Functional Immune Anatomy of the Liver-As an Allograft.

The liver is an immunoregulatory organ in which a tolerogenic microenvironment mitigates the relative "strength" of local immune responses. Paradoxically, necro-inflammatory diseases create the need for most liver transplants. Treatment of hepatitis B virus, hepatitis C virus, and acute T cell-mediated rejection have redirected focus on long-term allograft structural integrity. Understanding of insults should enable decades of morbidity-free survival after liver replacement because of these tolerogenic properties. Studies of long-term survivors show low-grade chronic inflammatory, fibrotic, and microvascular lesions, likely related to some combination of environment insults (i.e. abnormal physiology), donor-specific antibodies, and T cell-mediated immunity. The resultant conundrum is familiar in transplantation: adequate immunosuppression produces chronic toxicities, while lightened immunosuppression leads to sensitization, immunological injury, and structural deterioration. The "balance" is more favorable for liver than other solid organ allografts. This occurs because of unique hepatic immune physiology and provides unintended benefits for allografts by modulating various afferent and efferent limbs of allogenic immune responses. This review is intended to provide a better understanding of liver immune microanatomy and physiology and thereby (a) the potential structural consequences of low-level, including allo-antibody-mediated injury; and (b) how liver allografts modulate immune reactions. Special attention is given to the microvasculature and hepatic mononuclear phagocytic system.

Banff fibrosis study: multicenter visual assessment and computerized analysis of interstitial fibrosis in kidney biopsies.

Increasing interstitial fibrosis (IF) in native and kidney transplant biopsies is associated with functional decline and serves as a clinical trial end point. A Banff 2009 Conference survey revealed a range in IF assessment practices. Observers from multiple centers were asked to assess 30 renal biopsies with a range of IF and quantitate IF using two approaches on trichrome, Periodic acid-Schiff (PAS) and computer-assisted quantification of collagen III immunohistochemistry (C-IHC) slides, as well as assessing percent of cortical tubular atrophy% (TA%) and Banff total cortical inflammation score (ti-score). C-IHC using whole slide scans was performed. C-IHC assessment showed a higher correlation with organ function (r = -0.48) than did visual assessments (r = -0.32--0.42); computerized and visual C-IHC assessment also correlated (r = 0.64-0.66). Visual assessment of trichrome and C-IHC showed better correlations with organ function and C-IHC, than PAS, TA% and ti-score. However, visual assessment of IF, independent of approach, was variable among observers, and differences in correlations with organ function were not statistically significant among C-IHC image analysis and visual assessment methods. C-IHC image analysis correlated among three centers (r > 0.90, p < 0.0001, between all centers). Given the difficulty of visual IF assessment standardization, C-IHC image could potentially accomplish standardized IF assessment in multicenter settings.

C4d immunopositivity is uncommon in ABO-compatible liver allografts, but correlates partially with lymphocytotoxic antibody status.

AIMS: To determine whether C4d immunopositivity helps recognition of humoral rejection in dysfunctional liver allografts. METHODS AND RESULTS: C4d immunopositivity was retrospectively evaluated in liver allografts. There were three staining patterns: portal venular plexus, sinusoidal and hepatocellular. The latter was related to ischaemic necrosis and not scored as positive. C4d immunopositivity was not encountered in 10 preperfusion or 15 consecutive early protocol biopsies. However, three of 12 early protocol biopsy specimens from crossmatch-positive patients were C4d+, two showing repeated positivity on at least one further biopsy specimen, while others remained negative. C4d was also positive in 2/16 early moderate acute cellular rejections, 3/14 cases of centrilobular necroinflammation, 3/11 biliary obstructions, 3/13 chronic rejections and 1/10 primary non-functional allografts. CONCLUSION: C4d immunopositivity is uncommon in liver allografts. There is a weak positive correlation with a positive lymphocytotoxic crossmatch and some patterns of allograft dysfunction. The morphological associations resemble those reported in lymphocytotoxic crossmatch-positive patients, plus occasional sinusoidal and hepatocellular injury. Although the practical utility of C4d immunohistochemistry seems limited, it may identify a small subgroup of individuals in whom chronic humoral microvascular injury contributes to allograft dysfunction.

Transplant histopathology for the general histopathologist.

The number of patients undergoing solid organ transplants and surviving long-term has increased enormously in the last 10 years. This means that pathologists in non-specialist transplant centres are increasingly involved in the interpretation of biopsy and autopsy material from allograft recipients. This includes evaluation of allograft histology, or specimens from other native tissues, which nonetheless still have to be assessed in the setting of transplantation and immunosuppressive therapy. In this first review article we will provide an overview of the pathology of lung transplantation, and briefly describe heart and pancreatic transplants, as well as aspects of general surgical pathology and the role of the autopsy in these patients.