SummaryA previous paper has reported that blockade of NKG2D was effective in protecting allograft in murine models of cardiac transplantation, but the mechanism of NKG2D blockade on attenuated cardiac allograft vasculopathy (CAV) was still unknown. In our current study, we found that wild-type recipients treated with anti-NKG2D monoclonal antibody (mAb) plus cytotoxic T lymphocyte antigen (CTLA)-4-immunoglobulin (I)g showed prolonged allograft survivals (>90 days, P < 0·001) significantly and attenuated CAV. These in-vivo results correlated with reduced alloantibody production, low expression of interleukin (IL)-17 and IL-6, while infiltration of regulatory T cells increased. IL-6 administration induced shorter allograft survival and higher CAV grade in CTLA-4-Ig plus anti-NKG2D mAb-treated recipients, whereas IL-17 had no significant effect on allograft survival and CAV grade in CTLA-4-Ig plus anti-NKG2D mAb-treated recipients. Furthermore, the prolonged allograft survival induced by NKG2D blockade was abrogated partially with depletion of regulatory T cells. In conclusion, blockade of NKG2D combined with CTLA-4-Ig attenuated CAV and this effect was associated with lower alloantibody production, inhibited IL-6 expression and enhanced expansion of regulatory T cells.
Abstractcd T cell comprises about 5% of the overall T cell population, and they differ from conventional ab T cells. Previous studies have indicated the contribution of cd T cell to acute allograft rejection, but the role of cd T cell in cardiac allograft vasculopathy (CAV) is not investigated. Hearts of adult B6.C-H-2 bm12 KhEg were heterotopically transplanted into major histocompatibility complex (MHC) class II-mismatched C57BL/6 mice (wild-type, cd TCR À/À ), which is an established murine model of chronic allograft rejection without immunosuppression. The survival of grafts was monitored daily by abdominal palpation until the complete cessation of cardiac contractility. Our current study demonstrated that cd T cell receptor (TCR) deficiency significantly attenuated CAV, and this effect coincides with low expression of Hmgb1, IFN-c and IL-17 while increased number of CD4 + CD25 + Foxp3 + regulatory T cells, and depletion of regulatory T cells abrogated the prolonged allograft survival induced by cd TCR deficiency. cd TCR deficiency resulted in attenuated CAV and prolonged graft survival in murine models of cardiac transplantation, and this effect was associated with enhanced expansion of regulatory T cells.
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