Fabritius C et al. – This study elucidated the underlying cellular mechanisms involved in prolonging graft survival by neutralizing the activating natural killer (NK) cell receptor NKG2D when combined with co–stimulation blockade. Overall, the study revealed that NKG2D expression in the recipient is important for cardiac allograft survival, supporting the hypothesis that impairment of NK cells prevents the establishment of graft acceptance.

Methods

• Complete MHC (Major Histocompability Complex)–disparate BALB/c–derived cardiac grafts were transplanted into C57BL/6 wildtypes or mice deficient for NKG2D (Klrk1–/–).

Results

• Although the median survival was 8 days for both the groups, a significantly greater intragraft frequencies of NKp46+ NK cells, infiltration of CD4+, and a lesser infiltration of CD8+ T cell frequencies were observed in Klrk1–/– recipients compared with the wildtypes.
• Co–stimulation blockade with CTLA4–Ig resulted in a significant acceleration of cardiac rejection by Klrk1–/– recipients, which was confirmed by applying a neutralizing antibody against NKG2D to wildtypes.
• In both the groups, grafts derived from Klrk1–/– recipients were characterized by significantly greater levels of interferon gamma (IFNγ) mRNA and both CD4+ and CD8+ T cells, which indicate a greater capacity for degranulation and IFNγ production.