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
Viral infections are agreat risk for successful transplantation. Surprisingly, also the immuneresponse against viruses can affect transplantation outcome, as T cells thatare trained to recognize... Show moreViral infections are agreat risk for successful transplantation. Surprisingly, also the immuneresponse against viruses can affect transplantation outcome, as T cells thatare trained to recognize self-HLA presenting a viral peptide, can make a“mistake” and recognize allogeneic (donor) HLA. This phenomenon is known tooccur frequently, but its clinical relevance remains unknown. In this thesis, we investigated and optimized the methods to detectcross-reactivity of virus-specific T cells in vitro. Illustrating the scope ofthe problem, we found that infection with a single virus induces a broadrepertoire of alloreactive T cells. Conversely, cross-reactivity may also boostanti-viral immunity in immunocompromised patients. Also, we found thatvirus-specific T cells of unrelated individuals can recognize the sameallogeneic HLA much more frequently than anticipated. This knowledge may helpto predict which patient-donor combinations induce alloreactivity.Addressing clinical relevance in transplantation, we showed that the immunepotential against the viral and allogeneic target can be equally strong,depending on the expression of the (allo)epitope. However, clinical relevanceonly truly be determined when the peptides presented by the cross-reactingallo-HLA molecules are identified. A promising allopeptide-defining strategy iscurrently under development at Monash University (Melbourne, Australia),described in the Discussion. Show less
Heuvel, H. van den; Meer-Prins, E.M.W. van der; Miert, P.P.M.C. van; Zhang, X.Q.; Anholts, J.D.H.; Claas, F.H.J. 2019
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
Heuvel, H. van den; Heutinck, K.M.; Meer-Prins, E.M.W. van der; Franke-van Dijk, M.E.I.; Miert, P.P.M.C. van; Zhang, X.Q.; ... ; Claas, F.H.J. 2018
TCR gene transfer is a strategy that enables the rapid engineering of anti-leukemic T-cells with defined specificity, resulting in a so called __off the shelf __ therapy. An elegant strategy to... Show moreTCR gene transfer is a strategy that enables the rapid engineering of anti-leukemic T-cells with defined specificity, resulting in a so called __off the shelf __ therapy. An elegant strategy to promote persistence of TCR modified T-cells may be TCR gene transfer into CMV- and EBV-specific T-cells, which exhibit proper memory and effector phenotypes. Furthermore, these virus-specific T-cells do not induce GvHD after HLA identical allo-SCT, and thus can be safely administered. For efficient anti-leukemic reactivity of the introduced TCR coinciding with enhanced in vivo survival, a balance between cell surface expression of the introduced and endogenous TCR is required. The aim of this thesis was to optimize the efficacy of TCR gene transfer, study possibilities and restrictions of virus-specific T-cells as host cells for TCR gene transfer and characterize the occurrence of potentially harmful mixed TCR dimers and strategies to prevent their formation. Show less
