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A Shifting Balance: Innate Immunity Impacts Characteristics and Specificity of Alloimmune Responses in Aging

Heinbokel, Timm; Minami, Koichiro; Elkhal, Abdallah; Tullius, Stefan G.

doi: 10.1097/

Division of Transplant Surgery and Transplant Surgery Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.

Introduction: Accumulating evidence acknowledges the central relevance of aging and chronic antigen exposure in shaping the balance of innate and adaptive immunity.

Methods: Here, we assessed whether aging alters characteristics and specificity of alloimmune responses using a murine model of repeated allogenic stimuli.

Results: 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 γδ 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.

Conclusion: 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.

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