Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both... Show morePancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors and is resistant to immunotherapy. B cells play an essential role in PDAC progression and immune responses, both locally and systemically. Moreover, increasing evidence suggests that microbial compositions inside the tumor, as well as in the oral cavity and the gut, are important factors in shaping the PDAC immune landscape. However, the gut-associated lymphoid tissue (GALT) has not previously been explored in PDAC patients. In this study, we analyzed healthy vermiform appendix (VA) from 20 patients with PDAC and 32 patients with colon diseases by gene expression immune profiling, flow cytometry analysis, and microbiome sequencing. We show that the VA GALT of PDAC patients exhibits markers of increased inflammation and cytotoxic cell activity. In contrast, B cell function is decreased in PDAC VA GALT based on gene expression profiling; B cells express significantly fewer MHC class II surface receptors, whereas plasma cells express the immune checkpoint molecule HLA-G. Additionally, the vermiform appendix microbiome of PDAC patients is enriched with Klebsiella pneumoniae, Bifidobacterium animalis, and Adlercreutzia equolifaciens, while certain commensals are depleted. Our findings may suggest impaired B cell function within the GALT of PDAC patients, which could potentially be linked to microbial dysbiosis. Additional investigations are imperative to validate our observations and explore these potential targets of future therapies. Show less
Blood transfusions can lead to immunization or tolerance in the recipient. The latter is characterized by an improved transplant outcome after pretransplant blood transfusions. First observations... Show moreBlood transfusions can lead to immunization or tolerance in the recipient. The latter is characterized by an improved transplant outcome after pretransplant blood transfusions. First observations of improved kidney graft outcome after blood transfusion date 35 years back, however no exclusive immunological mechanism has been found yet. At the Leiden University Medical Center, patients on the waiting list for simultaneous pancreas-kidney transplantation (SPKT) received a non-leukocyte depleted, HLA-DR shared blood transfusion before transplantation. We showed that a pretransplant blood transfusion was able to diminish the severity of acute rejection episodes after SPKT. The need for HLA-DR sharing suggests a role for the indirect allorecognition. Our in vitro experiments focusing on the indirect allorecognition and on several subsets of recipient immune cells, showed that a pretransplant blood transfusion activates the recipient__s immune system. It is still not clear if and how this activation state can lead to transplantation tolerance. Additionally, there may be a role for microchimeric donor cells in the immunological mechanism leading to tolerance. Pretransplant blood transfusions may still be of clinical benefit in these times of potent immunosuppressive drug use, but requires the support of well-designed RCTs as well as more insight into the immunological mechanism. Show less
Osteoarthritis (OA) refers to a heterogeneous group of conditions. This thesis focuses on OA with a hereditary background; Familial OA at multiple joint sites and radiological hand OA at middle age... Show moreOsteoarthritis (OA) refers to a heterogeneous group of conditions. This thesis focuses on OA with a hereditary background; Familial OA at multiple joint sites and radiological hand OA at middle age. The main objective is to identify risk factors that play a role in the development of OA in order to gain further insight in the aetiology of OA. The secondary objective is to investigate factors that determine the outcome in OA. This thesis provides evidence that familial clustering of symptomatic OA is most prominent for hand and hip OA. In search for genetic risk factors, we present data suggesting that a proportion of the genetic susceptibility for OA at multiple sites is encoded by variation in innate cytokine activity. Further, we find HLA-DR antigens to be associated with radiological hand OA. In addition to genetic risk factors, this thesis demonstrates that other systemic risk factors such as hormonal status and local factors, to be important in the susceptibility of familial OA at multiple sites, underscoring the multicausal etioliology of this phenotype. Finally, this thesis addresses the resulting disability from OA. Using the International Classification of Functioning, Disability and Health as framework, we show illness perceptions and mental health to be important modifying factors in OA in the hands and lower extremities. Show less
