Reproduction de : Thèse d'exercice : Médecine : Nancy 1 : 2004. / Titre provenant de l'écran-titre.

Thèse de doctorat : Pharmacologie : Nancy 1 : 2008. / Titre provenant de l'écran-titre.

Thesis (Ph. D.)--Rutgers University, 2009. / "Graduate Program in Materials Science and Engineering." Includes bibliographical references.

Thesis (Ph. D.)--Case Western Reserve University, 2004. / [School of Medicine] Department of Pathology. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Thesis (Ph. D.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 171-191).

published_or_final_version / Surgery / Master / Master of Research in Medicine

Chronic rejection is a major obstacle to long-term survival of organ transplants. PPAR-γ agonist rosiglitazone has been shown to reduce graft rejection but the underlying mechanisms remain unclear. Combined treatment of rosiglitazone and anti-IL-5 antibody prevented MHC class II histoincompatiblecardiac graft rejection with a reduction of cellular infiltration, vasculopathy and interstitial fibrosis in a heterotopic heart transplantation model. In particularly, rosiglitazone decreased CD8 T cells infiltration and luminal occlusion, while anti-IL-5 antibody reduced eosinophil infiltration and collagen deposition. Adiponectin gene (APN) is a PPAR-γ target gene, and the expression of APN receptor AdipoRII in grafts, dendritic cells (DCs) and T cells are increased by rosiglitazone. These findings prompted me to further examine the immunomodulatory role of APN in graft rejection. APN is an anti-inflammatory adipocytokine, and has been shown to inhibitimmunostimulatory function of monocytes and macrophages. Rosiglitazone suppresses DCs maturation, activation and proliferation;hence, it is possible that APN could protect graft rejection through immunoregulation of DCs. Here, using in vitro culture systems, I found that APN has only moderate effect on the differentiation of bone marrow derived DCs but itcould alter DC phenotypes. APN-treated DCs showed an increased expression of PD-L1, which is consistent with the increased PD-L1 expression in rosiglitazone treated cardiac allografts. APN-treated DCs led to a decreased proliferation and reduction of IL-2production of T cell. Moreover, APN-treated DCs increased the expansion of Tregs (regulatory T cells) which could be inhibited by the blockage of PD-1/PD-L1 pathway, suggesting that PD-1/PD-L1 pathway and expansion of Tregs played important roles in APN-treated DCs mediated immunomodulation. Further, I employed APN-/-mice for functional and mechanistic studies, and found that cardiac allografts were not rejected by APN-/-recipient mice even after 120 days post-transplantation. Histological analyses revealed very little eosinophils, CD4 and CD8 T cells infiltration; no collagen deposit and no vessel occlusion in the cardiac allografts. Furthermore, Th2 cytokines such as IL-4 and IL-5 were lower in cardiac allografts and in the serum of APN-/-recipient. Inhibition of AMPK signaling, a major APN mediated pathway, reduced the eosinophils infiltration in wild type recipient. In contrast, AMPK activation increased eosinophils infiltration in APN-null recipient. APN enhanced T cell proliferation. AMPK and P38MAPK inhibitors as well as anti-IL-4 antibody inhibited APN-induced T cell proliferation. P38 MAPK inhibitors reduced IL-4 production in mature DCs but enhanced IL-4 expression in immature DCs. In EL-4 T cells, APN increased nuclear expressions of GATA-3 and p-STAT6 and augmented IL-4 expression, and the phenomenon was suppressed by target specific knockdown of AdipoR I and II. In summary, current study provides new mechanistic insights of PPAR-γ activation and APN signaling in the modulation of adaptive and transplantation immunity, establishing a link between metabolism and immune regulation. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Background: Hepatocellular carcinoma is one of the most fatal diseases worldwide. Liver transplantation dramatically improved the survival rate of HCC patients. However, tumor recurrence remains a huge threat to HCC patients without any promising curative treatment. Chemotherapy, as one of the potential treatments to recurrent HCC, did not show any significant effect either. Objective: We aim to investigate the role of interferon-gamma inducible protein 10 (IP10) in acute-phase liver graft injury induced late-phase cisplatin resistance after liver transplantation and to explore the underlying mechanism. Furthermore, a potential adjuvant therapy was expected to be identified to sensitize cisplatin treatment in HCC. Materials and methods: A rat orthotopic liver transplantation model was established with applying whole or small-for-size (50%) graft. Afterwards, a rat hepatoma cell (MH7777) was injected via portal vein to generate recurrent tumor. The expressions of genes linked to multi-drug resistance and graft injury were compared between tumors developed after liver transplantation using small and whole grafts. IP10 expression was further validated in clinical samples from two cohorts of patients including HCC patients with hepatectomy and HCC patients with liver transplantation. The extracellular and intracellular roles of IP10 were examined in vitro by using IP10 recombinant protein and IP10 stable transfectants in HCC cell lines. The correlation between IP10 expression and tumor growth was investigated in three in vivo nude mice models including a subcutaneous model, an orthotopic model and ischemia reperfusion injury model. The underlying mechanism was further explored in vitro, in vivo and in clinical samples. IP10 neutralizing antibody was employed as an adjuvant therapy to identify its effect on sensitizing cisplatin treatment in HCC. Results: The expressions of multidrug resistant genes were significantly up-regulated in liver and tumor from small-for-size group in rat liver transplantation model. IP10 was selected as the potential target for its constantly higher expression in liver and tumor tissues in small-for-size group. In clinical studies, IP10 was overexpressed in around 45% HCC patients with hepatectomy. The expression of circulating IP10 well correlated with tumor recurrence and small graft ratio in HCC patients after liver transplantation. In in vitro studies, it was demonstrated that overexpression of IP10 could significantly promote HCC cell proliferation either in short term or in long term cisplatin administration. In in vivo studies, subcutaneous and orthotopic nude mice models showed that the overexpression of IP10 have significant correlations with larger tumor volume and less tumor necrosis after cisplatin treatment. In mechanism studies, IP10 overexpression was found to be well correlated with the activation of endoplasmic reticulum (ER) stress signaling pathways in vitro and further validated in vivo models and in clinical specimens. IP10 neutralizing antibody was identified as a potential therapy which could sensitize cisplatin treatment in vitro and in vivo. Conclusions: The high expression of IP10 was identified in two cohorts of clinical samples and showed significant correlations with tumor recurrence. Graft injury induced IP10 overexpression could significantly increase cisplatin resistance after liver transplantation via ER stress signaling pathways. IP10 neutralizing antibody may be applied as an alternative treatment for recurrent HCC after liver transplantation. / published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Idag väntar många patienter på transplantation av ett eller flera organ. Med nuvarande lagstiftning identifieras inte alla potentiella organdonatorer och därför kan inte dessa organ tas tillvara. Regeringen har därför tillsatt en utredning om det kan bli aktuellt med organdonation efter hjärtdöd. Detta uttrycks internationellt som Donation after Cardiac Death (DCD). Denna studiens syfte var att beskriva intensivvårdssjuksköterskors uppfattningar, tankar och känslor, samt förbereddhet kring begreppet donation efter hjärtdöd. Sju intervjuer av intensivvårdssjuksköterskor på två sjukhus i västra Sverige genomfördes och data analyserades med kvalitativ innehållsanalys. Resultatet presenteras som fyra kategorier: Upplevda farhågor och potentiella konsekvenser av DCD, Mötet med anhöriga, Tankar och känslor kring organisatoriska svårigheter och Tankar och känslor kring etiska dilemman. Slutsatser var att de intervjuade intensivvårdssjuksköterskorna ställde sig positiva till DCD och tidigare forskning visar att det kan vara en källa till ökning av organtillgång förutsatt att det är organisatoriskt genomförbart. / Today there are many patients on the waiting list to receive one or more organ transplants. With the current Swedish legislation not all potential organ donors are identified and therefore these organs are omitted as potential transplants. The government is in the process of investigating the possibility to implement organ donation after cardiac death, i.e. DCD. The aim of the study was to describe ICU nurses’ understanding, thoughts and emotions, as well as their preparations regards to DCD. Seven ICU nurses at two hospitals in western Sweden were interviewed and data were processed through qualitative content analysis. The results are presented as four categories: Perceived fears and potential consequences regarding DCD, the meeting with relatives, Thoughts and emotions regarding organizational difficulties and Thoughts and emotions regarding ethical dilemmas. Conclusions derived from the findings in the interviews with ICU nurses were a fully positive perception of DCD and that DCD could mean an increase in the amount of available organ donors given that legalisation and organisation processes are clear and possible to carry out.

