| Disruption of the CD28 and CD40 costimulatory pathways over a short time course in mice and non-human primates at the time of transplantation leads to allospecific hyporesponsiveness and prolonged, but not indefinite, allograft survival. In recent years, costimulation blockade has played a central role in the development of protocols aimed at establishing mixed allogeneic chimerism and donor-specific tolerance. Using these strategies, lifelong acceptance of donor skin grafts and high levels of mixed allogeneic chimerism have been achieved. In this study we have analyzed the interaction between costimulation blockade-based tolerance induction strategies and antiviral immunity.; Mice acutely or chronically infected with lymphocytic choriomeningitis virus (LCMV) at the time of tolerance induction rapidly reject donor skin grafts and fail to either develop mixed chimerism or delete donor-reactive T cells. However, mice that have resolved an acute infection or are infected after tolerance induction display no impairment in allograft survival or chirtierism development. While we find little evidence for substantial cross-reactivity to alloantigen in the antiviral response at a single cell level, LCMV-induced CD28/CD4p-independent rejection of skin allografts correlates with increased maturation of splenic dendritic cells, indicating that perhaps their costimulatory function is heightened during infection. Conversely, costimulation blockade can inhibit effector T cell responses during chronic infection and prevent control of the virus. We further find that memory T and B cells are maintained indefinitely following chimerism induction and retain the ability to protect against pathogenic rechallenge. Conversely, chimeric mice exhibit potentially dangerous deficiencies in their ability to deal with primary viral infections, due to both impaired thymic selection and replacement of recipient antigen presenting cells (ADCs).; The balance between transplant tolerance and antiviral immunity is a complex issue, particularly as strategies for inducing tolerance and mixed chimerism move closer to clinical application. Not only can viral infection lead to disruption of tolerance induction regimens, but such regimens can also induce tolerance to viruses. Identification of the precise mechanisms utilized by LCMV to circumvent costimulation blockade remains a crucial field of study. |
