Colorectal cancer is one of the most diagnosed cancer types worldwide and incidence remains on the rise, especially in patients under 50. The prognosis for patients with CRC differs greatly and... Show moreColorectal cancer is one of the most diagnosed cancer types worldwide and incidence remains on the rise, especially in patients under 50. The prognosis for patients with CRC differs greatly and although immunotherapy has shown promising results in a number of cancer types, not all CRC patients respond well to these treatments. This can in part be attributed to the differences in T cell infiltration between cancers but does not one on one translate to clinical response. Moreover, the activity of specific immune cells can directly influence other immune cells, both in an activating and inhibitory manner. This highlights the complexity of the tumour immune microenvironment and requires an comprehensive multiplex approach to simultaneously investigate all the players of the tumour immune microenvironment. Furthermore, the interaction between different immune cells and between those and cancer cells is essential to take into account, hence the need for an approach that combines multiplex immunophenotyping with spatial cell context. This will provide hints into the behaviour of the players of the tumour immune microenvironment and aid the understanding of CRC, but potentially of other cancer types as well. In this work we developed and applied multispectral immunophenotyping methodologies to strengthen our understanding of CRC Show less
This thesis contains a variety of information about the natural and vaccine induced immunity against the human papillomavirus. The spontaneously induced HPV-specific humoral response after... Show moreThis thesis contains a variety of information about the natural and vaccine induced immunity against the human papillomavirus. The spontaneously induced HPV-specific humoral response after infection was assessed in population-based studies. The vaccine-induced changes in HPV-seroprevalence among the HPV unvaccinated Dutch population aged 0-89 years, where we compared the HPV-seroprevalence before the introduction of the HPV vaccine with data of approximately six years post-implementation of the national HPV vaccination program. Also, the HPV immune status of the Dutch Caribbean population just after introduction of HPV vaccination was determined. Moreover, the longitudinal relation between the hr-HPV antibody levels and the prevalence of HPV infections in three-dose vaccinated girls were studied. And more insight was gained into humoral and cellular immune responses after just a one-dose of the HPV vaccine. At last, the kinetics of innate and adaptive immune responses directly after vaccination different HPV vaccines were investigated. In the coming years some important changes are expected regarding HPV screening and vaccination. The effectiveness of the one-dose schedule will become clear as clinical trials end. In the Netherlands, a sex-neutral vaccination will be implemented soon. These changes will need to be monitored to provide scientific answers about the effectiveness and immunogenicity. Show less
Pregnancy can be seen as an immunologic paradox. Even though the fetus expresses paternally inherited alloantigens it is protected from rejection by a proper regulation of the maternal immune... Show morePregnancy can be seen as an immunologic paradox. Even though the fetus expresses paternally inherited alloantigens it is protected from rejection by a proper regulation of the maternal immune system. With the studies described in this thesis, we want to get more insight in the immunologic mechanisms that play a role in pregnancy. The results of this research can help to identify underlying etiologies in patients with unexplained pregnancy complications, such as recurrent miscarriage. Identifying these causes is important for providing answers and taking away anxiety in these couples, and eventually for the development of effective therapies. Furthermore, elucidating the mechanism leading to survival or rejection of the fetal allograft is not only essential for our understanding of processes leading to normal and abnormal pregnancies, but may also result in important concepts in the field of transplantation and autoimmunity. Show less
During pregnancy a unique situation arises in which the mother's immune system accepts the fetus, which carries both maternal and paternal genes, and does not reject it as can occur in solid organ... Show moreDuring pregnancy a unique situation arises in which the mother's immune system accepts the fetus, which carries both maternal and paternal genes, and does not reject it as can occur in solid organ transplantation. The aim of this dissertation was to unravel the immunological mechanisms that ensure tolerance during a healthy pregnancy and uncover how alterations could contribute to the development of pregnancy complications, such as pre-eclampsia and preterm birth.We applied the new technique mass cytometry and the associated computational analyzes to map all immune cells of the mother during a healthy pregnancy. Furthermore, we demonstrated the presence of three types of functional regulatory CD4+ T cells, identified a phenotype of CD8+ T cells that can offer both tolerance and immunity against infections, and demonstrated potential cross-reactivity of T cells against fetal allo-antigens. The results described in this thesis have contributed to a better understanding of healthy pregnancies and form a basis on which further research can be built. Show less
In the clinic, several forms of immunotherapy are combined with the standard treatments, including chemotherapy. Translational studies trying to understand the different outcomes in patients have... Show moreIn the clinic, several forms of immunotherapy are combined with the standard treatments, including chemotherapy. Translational studies trying to understand the different outcomes in patients have led to new questions and hypotheses. The studies described in this thesis are to answer some of these questions. We revealed the immunostimulatory effect of the chemotherapy agent; cisplatin. Next, we studied the mechanism of relapse following immunotherapy with HPV16 SLP vaccination in mice. We demonstrated that unsuccessful immunotherapy results in immune editing and secondary resistance. To overcome this, the combination therapies are required. Moreover, we showed the importance of IL-6 producing by tumors in dampening anti-tumor response. To induce a long-term sustained effector T cell response, we examined the potency of mouse cytomegalovirus as a viral vector-based vaccine. We demonstrated that the demarcated thresholds of vaccine-specific T cells correlate to tumor protection. Recognizing the fact that at each phase of the antitumor immune response a different type of help might have to be provided to obtain maximal therapeutic efficacy, the correct timing of various types of chemotherapeutic agents or immune modulators when used in combination is discussed. Finally, we discussed the general aspects and relevance of the studies mentioned in this thesis. Show less
