Humorally mediated posttransplantation septal capillary injury syndrome as a common form of pulmonary allograft rejection: A hypothesis

Background. Cellular immunity is the reputed mechanism of lung allograft failure. Humoral immunity is not a commonly recognized pathway. Material and Methods. We describe 22 patients who developed a posttransplantation septal capillary injury syndrome in the absence of panel-reactive antibodies. Factor VIII levels served as an index of microvascular injury. Routine light microscopic studies were performed in a total of 73 biopsies; 54 biopsy specimens were analyzed for deposition of C1q, C4d, C5b-9, and immunoglobulin (IgG, IgM, and IgA). Indirect immunofluorescent testing to assess for antiendothelial cell antibodies was performed using patient serum and human pulmonary microvascular endothelial cell cultures as substrate. Control samples were based on patients who were clinically well at the time of the biopsy. Results. All presented with a deterioration in respiratory function. All patients had elevated factor VIII levels; the levels were significantly greater compared with pretransplantation baseline values (P=<0.03). The biopsy specimens were remarkable for septal capillary necrosis with significant septal capillary deposition of C1q, C3, C4d, and/or C5b-9 along with immunoglobulin, including IgG, with variable endothelial cell localization. The degree of septal capillary necrosis was significantly less in posttransplantation patients who were clinically doing well (P<0.0001) as was the degree of C1q, C3, C4d, and C5b-9 (P<0.05). Indirect antiendothelial cell antibody studies were positive in most patients. Treatment interventions included plasmapheresis, resulting in functional improvement: the postpheresis biopsy specimens showed a reduction in both the degree of septal capillary injury (P<0.0003) and the amount of C1q, C3, C4d, and C5b-9 deposition (P<0.05). Conclusions. Septal capillary injury accompanied by direct and indirect immunofluorescent evidence of humoral immunity is a frequent finding on transbronchial biopsies. The findings suggest that humoral immunity to endothelial-based alloantigen is a common occurrence in lung grafts and may be a critical factor in chronic graft dysfunction.