Virus-specific T cells have been shown to cross-react with allogeneic HLA (allo-HLA) at a clonal level. However, the impact of a single virus on the allorepertoire has never been investigated at... Show moreVirus-specific T cells have been shown to cross-react with allogeneic HLA (allo-HLA) at a clonal level. However, the impact of a single virus on the allorepertoire has never been investigated at the polyclonal level.We made an inventory of the incidence and specificity of allo-HLA-cross-reactive-virus-specific CD8(+) T cells in 24 healthy individuals. T cells were stained for 25 virus-specific tetramers, and mixed-lymphocyte reactions were performed against a panel of HLA-typed allostimulators. Allospecificity was confirmed by IFN gamma-ELISA using T-cell clones against a panel of HLA-typed cell-lines.The polyclonal immune repertoire directed against CMV alone was associated with a memory response against six allo-HLA molecules. Besides, a single allostimulator activated memory T-cell responses with multiple viral specificities.Concluding, a single virus can substantially broaden the allo-HLA memory T-cell repertoire. This study only looked at CMV- and EBV-specific T cells, whereas the immune repertoire consists of T cells directed against many different viruses. Hence, transplant patients receiving an HLA-mismatched graft may already express a poly clonal repertoire of anti-donor-memory T cells before transplantation. Show less
Clinical studies demonstrated that HLA-DPB1 mismatched stem cell transplantation (SCT) is associated with a decreased risk of disease relapse and an increased risk of graft versus host disease ... Show moreClinical studies demonstrated that HLA-DPB1 mismatched stem cell transplantation (SCT) is associated with a decreased risk of disease relapse and an increased risk of graft versus host disease (GVHD) compared to HLA-DPB1 matched SCT. In T-cell depleted SCT, mismatching of HLA-DPB1 was not associated with an increased risk of severe GVHD, whereas a significant decreased risk of disease relapse was still observed. In this thesis we showed that HLA-DPB1 mismatched allo-SCT followed by donor lymphocyte infusion (DLI) late after transplantation can result in selective graft versus leukemia (GVL) reactivity. Although several studies have suggested that some HLA-DPB1-mismatches were less immunogenic, we demonstrated that all HLA-DPB1-mismatches as defined by allele typing are immunogenic and resulted in vitro in high frequency immune responses. Finally, in a cohort of 24 patients transplanted for various hematological ma lignancies with a 10 out 10 matched HLA-DPB1 mismatched SCT followed by DLI, HLA-DP specific immune responses were frequently found. The presence of HLA-DP specific CD4+ T cells correlated with clinical immune responses including both selective GVL-reactivity and GVHD. It is likely that in each individual local environmental circumstances possibly in combination with the induction of other immune responses may finally determine the balance between GVHD and GVL-reactivity HLA-DP HLA-class II mismatch alloreactivity hematopoietic stem cell transplantation donor lymphocyte infusion graft versus host disease graft versus leukemia reactivity immunotherapy Show less
The research described in this thesis investigates the effect of viral infection on the risk of rejection. It was previously thought that a viral specific T-cell receptor could not crossreact... Show moreThe research described in this thesis investigates the effect of viral infection on the risk of rejection. It was previously thought that a viral specific T-cell receptor could not crossreact against allogeneic HLA molecules, however here it is proven that this is not only possible but is also common. The research performed in this thesis has important clinical implications for solid organ (kidney) and bone marrow transplantation. Viral infection commonly generates alloreactive T-cells, and may therefore be responsible for the failure of tolerance inducing regimens in primates and humans. It is shown that vaccination can also induce HLA-specific alloreactive T-cell responses and it is therefore recommended that vaccines be given to transplantation candidates at least three months prior to expected transplantation date. It is also shown that alloreactive T-cells can be tissue specific. In the final chapter of the thesis thesis it is shown that allogeneic cell therapy could conversely be useful to elicit a viral specific T-cell response in patients with infections, such as HIV. Show less
