Overall, the human immune system is a well-regulated system. However, it may experience disturbances caused by diseases, pathogens, or the use of medications, leading to over- or underactivity.... Show moreOverall, the human immune system is a well-regulated system. However, it may experience disturbances caused by diseases, pathogens, or the use of medications, leading to over- or underactivity. While an overactive immune system can result in the attack of healthy tissue, an underactive immune response increases the risk of the development of infections or cancers. Immunomodulatory drugs can be used to balance such immune system disturbances. However, since these drugs have a significant effect on the immune system, the use of immunomodulatory medication can also result in adverse effects, similar to those seen in immune-related diseases. To prevent immune dysregulation, it is therefore very important to select the right immunomodulatory medication at the right dose. As the immune system comprises many different cells and molecules, this can be a challenge. Monitoring of immune functionality, referred to as immunomonitoring, can be a useful approach to monitor the effects of immunomodulatory drugs on their proximal targets.In this thesis different methods and applications of immunomonitoring are described. Section 1 depicts the search for biomarkers to monitor the immune function under treatment for transplant patients. In section 2, comparable methods of immunomonitoring were used to gain a better insight in the mechanism of action and the dose-effect relationship of the immunosuppressant HCQ. Show less
This thesis aimed to understand the humoral autoimmune response and to translate our knowledge to improve the targeting of autoimmunity in AAV and SLE patients. Our studies demonstrate that NETs... Show moreThis thesis aimed to understand the humoral autoimmune response and to translate our knowledge to improve the targeting of autoimmunity in AAV and SLE patients. Our studies demonstrate that NETs have a pivotal role in both AAV and SLE patients. NETs function as autoantigens, can cause direct glomerular inflammation and can be part of immune-complexes in SLE. Importantly, AAV and SLE-induced NETs are disease specific processes that each encompassed their own unique properties. This should be taken into account when evaluating targeting of NETs in AAV and SLE. In SLE patients, NETs could be targeted through reducing the autoantibody repertoire, specifically high avidity anti-dsDNA and anti-C1q autoantibodies that drive immune complex formation. These autoantibodies were effectively targeted by combined treatment with RTX and BLM. During B-cell targeted therapy in AAV and SLE patients, the presence and reoccurrence of autoreactive B-cells and relevant autoantibodies are components of minimal residual autoimmunity (MRA), which often persists after B-cell therapy. Interestingly, both in AAV and SLE, double negative (DN) B-cells have a key role in the humoral autoimmune response and were associated with reoccurrence of autoantibodies. However, it remains to be established how MRA is associated with disease flares and to find the best way to use it as immunomonitoring tool to guide and personalize treatment. Show less
Bidmon, N.; Kind, S.; Welters, M.J.P.; Joseph-Pietras, D.; Laske, K.; Maurer, D.; ... ; Burg, S.H. van der 2018
Conventional therapies as chemotherapy and radiotherapy impact immune populations and immune responses in cervical cancer patients. This led to new perspectives into the important role of the... Show moreConventional therapies as chemotherapy and radiotherapy impact immune populations and immune responses in cervical cancer patients. This led to new perspectives into the important role of the immune system and possibilities to optimally implement immunotherapy in the treatment of cervical cancer. Immunotherapy with HPV16-SLP vaccination is a suitable candidate for combined therapy with chemotherapy, when administered within the optimal time window, as it maximizes vaccination efficacy while tumor-induces immune suppression is tackled. To eventually improve clinical outcome in cervical cancer patients, multimodality treatment approaches need further exploration. Within that approach, the assignment of treatment dose, timing and route of administration of both immunotherapy and the classic conventional therapies are important. In addition, individualization of patients therapy based on immune markers prior to treatment should be a goal to optimize combination therapy, minimize side effects and improve clinical outcomes. Show less