Antibiotic resistance is an increasing problem in the battle against (bacterial) infectious diseases. The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) threatens to render... Show moreAntibiotic resistance is an increasing problem in the battle against (bacterial) infectious diseases. The emergence of drug-resistant Mycobacterium tuberculosis (Mtb) threatens to render tuberculosis (TB) untreatable. Efforts to develop novel antibiotics have so far been unsuccessful, calling for additional approaches for treatment of bacterial infections. Intracellular pathogens like Mtb and Salmonella can survive in the host by manipulating host cell signaling. This provides opportunities for novel therapeutic strategies by targeting the host, rather than the bacterium (host-directed therapy). In this thesis we report the development and application of novel (in vitro and in vivo) methods for identifying host genes and proteins involved in host control of intracellular bacteria, as well as chemical compounds that target host molecules as a basis for drug development for host-directed therapies. As a result, we report the identification of RTK inhibitors, the novel kinase inhibitor 97i, the human kinase family PCTAIRE and the host protein DRAM1 as promising leads for further drug development for host-directed therapeutic strategies for intracellular bacterial infections. Show less
In normal pregnancy the fetus, although a semi-allograft, is tolerated by the maternal immune system. It has been suggested that an inadequate maternal allo-immune response to the paternal... Show moreIn normal pregnancy the fetus, although a semi-allograft, is tolerated by the maternal immune system. It has been suggested that an inadequate maternal allo-immune response to the paternal antigens of the fetus is responsible for a proportion of the unexplained recurrent miscarriage. In chapter 2 we provide an overview on the possible role of the HLA system in recurrent miscarriage. No consistent conclusions can be drawn since the observed odd ratios found were relatively small and the risk of bias in the selected studies was high. In chapter 3 we compared the genetic polymorphisms of HLA-G in women with recurrent miscarriage with women with uneventful pregnancy. The HLA-G UTR-4 haplotype was less frequently observed in women with recurrent miscarriage, suggesting an immunoregulatory role of this haplotype. The combined results from chapter 4, chapter 6 and chapter 7 suggest that in a portion of women with unexplained recurrent miscarriage antibody-mediated rejection of the fetal allograft may play a role. We showed in chapter 8 that human seminal plasma contains all kinds of immunoregulatory factors and has an immunomodulatory effect on T cells. In chapter 9 a matched case-control study practicing oral sex was negatively associated with the occurrence of recurrent miscarriage. Show less
In this thesis, new insights in the complex and intertwined relationship between viral infections, T cells and natural killer cells after allogeneic HSCT in children are provided and discussed.... Show moreIn this thesis, new insights in the complex and intertwined relationship between viral infections, T cells and natural killer cells after allogeneic HSCT in children are provided and discussed. Patients are at high risk of viral complication during the T cell deficient period early after HSCT. When viral infections occur, interventions to bridge the period until the recovery of antiviral T cell immunity are of great importance to improve the clinical outcome after HSCT. Besides antiviral medication and the use of adoptive immunotherapy, NK cells may play a role in the protection against viruses when T cells are not available to perform their task. Show less
This thesis identifies specific targets, illustrates the role of these targets, and explores personalized therapeutic possibilities to inhibit tumor growth by using new treatment strategies.... Show moreThis thesis identifies specific targets, illustrates the role of these targets, and explores personalized therapeutic possibilities to inhibit tumor growth by using new treatment strategies. And the thesis describes a new animal model for CM. A proper model can mimic the human disorder and provide opportunities for studying tumor biology, and for seeking novel effective therapies to inhibit the dissemination of malignant cells. Subsequently, the potential role of immune checkpoint molecules and the presence of HLA class I antigens are studied. New animal models and therapeutic targets will broaden our understanding of CM, and help us to develop better treatments for primary and metastatic CM, thus prolonging patients’ survival. Show less
Type 1 Diabetes is caused by destruction of insulin producing beta-cells by autoimmune T-cells. Replacement of beta-cells through transplantation can supply new beta-cells, however these are at... Show moreType 1 Diabetes is caused by destruction of insulin producing beta-cells by autoimmune T-cells. Replacement of beta-cells through transplantation can supply new beta-cells, however these are at renewed peril of destruction through auto- and alloreactive immune responses. In this thesis, immune challenges, intervention strategies and biomarkers to guide treatment are investigated. Patient heterogeneity was identified as contributing factor to variations in efficacy of immune intervention therapies for type 1 diabetes. Immune infiltrations that matched with immune monitoring results were seen around islets transplanted to the liver of a patient. Cytokine and autoantibody immune markers were described that correlated with outcome of islet transplantation and combined kidney and pancreas transplantation. Immune consequences of tapering immune suppression after islet transplantation to minimize side effects were explicated. The immunological challenges that await beta-cells of alternative sources after transplantation, such as beta-cell lines and embryonic stem cells, were explored and pointed to need for immune protection and immune monitoring in early transplantation trials. These results support further investigation of immune intervention with disease specific immune modulation and beta-cell encapsulation strategies to achieve the desired drastic improvement in efficacy-risk balance for type 1 diabetes therapies. Show less