This dissertation examines the extent to which individual-level and social network-level factors explain disparities in living donor kidney transplantation (LDKT) and considers the moral implications. Paper One examines whether patient characteristics explain racial disparities in the rate of donor presentation and LDKT in a sample of 752 potential kidney recipients and 654 potential kidney donors. Propensity score matching and subclassification were used to balance the patient characteristics. Survival models revealed that only 24% of blacks compared to 39% of whites would have at least one potential donor evaluated within the first year, even after accounting for differences in the distribution of patient characteristics. Thus, lower rates of donor presentation among black recipients cannot be explained by differences in individual-level characteristics. Paper Two examines whether differences in social networks contribute to disparities in LDKT. Using interview and medical record data from a representative sample of 389 dialysis patients in Greater Boston and a subsample of 302 alters, we found that social network characteristics, especially network size, were strongly predictive of pursuing LDKT. Significant racial disparities in health and medical distrust among social networks of black patients present compelling evidence for network effects. Fewer network members of black patients may be eligible for donation owing to compositional health differences, and those eligible may be less willing to donate due to greater distrust or poor socioeconomic position. Paper Three argues that society ought to be concerned with previously neglected disparities in LDKT, specifically the fraction stemming from disparities in social networks because networks provide one pathway by which inequalities can be perpetuated throughout society and over time. Insofar as social networks are influenced by an unjust distribution of social forces, and social networks influence life chances by restricting (or enhancing) one’s ability to obtain a LDKT, then life chances of dialysis patients are unjustly determined by social networks. Potential policies aimed at providing compensatory damages to patients whose networks have been adversely affected by the unjust influence of social determinants are examined.