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
About this Master's Thesis
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