Alex Bishop

Intrahepatic Murine CD8 T-Cell Activation Associates With a Distinct Phenotype Leading to Bim-Dependent Death

BACKGROUND & AIMS Chronic infections by hepatotropic viruses such as hepatitis B and C are generally associated with an impaired CD8 T-cell immune response that is unable to clear the virus. The liver is increasingly recognized as an alternative site in which primary activation of CD8 T cells takes place, a property that might explain its role in inducing tolerance. However, the molecular mechanism by which intrahepatically activated T cells become tolerant is unknown. Here, we investigated the phenotype and fate of naïve CD8 T cells activated by hepatocytes in vivo. METHODS Transgenic mouse models in which the antigen is expressed in lymph nodes and/or in the liver were adoptively transferred with naïve CD8 T cells specific for the hepatic antigen. RESULTS Liver-activated CD8 T cells displayed poor effector functions and a unique CD25(low) CD54(low) phenotype. This phenotype was associated with increased expression of the proapoptotic protein Bim and caspase-3, demonstrating that these cells are programmed to die following intrahepatic activation. Importantly, we show that T cells deficient for Bim survived following intrahepatic activation. CONCLUSIONS This study identifies Bim for the first time as a critical initiator of T-cell death in the liver. Thus, strategies inhibiting the up-regulation of this molecule could potentially be used to rescue CD8 T cells, clear the virus, and reverse the outcome of viral chronic infections affecting the liver.

Lymphomatoid Papulosis in an 11‐month‐old Infant

Abstract: Lymphomatoid papulosis was seen in an 11‐month‐old child. The condition resolved spontaneously after a course of only 8 weeks and the patient has now been disease free for 9 months. Electron microscopy showed infiltrating lymphocytes with cleaved nuclei suggestive of T cells. Monoclonal antibody studies confirmed the T cell nature of the infiltrate. In this case, suppressor (OKT8) T cells were more prominent than helper (OKT4) T cells, in contrast to previous reports.

Gene array analysis of a rat model of liver transplant tolerance identifies increased complement C3 and the STAT-1/IRF-1 pathway during tolerance induction

This study aimed to define the molecular mechanism during induction of spontaneous liver transplant tolerance using microarrays and to focus on molecular pathways associated with tolerance by meta‐analysis with published studies. The differences in the early immune response between PVG to DA liver transplant recipients that are spontaneously tolerant (TOL) and PVG to Lewis liver transplants that reject (REJ) were examined. Spleens from TOL and REJ on days 1 and 3 were compared by 2 color microarray. Forty‐six of 199 genes differentially expressed between TOL and REJ had an immunological function. More immune genes were increased in TOL vs. REJ on day 1, including STAT‐1, IRF‐1 and complement C3. Differential expression of selected genes was confirmed by quantitative RT‐PCR. The results were compared to two published high‐throughput studies of rat liver transplant tolerance and showed that C3 was increased in all three models, while STAT‐1 and IRF‐1 were increased in two models. The early increases in immune genes in TOL confirmed previous reports of an active early immune response in TOL. In conclusion, the increase in STAT‐1, IRF‐1 and complement component C3 in several models of liver transplant tolerance suggests that the STAT‐1/IRF‐1 apoptotic pathway and C3 may be involved in the tolerogenic mechanism. Liver Transpl 12:636–643, 2006.

Reliable and Reproducible Murine Models for Commonly Used Abdominal Plastic Surgical Flaps

Animal models have been used for many years in surgical research to develop different surgical techniques, improve understanding of anatomy and physiology and hone surgical skills. The benefit of such models has been particularly important in developing relatively young specialties like plastic surgery and many plastic surgical techniques are designed and studied in animals long before they are used in humans. We describe techniques for raising several reliable and reproducible abdominal flaps in rodents, including transverse rectus abdominis myocutaneous flaps in rats and mice, superficial inferior epigastric artery flaps in rats and perforator flaps in rats. The intention of this paper is to act as a point of reference for any microvascular or plastic surgeon who is planning to perform abdominal plastic surgical flap research or further microvascular skills.

Biomarkers of Operational Tolerance in Liver Transplantation

Operational tolerance (OT), defined as continued function of a transplanted organ in the absence of immunosuppression (IS) with a follow up of >1 year, appears to occur relatively frequently after liver transplantation (LTx). There is a pressing need to establish reliable biomarkers to monitor patients who may discontinue IS without risk of rejection. In addition, identification of biomarkers might provide insight into mechanisms of OT that could lead to development of novel therapies for induction of tolerance. Several potential clinical biomarkers have been identified, mainly by retrospective studies using either peripheral blood or graft biopsy tissues. These candidate biomarkers include regulatory T cells (Tregs), γδ T cells, natural killer (NK) cells, B cells, donor-specific antibody (DSA) and/or C4d deposition, dendritic cell (DC) subset ratio, serum human leukocyte antigen-G (HLA-G), and cytokine expression or polymorphism. In the next phase, further large-scale prospective studies are needed to validate existing candidate biomarkers of OT in LTx patients.