Following allograft transplantation, the immune system is triggered to induce an immunogenic response against the non-self organ. To prevent the induction of this immunogenic response, recipients... Show moreFollowing allograft transplantation, the immune system is triggered to induce an immunogenic response against the non-self organ. To prevent the induction of this immunogenic response, recipients are treated with immunosuppressive medication. The majority of these medications target T cells, which play a key role in the rejection process, and thereby prevent acute rejection in most of the recipients. Non-specific targeting of these T cells not only prevents acute rejection, it also prevents responses against pathogens or tumor growth. In addition, long-term use of immunosuppressive agents may cause organ failure due to toxic effects on the organ [1]. Therefore, the ultimate goal is to develop a therapy, which targets alloreactive T cells, allowing a normal response against pathogens and tumors, in the absence of chronic use of immunosuppressive agents. Various strategies have been employed to induce such a donor-specific tolerance, amongst which treatment with immature DC [2]. These immature DC have, in contrast to mature DC, the capacity to induce tolerogenic responses and are therefore an attractive candidate for cellular therapy. The studies presented in this thesis demonstrate that in fully mismatched kidney transplantation models, administration of modulated donor-derived DC to recipient__s results in regulation of recipient__s immune response. Both the donor-specific hyporesponsiveness of recipient T cells and the reduced influx of CD8+ T cells into the graft of LPS-DexDC treated recipients indicate a positive effect of this treatment. However, optimization of this treatment is necessary, since no prolonged allograft survival was induced. Several mechanisms, which are not regulated by LPS-DexDC, may be responsible for the observed rejection, amongst which the preformed alloantibodies, increased levels of C3 in the graft and the increased influx of NK cells. Additional studies are required to explore the modulating effects of antibodies which block co-stimulation and/or short courses of immunosuppressive drugs as a co-treatment in these settings. Show less
Rheumatoid arthritis (RA) is a relatively common disease that is characterized by chronic inflammation of joints. The research as described in this thesis focused on the question of whether... Show moreRheumatoid arthritis (RA) is a relatively common disease that is characterized by chronic inflammation of joints. The research as described in this thesis focused on the question of whether adoptive cellular therapy is effective in a mouse model of RA. The most generally known type of adoptive cellular therapy is, probably, bone marrow transplantation (BMT), i.e. BM cells from a healthy donor are transplanted to the patient. Especially, hematological disorders like leukemia are treated with BMT; however, the research presented in this thesis strongly suggests that BMT may also effectively treat diseases, such as RA, in the (near) future. The efficacy of other types of adoptive cellular therapies was also investigated, including the transfer of regulatory T cells. Most strikingly, the disappearance of autoaggressive immune cells was associated with the efficacy of the treatment. These results suggest that these immune cells that, directly or indirectly, cause damage to the patient___s joints were eliminated and/or were kept quiescent. These studies are of importance for the future improvement of the treatment of rheumatic diseases like RA. Show less
Many patients in need of haematopoietic stem cell transplantation do not reach transplantation. An analysis on all unrelated donor searches for Dutch patients performed between 1987 and 2000 showed... Show moreMany patients in need of haematopoietic stem cell transplantation do not reach transplantation. An analysis on all unrelated donor searches for Dutch patients performed between 1987 and 2000 showed a significant decrease of the percentage of patients for whom no donor was available. Between 1996 and 2000, the efficiency of the donor search and transplantation process was the biggest constraint for patients of Northwest European origin. Thirty percent of patients became medically unfit for transplantation during the process, due to the duration of the process. Major Histocompatibility complex (MHC) differences between donor and patient can preclude successful transplantation. The assumption that highly diverged MHC class I molecules lead to more T cell alloreactivity was challenged. Single highly diverged (>=5alpha5beta) MHC class I molecules did not elicit an immune response by allogeneic CTL in vitro. I propose that in generating a T cell repertoire with a sufficiently narrow responsive for self-MHC, positive thymic selection limits the capacity to recognize allogeneic MHC molecules whose structure and sequence have diverged extensively. Its clinical relevance was evaluated. We could subdivide the donor-recipient pairs with a negative CTLp assay into a prognostic favourable and unfavourable group based on the (>=5alpha5beta) MHC mismatch category. Show less
