardial biopsy specimens w ith negative immunofluorescence, including multiple examples of modera te (grades 2 to 3B) and severe (grade 4) acute cellular rejection. In the five female patients with activated macrophages, acute vascular re jection recurred multiple times with one fatality. Review of the files showed three additional, similar cases. The one male patient with pos itive immunofluorescence but without activated macrophages had only a single episode of acute vascular rejection. Conclusions: Complement an d antibodies can activate macrophages, so this finding is not surprisi ng. To the best of our knowledge, this is the first report of the intr avascular activation of macrophages, and the first association of this process with acute vascular rejection. Activated macrophages may cont ribute to myocyte necrosis in acute vascular rejection by compromising blood flow in small vessels.