Measures of Viral Protective Immunity as Indicators of Alloimmunity in Renal Transplantation Pubblico
Beus, Jonathan Michael (2013)
Abstract
Solid organ transplantation is an important life-sustaining intervention for individuals with organ failure. Despite the significant benefits of replacing a failed organ and considerable improvements in transplantation that have occurred over the past decades, transplantation is associated with substantial morbidity due to the requirement for chronic immunosuppression. Despite the narrow therapeutic index of many immunosuppressive therapies, objective measures of therapeutic immunosuppression are lacking. One potential approach to monitoring immunosuppressive therapy is to exploit measures of viral protective immunity. Significant overlap exists in the biologic mechanisms that mediate viral protective immunity and those that effect alloimmunity. Sensitive measures of viral immunity are already available in the form of assays to detect virus-specific antibodies and polymerase chain reaction-based assays to detect circulating virus. The high sensitivity of such assays and the similarities between viral immunity and alloimmunity suggest that these tools could direct the clinical management of post-transplant immunosuppression. To explore this possibility, this thesis describes a retrospective cohort analysis of the outcomes of two independent cohorts of renal transplant recipients. An association is identified between decreased rates of acute rejection and low or high Epstein-Barr Virus (EBV) DNA load values. This pattern is interrupted at intermediate EBV-load values, likely as a result of over-aggressive changes in immunosuppression in response to viral reactivation. Additionally, patients with a specific pattern of humoral immunity to EBV demonstrate a significantly lower rate of acute rejection. This finding is consistent with similar studies in the autoimmune literature and raises the possibility of identifying a subset of patients who may benefit from lighter immunosuppressive regimens without sacrificing graft function. In summary, although future studies are likely to be required, this thesis provides evidence that measures of viral protective immunity may prove beneficial in the management of post-transplant immunosuppression.
Table of Contents
Introduction..........1
Background............4
Methods..............14
Results..............22
Discussion...........35
References...........44
Figures..............49
Tables...............66
Appendix.............75
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