Organs from older donors are increasingly utilized for transplantation. Clinically, organ age has been linked to compromised function as well as more frequent acute rejections. We dissected the impact of donor age on the recipient’s immune response.

Hearts from young (3 mo) or old (18 mo) C57BL/6 (B6) mice were transplanted into young (3 mo) DBA/2 recipients. Old hearts were rejected significantly faster than young hearts (MST: 9 vs. 11, p=0.002). Significantly higher ISHLT rejection scores (p< 0.05) were observed in old cardiac allografts by day 7. Of note, IL-17 mRNA levels were dramatically increased in old allografts (30 fold increase, p=0.0357). Moreover, recipients of old grafts displayed increased frequencies of alloreactive IFN-Γ producing splenocytes, higher percentages of CD8⁺effector and CD8⁺ IFN-Γ⁺ T cells (p<0.05 for all experiments).

After confirming that organ age is critically influencing recipient’s immune responses we dissected the role of old passenger leukocytes. Chimeric animals were generated by transplanting syngeneic bone marrow from young B6 mice into lethally irradiated old or young B6 mice. Transplantation of these chimeric hearts resulted in comparable survival rates (MST: 10 vs. 10), rejection scores and recipient systemic immune responses (p>0.05 for all experiments). Those data demonstrate that APCs but not organ age ‘per-se’ were responsible for the accelerated immune response.

Next, we depleted cardiac DC´s using liposomal clodronate. Depletion of CD11c⁺ cells resulted in comparable survival rates, and rejection scores. Systemic immune responses were not different after the engraftment of old or young allografts when DC's had been depleted. Furthermore, IL-17 mRNA levels were significantly reduced in old allografts when DC´s had been depleted and reached levels comparable to those in hearts from young donors.

Of clinical significance, systemic treatment with anti IL-17 resulted in a significantly prolonged survival of old allografts.

Taken together, these results show that donor age enhances CD11c⁺ cell immunogenicity through a potent Th-17 specific response. Blocking IL-17 in recipients of old organs abolishes donor age-related compromised survival.

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