Latent viral infections are a major concern among immunosuppressed transplant patients. Treatment with belatacept, a CTLA4-Ig fusion protein, was shown to reduce toxicity in kidney transplant recipients compared to standard CNI therapy, but is contraindicated in EBV- patients, due to an increased risk of PTLD associated with primary EBV infection. Therefore, treatments that can improve patients’ protective immunity without increasing alloreactivity to their grafts would be beneficial in this setting. Recent reports have shown that treatment with the immunosuppressant rapamycin (rapa) paradoxically enhances both the quantity and quality of T cell responses to certain bacterial and viral infections. This raised the enticing possibility that rapa could be used to help enhance primary responses to EBV in belatacept-treated patients. To investigate this, we employed a model using gammaherpesvirus 68 (gHV), the murine homolog of EBV, and used tetramers to track T cells specific for the immunodominant epitopes of gHV. Rapa treatment alone enhanced the T cell response to gHV, with a significant increase in p79 tetramer positive CD8 cells at Day 20 compared to mice that received no treatment (17.78±3.22% vs.14.48±3.20% p < 0.05). When splenocytes were harvested and restimulated in vitro with p56 and p79 peptide of the virus, CD8 T cells from animals treated with rapamycin exhibited enhanced IFN-Γ production (Rapa 1.37±0.37% and 1.32±0.36%, No Rx 1.00±0.40 and 0.95±0.32%, p < 0.05). In contrast, CTLA4-Ig treatment prevented rapa from enhancing gHV-specific responses. There was no significant improvement of p79 T cell responses in the periphery when rapa treatment was given in combination with CTLA4-Ig (CTLA4-Ig 14.44±2.33% vs. +Rapa 14.38±2.01%, p = 0.96). Likewise, no differences were seen in IFN-Γ production in response to p56 and p79 (CTLA4-Ig 0.92±0.37 and 0.67±0.37, +Rapa 0.84±0.37 and 0.87±0.54, p = 0.67 and 0.52). Taken together, these results suggest that the immunostimulatory effects of rapa are not maintained in the presence of costimulation blockade, suggesting a requirement for CD28 signals for the augmentation of T cell responses seen following mTOR inhibition. Further work is necessary to determine both the mechanism responsible for rapa-induced augmentation, as well as the mechanism by which CD28 blockade diminishes this effect.

Ford, M.: Grant/Research Support, Pfizer.

« Back to 2013 American Transplant Congress