The risk of (skin) cancer is highly increased in organ-transplant recipients who are kept on immunesuppressive drugs to prevent graft rejection. This thesis dealt with the epidemiologic aspects and... Show moreThe risk of (skin) cancer is highly increased in organ-transplant recipients who are kept on immunesuppressive drugs to prevent graft rejection. This thesis dealt with the epidemiologic aspects and risk factors for cancer focused on cutaneous squamous cell carcinoma and basal cell carcinoma. Show less
Multiple Sclerosis is a degenerative disease of the central nervous system (CNS), involving autoimmunity against myelin, resulting in demyelination and paralysis. Antigen-specific immunotherapy may... Show moreMultiple Sclerosis is a degenerative disease of the central nervous system (CNS), involving autoimmunity against myelin, resulting in demyelination and paralysis. Antigen-specific immunotherapy may reduce this pathological autoimmunity, without disturbing normal immune function. This could be achieved by targeting of myelin antigens towards C-type lectin receptors (CLR) that recognize carbohydrate structures and are expressed on immune cells, because targeting of CLR under steady state conditions can suppress immunity in an antigen-specific way. In vitro studies showed that mannosylation of peptides results in internalization via the mannose receptor. In this study we observed, that immunization with mannosylated peptide does not induce disease in EAE, a model for Multiple Sclerosis. Instead, antigen-specific tolerance was induced; CNS inflammation was absent and DTH responses were impaired. Using transfer of TCR transgenic T cells in vivo we visualized that immunization with mannosylated peptide enhanced antigen presentation and induced vigorous expansion of T cells. However, T cells showed reduced blast formation and did not transfer EAE, despite normal production of inflammatory cytokines and chemokines. Lymphocytes accumulated in the lymph node of tolerized mice, which was counteracted by injection of Pertussis Toxin. Established EAE or ongoing DTH responses were ameliorated after mannosylated peptide treatment. In conclusion, mannosylated myelin peptide induced tolerance to EAE due to incomplete differentiation of encephalitogenic T cells and can be used to treat ongoing autoimmunity. Therefore, mannosylated antigens may represent a novel therapeutic approach for antigen-specific modulation of autoreactive T cells in vivo. 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
