Purpose: Infection induces costimulation-resistant memory T cells with heterologous alloreactivity. Rapamycin has been shown to mitigate the effect of these cells in transplant rejection. Previous studies have commonly employed atypical acute infections, such as LCMV and VV, and skin transplantation, a secondarily vascularized allograft, with immunotherapy regimens not clinically available. In this study, we sought to perform a targeted evaluation of viruses most commonly seen and interrogated clinically in the transplant population utilizing heterotopic heart transplants, which are primarily vascularized.

Methods: C57Bl6 mice were mock infected or infected with polyomavirus (PyV, murine BK virus), murine CMV, and HV68 (murine EBV) in the presence or absence of rapamycin. Blood was collected at baseline, peak and memory time points and analyzed by flow cytometry to characterize changes in the immune cell repertoire. On day 70 post infection, mice received heterotopic heart transplants from Balb/c donors and were treated with either CTLA4-Ig alone, or CTLA4-Ig with rapamycin.

Results: Mice that received PyV, mCMV and HV68 exhibited a marked increase in effector memory T cells (TEM) in both the CD4 and CD8 T cell compartment (p<0.01), as well as an increase in KLRG1 expression on CD8 T cells (p<0.01). Percentages of memory T cells were not significantly altered in the presence of rapamycin during infection. Remarkably, unlike seen with atypical acute infections, graft survival was not influenced by the presence of persistent and latent infections. Heart allografts are currently being interrogated for viral titers and graft infiltrates. Mice that received rapamycin during infection were recently transplanted and grafts are being monitored for survival.

Discussion: Heterologous alloreactivity with atypical acute infections has been shown to significantly decrease allograft survival in the context of costimulation blockade. Thus far, we have observed no difference in allograft survival in mice infected with PyV, mCMV and HV68 compared to mock infected mice, and no difference in the magnitude of the TEM expansion with or without rapamycin present during primary infection. These studies suggest the type of infection and degree of vascularization play a large role in the heterologous response to allogeneic antigen.

CITATION INFORMATION: Espinosa J, McRae M, Wang J, Kirk A. Heterologous Persistent and Latent Viral Infections Do Not Impact Graft Survival. Am J Transplant. 2016;16 (suppl 3).

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