The Induction of IgM and IgG Antibodies against HLA or MICA after Lung Transplantation

The production of IgG HLA antibodies after lung transplantation (LTx) is considered to be a major risk factor for the development of chronic rejection, represented by the bronchiolitis obliterans syndrome (BOS). It has recently been observed that elevated levels of IgM HLA antibodies also correlates with the development of chronic rejection in heart and kidney transplantation. This study investigates the relationship between IgM and IgG antibodies against HLA and MICA after lung transplantation. Serum was collected from 49 patients once prior to transplantation and monthly for up to 1 year after lung transplantation was analyzed by Luminex to detect IgM and IgG antibodies against HLA and MICA. The presence of either IgM or IgG HLA and/or MICA antibodies prior to or after transplantation was not related to survival, gender, primary disease, or the development of BOS. Additionally, the production of IgG alloantibodies was not preceded by an increase in levels of IgM, and IgM levels were not followed by an increase in IgG. Under current immune suppressive regimen, although the presence of IgM antibodies does not correlate with BOS after LTx, IgM high IgG low HLA class I antibody titers were observed more in patients with BOS compared to patients without BOS

Biomarkers for the prediction of the bronchiolitis obliterans syndrome after lung transplantation

The main limitation for overall survival after lung transplantation (LTx) is the development of chronic rejection, which is represented by the bronchiolitis obliterans syndrome (BOS). The diagnosis BOS is based on lung function testing, however, it is a surrogate marker. And because BOS is an irreversible and unmanageable disease a better prediction of patients at risk could be beneficial for treatment after LTx. In this thesis we focus on finding a biomarker in the blood of LTx recipients. After LTx, patients receive a stringent immune suppressive regimen. Therefore, many factors in the blood of LTx patients are altered when compared to healthy controls. We found that there was a distorted distribution of PBMC and NKT cells are elevated but central memory CD8 T cells are decreased in the blood of patients with BOS compared to non-BOS patients, but these were not predictive. Furthermore, NK cells were more activated one after LTx compared to prior to LTx. Cells of donor origin could also be detected in the peripheral blood of patients, this microchimerism could be observed for several cell types. However, plasmacytoid dendritic cells were never detected. HLA antibodies are a major risk factor for the development of BOS. However, in our patient group IgM or IgG HLA antibodies were only weakly present and did not correlate with the development of BOS. The HLA antibodies are probably influenced by the immune suppressive regimen applied after LTx. Studying HLA antibodies of both the IgM and IgG isotypes no isotype switch could be detected. BOS patients had higher titers IgM HLA antibodies but lower titers IgG HLA antibodies, but these titers were not predictive of BOS. Non-HLA antibodies can also be detected after LTx. These antibodies might fix and activate the complement system. MBL, one pathway of the complement system, was studied prior to an after LTx and it was observed that low MBL leads to more CMV infections but also better overall survival. However, there was no relation with BOS. Clara cell secretory protein (CCSP) is produced by cells in the lungs. These cells are damaged during the development of BOS, and a decrease in serum CCSP in all patients developing BOSis observed. But serum CCSP levels are very fluctuating and as the decrease is observed when the process is ongoing serum CCSP is not predictive of BOS. The chemokine TARC is able to migrate T cells expressing CCR4 to the site of inflammation. It was observed that patients developing BOS had lower serum TARC levels 1 month after LTx and this was predictive of development of BOS when compared to non-BOS patients. This relation was not seen for its receptor CCR4. In conclusion we found that risk factors for the development of BOS are influenced by the type of immune suppressive regimen applied after LTx. And that CCSP although decreasing in all BOS patients cannot be used as a biomarker for the development of BOS. But, serum TARC levels at 1 month after LTx might be a promising easy to detect biomarker for the development of BOS

Improving clinical evaluation and decision-making in military personnel with mid-portion Achilles tendinopathy: Focusing on Ultrasound Tissue Characterization

Chapter 1: Introduction We aimed to improve the clinical evaluation and decision-making process in military healthcare aimed at personnel with Achilles tendinopathy (AT), primarily focusing on mid-portion Achilles tendinopathy (mid-AT). Six studies were undertaken, with three core themes being the subject of research: I. ultrasonographical assessment of mid-portion tendon structure; II. clinical effectiveness of extracorporeal shockwave therapy (ESWT); III. thresholds on the Victorian Institute of Sport Assessment – Achilles (VISA-A) questionnaire. The primary objective was to evaluate ultrasound tissue characterization (UTC) as an outcome measure for mid-AT. Chapter 2: Inter-rater reliability of ultrasonography for Achilles tendon structure. In asymptomatic subjects, conventional ultrasonography showed: 1. almost perfect agreement in grading mid-portion tendon structure (kw 0.87, 95% CI: 0.79, 0.95); 2. a very high inter-observer correlation in measuring mid-portion diameter in short-axis plan

European Union: political participation. Report for the project on policy frames and implementation problems: the case of gender mainstreaming

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Multiple pathways are involved in the anoxia response of SKIP3 including HuR-regulated RNA stability, NF-kappaB and ATF4.

Under anoxia a coordinated, cytoprotective program is induced, called the unfolded protein response (UPR). Activating transcription factor 4 (ATF4) is a mediator of the UPR and activates a gene expression program, promoting tumour growth and survival under anoxia. A key gene induced by ATF4 under normoxic conditions is SKIP3. We characterized the induction of SKIP3 during anoxic exposure to determine whether UPR alone was sufficient or there was a more complex regulatory response to anoxia. There was temporal separation of acute hypoxia-inducible factor (HIF)-1alpha- and chronic ATF4-dependent gene expression programs. SKIP3 was regulated by chronic (48 h) rather than acute anoxia (<24 h) by a complex set of pathways and mechanisms, besides ATF4 induced by the classical UPR, there was transcriptional regulation by nuclear factor-kappa B (NF-kappaB) and RNA stabilization by HuR. Temporal activation of the NF-kappaB pathway under anoxia protected cells from negative consequences of the oxygen stress and involved the canonical signalling pathways that promote IkappaBA phosphorylation and degradation, and reduced mRNA level of the inhibitory protein IkappaBA followed by the translational repression of IkappaBA. We also show that SKIP3 acts as an inhibitor of NF-kappaB and ATF4-dependent transcription under anoxia and provides a regulatory feedback loop. Repression of the survival pathway NF-kappaB by SKIP3 sensitized cells to metabolic consequences of the anoxic stress. Thus, the response to anoxia is mediated by three pathways independently of HIF, suggesting that combined therapeutic approaches would be needed to maximize effects against this pathway