Accumulating evidence acknowledges the central relevance of aging and chronic antigen exposure in shaping the balance of innate and adaptive immunity. Here, we assessed whether aging alters characteristics and specificity of alloimmune responses using a murine model of repeated allogenic stimuli.

Young and old (3 vs. 18 months) C57BL/6 recipient mice were sensitized with fully mismatched skin grafts from young DBA/2 mice. Graft survival following this first transplantation showed well known age-dependent kinetics with prolonged survival in old recipients (p=0.0195 in old vs. young recipients). After 3 weeks, mice received a second skin graft from either DBA/2 donors (i.e. re-challenge with the same donor-specific antigen) or CBA/J donors (i.e. challenge with third party antigen). The donor-specific re-challenge with DBA/2 antigens accelerated graft rejection in both groups regardless of age (p=0.0304, compared to non-sensitized first grafts). Third party grafts from CBA/J donors, however, were rejected in a dramatically accelerated fashion by old but not young recipients (p=0.0198).

Dissecting this intriguing shifting balance of innate and adaptive immunity in aging, we found increased frequencies of central memory T cells in old animals subsequent to secondary third party (CBA/J) grafts. While splenic regulatory B cells and B1a cells did not exhibit significant differences between old and young recipients, splenic gd T cells displayed a highly increased IFN-γ expression in old but not young mice subsequent to a secondary third-party graft. Moreover, the expression of NK-like receptors (NKG2D, CD94/NKG2) on T cells was significantly increased in old animals that received a secondary third party graft. Next, we transplanted young and old mice three weeks after sensitization with grafts procured from F1 (C57BL/6-CBA/J) animals presenting, 'non-self' and 'self' antigens. Graft survival of secondary F1 grafts was prolonged in an age-dependent fashion with a more rapid rejection in old recipients, indicating that unspecific innate responses in aging remain augmented even after exposure to 'self' antigen.

Collectively, these results highlight a shift in the balance of innate and adaptive immune responses in old recipients leading with clinical relevance when transplanting older patients.

CITATION INFORMATION: Heinbokel T, Minami K, Elkhal A, Tullius S. Accelerated Rejection of Secondary Third Party Allografts in Older Recipients Is Facilitated by an Augmented Innate Immune Response. Am J Transplant. 2017;17 (suppl 3).

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