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Transplantation immunology: aspects of allo- and EBV-specific reactivity : the EBV non-infected elderly - factors of resistance

Durovic, Bojana. Transplantation immunology: aspects of allo- and EBV-specific reactivity : the EBV non-infected elderly - factors of resistance. 2010, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_9258

Abstract

Defining the relevant components of cellular alloimmunity remains an important unresolved issue in clinical transplantation. The most promising marker of cellular alloreactivity available to date is donor-specific secretion of interferon-gamma (IFN-) as captured in Enzyme Linked Immuno-Spot (ELISPOT) assays (1, 2). How pre-transplantation allo-specific secretion of acute phase cytokines relates to allograft damage and to classic measures of adaptive allo-specific immune function has not been defined. We longitudinally assessed allo-specific secretion of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) in a prospective observational cohort of 38 renal transplant recipients. Allo-specific secretion of IL-6 pre-transplantation was more often detected in individuals with subsequent rejection. Levels of IL-6 correlated with the frequency of IFN- secreting cells, which themselves identified a subset of rejecting individuals with high specificity. These data for the first time link allo-inducible secretion of the acute phase signature cytokine IL-6 with subsequent allograft rejection and the frequency of IFN- secreting cells, suggesting a link between innate/acute phase and adaptive immunity in the pathogenesis of transplant injury. (Durovic, et al – in revision)
Post-transplant Non-Hodgkin lymphoma is a life-threatening complication after solid organ and hematopoietic stem cell transplantation (HSCT). While pharmacologically suppressed adaptive immunity plays a major role in its development, the precise circumstances leading to tumor growth remain unclear (4). We explored the possibility that factors intrinsic to EBV-transformed B cells may induce EBV-specific T cell immunodeficiency as observed in individuals developing post-transplant lymphoproliferative disease (PTLD). Expression of T cell co-stimulatory molecules, MHC or maturation markers on EBV-transformed B cell clones did not impact their immunogenicity vis-à-vis T cells. By contrast, proliferation rates of B cell clones positively correlated with their capacity to induce IFN- secretion in EBV-specific CD8+ T cells, whereas they were associated inversely with CD8+ T cell mediated cytotoxicity. Induction of IFN- secreting, yet poorly cytotoxic, T cells represents an unexpected potential of EBV to induce CD8+ T cell responses skewed towards inefficiency. Knowledge of this viral capacity has Defining the relevant components of cellular alloimmunity remains an important unresolved issue in clinical transplantation. The most promising marker of cellular alloreactivity available to date is donor-specific secretion of interferon-gamma (IFN-) as captured in Enzyme Linked Immuno-Spot (ELISPOT) assays (1, 2). How pre-transplantation allo-specific secretion of acute phase cytokines relates to allograft damage and to classic measures of adaptive allo-specific immune function has not been defined. We longitudinally assessed allo-specific secretion of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) in a prospective observational cohort of 38 renal transplant recipients. Allo-specific secretion of IL-6 pre-transplantation was more often detected in individuals with subsequent rejection. Levels of IL-6 correlated with the frequency of IFN- secreting cells, which themselves identified a subset of rejecting individuals with high specificity. These data for the first time link allo-inducible secretion of the acute phase signature cytokine IL-6 with subsequent allograft rejection and the frequency of IFN- secreting cells, suggesting a link between innate/acute phase and adaptive immunity in the pathogenesis of transplant injury. (Durovic, et al – in revision)
Post-transplant Non-Hodgkin lymphoma is a life-threatening complication after solid organ and hematopoietic stem cell transplantation (HSCT). While pharmacologically suppressed adaptive immunity plays a major role in its development, the precise circumstances leading to tumor growth remain unclear (4). We explored the possibility that factors intrinsic to EBV-transformed B cells may induce EBV-specific T cell immunodeficiency as observed in individuals developing post-transplant lymphoproliferative disease (PTLD). Expression of T cell co-stimulatory molecules, MHC or maturation markers on EBV-transformed B cell clones did not impact their immunogenicity vis-à-vis T cells. By contrast, proliferation rates of B cell clones positively correlated with their capacity to induce IFN- secretion in EBV-specific CD8+ T cells, whereas they were associated inversely with CD8+ T cell mediated cytotoxicity. Induction of IFN- secreting, yet poorly cytotoxic, T cells represents an unexpected potential of EBV to induce CD8+ T cell responses skewed towards inefficiency. Knowledge of this viral capacity has implications with regards to lymphomagenesis, and may help directing future screening and therapeutic strategies. (Durovic, et al – submitted)
Epstein-Barr virus (EBV) is ubiquitous among the world’s population with greater than 90% of adults being infected. Why 5-10% of the adult population remain EBV-seronegative throughout their lives is not known. Insights into mechanisms that confer protection from EBV infection might help in understanding EBV-associated disease and disclose targets for therapeutic interventions. We screened 515 healthy donors aged >60 years and identified 17 EBV-negative individuals with no evidence of viral infection in terms of humoral and cellular immunity and absence of viral genome within peripheral B cells. In these 17 EBV-negative individuals and 39 EBV-positive age- and sex-matched controls, medical history, immunological profiles and immunogenetic factors were assessed. EBV-negative donors presented significantly more often with a history of tonsillectomy than EBV-positive controls. At the molecular level, detailed analysis of MHC class I / killer cell immunoglobulin receptor compound genotypes, associated an HLA-Bw4 / KIR3DL1 compound genotype –representing an inhibitory interaction– with EBV-negativity. These data identify anatomical and immunogenetic factors likely to be involved in protection from becoming latently infected with EBV. (Durovic, et al – in preparation)
Advisors:Hess, Christoph
Committee Members:Finke, Daniela and Rolink, Antonius G.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Immunobiology (Hess C)
Item Type:Thesis
Thesis no:9258
Bibsysno:Link to catalogue
Number of Pages:71 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:41
Deposited On:27 Dec 2010 10:27

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