You are here: Symposia and Workshops Past ROTRF Symposia and Workshops Satellite Symposium, San Diego 2010
T Cell-mediated Rejection: Emerging Relationships — Puzzles and Paradoxes
12:55: Pathology of Rejection versus Acceptance — Lessons from the Liver
Anthony J. Demetris, University of Pittsburgh Medical Center, Pittsburgh, USA
The routine histopathologic manifestations of antibody-mediated, acute cellular and chronic liver allograft rejection have been well described and can be distinguished from other causes of liver allograft dysfunction such as recurrence of the original disease. These areas are the subject of well-received consensus documents on the topics. Liver allografts are “generally tolerogenic”, very resistant to antibody-mediated rejection. Chronic rejection has decreased greatly in incidence and prevalence since the introduction of tacrolimus – currently, 5% or less of recipients are affected. Therefore, a number of programs throughout the world actively wean stable, long-surviving recipients from all immunosuppression, and such patients are deemed “operationally tolerant” usually after one to two immunosuppression-free years with stable and normal or near normal liver injury tests. In some series 10–15% of long-surviving stable liver allograft recipients can be weaned from all immunosuppression. Consequences to the allograft of long-term survival after withdrawal of immunosuppression, however, are not yet available.
Liver injury tests are a notoriously suboptimal method of monitoring allograft structural integrity. Therefore, most programs weaning patients now mandate protocol biopsies as a method of follow-up after immunosuppression withdrawal. An ongoing effort to develop a more precise clinicopathologic consensus definition of operational tolerance, which includes permissible and non-permissible biopsy changes, will be discussed. Biopsy analysis and interpretation can be quite problematic for long-surviving recipients, and pathologists need to provide “greater value” in these settings. Areas of interpretational difficulties include: 1) distinguishing morphologically and mechanistically among: a) very low-grade cellular rejection, b) “autoimmune” hepatitis, and c) a regulatory cell infiltrate in long-surviving recipients; 2) determining “permissible” changes in biopsies, which frequently contain minimal lymphocytic infiltrates and variable fibrosis in patients completely weaned from immunosuppression; 3) distinguishing between immune-related injury from injury related to “altered physiology”; and 4) the functional significance of various patterns of C4d deposits.
The advent of multiplex quantum dot tissue immunostaining in combination with high resolution whole slide scanning and automated image analysis, however, is opening a new era in pathology. It enables pathologists to more specifically characterize inflammatory cell phenotypes, reaction patterns of endothelial cells, activation states of myofibroblasts, cytokine expression patterns, donor versus recipient composition of the allograft, and specific molecular signaling patterns of interest. Examples aimed at addressing the above problematic areas will be shown. These determinations, in turn, will enable pathologists to better contribute to patient management.