The mechanisms underlying latent-virus-mediated heterologous immunity， and subsequent transplant rejection， especially in the setting of T cell costimulation blockade， remain undetermined. To address this， we have utilized MHV68 to develop a rodent model of latent virus-induced heterologous alloimmunity. MHV68 infection was correlated with multimodal immune deviation， which included increased secretion of CXCL9 and CXCL10， and with the expansion of a CD8(dim) T cell population. CD8(dim) T cells exhibited decreased expression of multiple costimulation molecules and increased expression of two adhesion molecules， LFA-1 and VLA-4. In the setting of MHV68 latency， recipients demonstrated accelerated... More
The mechanisms underlying latent-virus-mediated heterologous immunity， and subsequent transplant rejection， especially in the setting of T cell costimulation blockade， remain undetermined. To address this， we have utilized MHV68 to develop a rodent model of latent virus-induced heterologous alloimmunity. MHV68 infection was correlated with multimodal immune deviation， which included increased secretion of CXCL9 and CXCL10， and with the expansion of a CD8(dim) T cell population. CD8(dim) T cells exhibited decreased expression of multiple costimulation molecules and increased expression of two adhesion molecules， LFA-1 and VLA-4. In the setting of MHV68 latency， recipients demonstrated accelerated costimulation blockade-resistant rejection of skin allografts compared to non-infected animals (MST 13.5 d in infected animals vs 22 d in non-infected animals， p<.0001). In contrast， the duration of graft acceptance was equivalent between non-infected and infected animals when treated with combined anti-LFA-1/anti-VLA-4 adhesion blockade (MST 24 d for non-infected and 27 d for infected， p?=?n.s.). The combination of CTLA-4-Ig/anti-CD154-based costimulation blockade+anti-LFA-1/anti-VLA-4-based adhesion blockade led to prolonged graft acceptance in both non-infected and infected cohorts (MST>100 d for both， p<.0001 versus costimulation blockade for either). While in the non-infected cohort， either CTLA-4-Ig or anti-CD154 alone could effectively pair with adhesion blockade to prolong allograft acceptance， in infected animals， the prolonged acceptance of skin grafts could only be recapitulated when anti-LFA-1 and anti-VLA-4 antibodies were combined with anti-CD154 (without CTLA-4-Ig， MST>100 d). Graft acceptance was significantly impaired when CTLA-4-Ig alone (no anti-CD154) was combined with adhesion blockade (MST 41 d). These results suggest that in the setting of MHV68 infection， synergy occurs predominantly between adhesion pathways and CD154-based costimulation， and that combined targeting of both pathways may be required to overcome the increased risk of rejection that occurs in the setting of latent-virus-mediated immune deviation.
