Re‐examination of the Lymphocytotoxic Crossmatch in Liver Transplantation: Can C4d Stains Help in Monitoring?

C4d-assisted recognition of antibody-mediated rejection (AMR) in formalin-fixed paraffin-embedded tissues (FFPE) from donor-specific antibody-positive (DSA+) renal allograft recipients prompted study of DSA+ liver allograft recipients as measured by lymphocytotoxic crossmatch (XM) and/or Luminex. XM results did not influence patient or allograft survival, or cellular rejection rates, but XM+ recipients received significantly more prophylactic steroids. Endothelial C4d staining strongly correlates with XM+ (<3 weeks posttransplantation) and DSA+ status and cellular rejection, but not with worse Banff grading or treatment response. Diffuse C4d staining, XM+, DSA+ and ABO- incompatibility status, histopathology and clinical-serologic profile helped establish an isolated AMR diagnosis in 5 of 100 (5%) XM+ and one ABO-incompatible, recipients. C4d staining later after transplantation was associated with rejection and nonrejection-related causes of allograft dysfunction in DSA- and DSA+ recipients, some of whom had good outcomes without additional therapy. Liver allograft FFPE C4d staining: (a) can help classify liver allograft dysfunction; (b) substantiates antibody contribution to rejection; (c) probably represents nonalloantibody insults and/or complete absorption in DSA- recipients and (d) alone, is an imperfect AMR marker needing correlation with routine histopathology, clinical and serologic profiles. Further study in late biopsies and other tissue markers of liver AMR with simultaneous DSA measurements are needed.     

Concanavalin A simultaneously primes liver hematopoietic and epithelial progenitor cells for parallel expansion during liver regeneration after partial hepatectomy in mice

Liver hematopoietic progenitor cells (LHPC) and liver epithelial progenitor cells (LEPC) share a remarkable number of growth and differentiation-controlling receptor-ligand signaling systems. These likely account for the ability of the liver to support hematopoiesis in fetal life, and possibly for suggestions that LHPC can differentiate into hepatocytes. In these experiments, the kinetics and magnitude of LHPC and LEPC activation and expansion were studied by using a concanavalin A (Con A) liver injury model followed by partial hepatectomy (PH). Studies were performed in interleukin 6-deficient (IL-6(-/-)) mice and wild-type (IL-6(+/+)) controls, which show equal susceptibility to Con A- induced injury, because IL-6/gp130 signaling has been implicated in both LHPC and LEPC expansion. Con A pretreatment primed LHPC and LEPC for a rapid and parallel expansion after PH in IL-6(+/+) mice, which was significantly blunted and delayed in the IL-6(-/-) mice. Exogenous IL-6 given immediately before PH after Con A, augmented both LHPC and LEPC expansion in the IL-6(-/-) mice. Thus, the proinflammatory cytokine IL-6, commonly produced in liver injury and inflammatory disease, is an important growth factor involved in the expansion of LHPC and LEPC. This observation has implications for both hepatic carcinogenesis and transplantation.     

Pathology of human intestinal transplantation

BACKGROUND & AIMS: Intestinal transplantation is a developing therapeutic option for patients with irreversible intestinal failure or short bowel syndrome. The aim of this study was to delineate the histopathology of human intestinal allografts and to define the features of intestinal rejection. METHODS: The histological features of 3015 endoscopic biopsy specimens and 23 allograft specimens from 62 intestinal recipients were analyzed retrospectively and correlated with clinical findings. RESULTS: Acute allograft rejection was characterized by a varying combination of crypt injury, mucosal infiltration primarily by mononuclear cells (including blastic lymphocytes), and increased crypt cell apoptosis (more than 2 per 10 crypts). It represented a patchy, often ileal-centered process that could progress to mucosal ulceration; later episodes (more than 100 days posttransplant) tended to show lesser cellular infiltration and greater apoptosis than earlier episodes. Correlation with clinical rejection was good (false-positive rate of 9%; false-negative rate of 26%). Two resected specimens showed obliterative arteriopathy indicative of chronic rejection. In other specimens, preservation injury, cytomegalovirus infection, post-transplant lymphoproliferative disorder, and nonspecific features of active or past mucosal injury could be recognized. CONCLUSIONS: Mucosal biopsy specimens are a useful means of monitoring intestinal allografts. Based on features validated by clinical correlation, acute rejection can be identified reliably and can be differentiated from the other pathological processes affecting the intestinal allograft. (Gastroenterology 1996 Jun;110(6):1820-34)     

De novo malignancies after intestinal and multivisceral transplantation

BACKGROUND: Maintenance immunosuppression required after organ transplantation creates a permissive environment in which cancer cells can proliferate because of lack of natural immunologic surveillance. With more than a decade of clinical experience, this report is the first to address the risk of de novo cancer after intestinal transplantation. METHODS: A total of 168 consecutive intestinal transplant recipients (86 children and 82 adults) were studied, of whom 52% were male and 91% were white. Surveillance, Epidemiology, and End Results data was used to count expected rates of de novo cancers in the general population matched for age, sex, and length of follow-up. RESULTS: With a mean follow-up of 47+/-41 months, 7 (4.2%) patients developed nonlymphoid de novo cancer, with a cumulative risk of 3% at 5 years and 28% at 10 years. Of these malignancies, one was donor-driven adenocarcinoma. With 0.58 being the expected rate of malignancy for the general population, the risk among intestinal recipients was 8.7 times higher (P =0.01). Such morbidity was significantly higher (50 times) among younger patients (<25 years), with a slight male preponderance. Induction immunosuppression was associated with early onset of de novo cancer. Patient survival after diagnosis of de novo cancer was 72% at 1 year, 57% at 2 years, and 29% at 5 years. CONCLUSION: With conventional immunosuppression, intestinal recipients are at a significantly higher risk of developing de novo cancer when compared with the general population. Thus, a novel tolerogenic immunosuppressive strategy has been recently implemented to reduce the lifelong need for immunosuppression.     

Genotyping of presenilin-1 polymorphism in amyotrophic lateral sclerosis

The mechanisms underlying motor neuron degeneration in amyotrophic lateral sclerosis are not fully understood. Recent studies suggest that apoptosis is involved in the abnormal neural death that occurs in this devastating disease. Presenilin-1, a transmembrane protein, seems to be implicated in apoptosis. To determine whether presenilin-1 intron 8 polymorphism has an influence in the course of amyotrophic lateral sclerosis, we examined this polymorphism genotypes in a large group of patients (n=72) with amyotrophic lateral sclerosis and in a random sample of 213 healthy individuals. The results showed a significant difference in genotype (P < 0.04) and allele (P < 0.03) distribution between patients and controls. These results suggest a possible intervention of presenilin-1 in the pathogenesis of amyotrophic lateral sclerosis. Received: 14 February 2000 / Received in revised form: 20 April 2000 / Accepted: 4 June 2000