Neutralizing IL‐7 Promotes Long‐Term Allograft Survival Induced by CD40/CD40L Costimulatory Blockade

Memory T cells are somewhat resistant to immunosuppresion. They therefore pose a threat to inducing long‐term allograft survival. IL‐7 is essential for memory T‐cell generation. Here, we investigated whether neutralizing IL‐7 promotes allograft survival. We found that neutralizing IL‐7 alone did not significantly prolong allograft survival. However, blocking both IL‐7 and CD154 signaling synergistically prolonged allograft survival. In contrast, neutralizing IL‐2 failed to further prolong allograft survival induced by CD40/CD154 costimulatory blockade. Allospecific memory CD8+ T‐cell generation was severely impaired under the treatment of anti‐IL‐7 plus anti‐CD154 Ab while administering recombinant IL‐7 enhanced CD8+ memory generation even under donor‐specific transfusion plus anti‐CD154 Ab treatment. Neutralizing IL‐7, but not IL‐2, together with blocking CD154 synergistically suppressed the proliferation of naïve/effector CD8+ T cells infiltrating grafts. Nevertheless, neutralizing IL‐7 did not alter regulatory T‐cell generation while neutralizing IL‐2 suppressed their generation. Hence, targeting IL‐7 represents a new strategy to prolong allograft survival by acting on both naïve and memory T cells. Long‐term allograft survival may be achieved by neutralizing IL‐7 plus CD40/CD154 blockade, since CD40/CD154 costimulatory blockade prevents acute rejection while neutralizing IL‐7 suppresses the generation of memory T cells that persist and mediate late or chronic rejection. Neutralizing IL‐7 further prolongs anti‐CD154‐induced allograft survival by suppressing both naïve and memory CD8 T cells, suggesting that targeting IL‐7 represents a new strategy to prolong allograft survival.