Virus-specific T cells play a key role in the control of viral-reactivations in healthy individuals and this cellular immunity is impaired in patients receiving allogeneic stem cell transplantation... Show moreVirus-specific T cells play a key role in the control of viral-reactivations in healthy individuals and this cellular immunity is impaired in patients receiving allogeneic stem cell transplantation. In the period around the transplantation, donor-derived T cells are either depleted or suppressed to reduce the risk of graft versus host disease (GVHD). However, in the absence of donor-derived T cells, latent viruses such as CMV, EBV and AdV can reactivate and remain uncontrolled and at the same time the curative graft versus leukemia (GVL) effect is abrogated. Therefore, the major challenge in the field of alloSCT is to find a balance between the GVL effect, protection against viruses and GVHD. The research described in this thesis focusses on the options to control for viral reactivations using adoptive transfer of virus-specific T cells or TCRs and the risks associated with this. Show less
Heiden, P. van der; Marijt, E.; Falkenburg, F.; Jedema, I. 2018
This thesis describes the role of the immune system as an important phenomenon in the most frequently occurring form of eye cancer in adults, namely in uveal melanoma. We show that the immune... Show moreThis thesis describes the role of the immune system as an important phenomenon in the most frequently occurring form of eye cancer in adults, namely in uveal melanoma. We show that the immune system can be the cause of the tumor, and also plays a role in the development of a tumor, and may be an entry for therapy. In the first chapters of this thesis, we describe the phenomenon of "an inflammatory phenotype" in uveal melanoma. It appears that when this type of cancer shows more inflammation, the survival of patients decreases. A possible explanation for this observation is that one of the key players among the immune cells, the macrophage, plays an essential role in intra-ocular tumor growth. We demonstrate this in patient material, but also in experimental studies; we are able to inhibit tumor growth when we modulate the presence of macrophages. In this thesis, we also show that the immune system can be used effectively to eradicate eye melanomas in experimental models. T cell vaccination in combination with monoclonal antibodies gave promising results for treating eye cancer. Further research has to be performed to translate this into the clinic. Show less
Following antigen encounter, activated T cells can give rise to functionally distinct T cell subsets. Understanding how different T cell subsets arise requires technologies that can monitor the... Show moreFollowing antigen encounter, activated T cells can give rise to functionally distinct T cell subsets. Understanding how different T cell subsets arise requires technologies that can monitor the developmental potential of single precursor cells (chapter 2). This thesis describes the development and use of two novel genetic tagging strategies aimed at following cell differentiation in vivo. These strategies are based on the marking of precursor cells with unique DNA sequences (barcodes), following which cell fate is analyzed by barcode comparison of different daughter populations. The first technology, termed cellular barcoding, makes use of a retroviral barcode library to provide T cells with unique genetic tags via in vitro transduction. Cellular barcoding was used to analyze the kinship of diverse T cell populations (chapter 3-5) as well as to measure the clonality of antigen-specific T cell responses under varying conditions of infection (chapter 6). The second technology, termed in vivo barcoding, makes use of a transgenic mouse model in which unique DNA sequences are introduced via inducible VDJ recombination. The feasibility of in vivo barcoding was demonstrated by conditionally labeling lung and liver cells with different barcodes (chapter 7). Together, these studies have yielded important new insights for vaccine optimization. Show less
Cancer cells often escape the attack of immune cells because they originate from self-tissue. Through T cell receptor gene transfer it is possible to equip peripheral T cells with a desired... Show moreCancer cells often escape the attack of immune cells because they originate from self-tissue. Through T cell receptor gene transfer it is possible to equip peripheral T cells with a desired specificity, and this strategy may be useful to generate tumor-specific T cells for the treatment of cancer in humans. This thesis describes several aspects in the functionality, safety and longevity of T cells modified by T cell receptor gene transfer in animal models. Show less
The studies described in this thesis focus on the feasibility of using carcinoembryonic antigen (CEA) as a target for immunotherapy of colorectal cancer and on the balance between anti-tumor... Show moreThe studies described in this thesis focus on the feasibility of using carcinoembryonic antigen (CEA) as a target for immunotherapy of colorectal cancer and on the balance between anti-tumor immunity and autoimmune pathology. The potential of CEA as a target antigen for immunotherapy of cancer is conceivably restricted by the fact that CEA is expressed in several abundant and vital tissues, including intestine and stomach, and is even routinely found in the serum of healthy individuals. We demonstrate that the CEA-specific CD4+ T-cell repertoire in CEA-tg mice is severely limited compared to wild-type mice and that this CD4+ T-cell tolerance for CEA was induced by the thymus. In addition we showed that CEA was expressed in medullary thymic epithelial cells (mTEC) in both mice and human beings. The latter suggests that the CEA-specific T-cell repertoire may also be tolerized in people. In further studies we have focussed on possibilities to overcome tolerance of CEA by reconstituting the T-cell repertoire of CEA-tg mice by adoptive transfer of the T-cell repertoire of CEA-immunized wild-type mice into tumor-bearing CEA-tg mice. Adoptive transfer in combination with immune modulation can result in efficient eradication of CEA-positive tumors. However, in order to prevent hazardous CEA-specific autoimmune reactions, the choice of the right immune modulation protocol is critical. Show less
