CD28:CD80/86 pathway costimulation blockade (CoB) with the CD80/86-specific fusion protein CTLA4-Ig prevents T cell-mediated allograft rejection in mice. However, in humans, transplantation with CoB has been hampered by CoB-resistant rejection (CoBRR). CoBRR has been attributed in part to pathogen-driven T cell repertoire maturation and resultant heterologous alloreactive memory. This has been demonstrated experimentally in mice. However, prior murine models have used viral pathogens, CoB regimens, graft types, and/or antigen systems atypically encountered clinically. We therefore sought to explore whether CoBRR would emerge in a model of virus-induced memory differentiation designed to more closely mimic clinical conditions. Specifically, we examined mouse homologs of clinically prevalent viruses including murine polyomavirus, cytomegalovirus, and gammaherpesvirus 68 in the presence of clinically relevant maintenance CoB regimens using a fully MHC-mismatched, vascularized allograft model. Infected mice developed a significant, sustained increase in effector memory T cells consistent with that seen in humans, but neither developed heterologous alloreactivity nor rejected primarily vascularized heterotopic heart transplants at an increased rate compared with uninfected mice. These results indicate that memory acquisition alone is insufficient to provoke CoBRR and suggest that knowledge of prior latent or persistent viral infection may have limited utility in anticipating heterologous CoB-resistant alloimmunity.
Bibliographical noteFunding Information:
Viruses used in these studies were generously donated by the Lukacher Lab (PyV), Mocarski Lab (mCMV), and Speck Lab (HV68) at Emory University. Critical assistance with the virology was provided by Elizabeth Frost for work with PyV, Linda Roback for work with mCMV, and Christopher Collins for work with HV68. This work was supported by National Institutes of Health Grants R01 A1097423, T32 A1007610, and T32 A1070081.
© 2018 Espinosa, Mou, Adams, DiBernardo, MacDonald, McRae, Miller, Song, Stempora, Wang, Iwakoshi and Kirk.
- Costimulation blockade
- Heterotopic heart transplantation
- T cell memory
- Viral infections