Innate immune responses to transplants: A significant variable with cadaver donors

William M. Baldwin, Christian P. Larsen, Robert L. Fairchild

Research output: Contribution to journalArticlepeer-review

Abstract

Much of our knowledge of the biology of allograft rejection has come from carefully designed reductionist rodent experimental systems. While these models have provided powerful tools for dissecting the mechanisms of the adaptive immune response to an allograft, it is likely that they have underestimated the importance of innate immune responses that are involved in the recipient's response to an allograft in clinical transplantation. In the clinical setting, cadaveric organs are harvested from donors who have suffered acute brain death, subjected to variable periods of cold and warm ischemia, and transplanted into critically ill recipients, providing a powerful stimulus to the innate immune system. These systemic and local factors could promote the activation of the complement cascade via CRP, natural antibody, and MBL-dependent mechanisms. Complement activation promotes allograft injury directly via MAC and indirectly via the activating and chemoattractant effects of C3a and C5a on macrophages, neutrophils, basophils, eosinophils, and endothelial cells. Interestingly, while most acute rejection responses are characterized by lymphocytic infiltrates, a subset contains large numbers of eosinophils and/or basophils, which has been suggested to be a marker of poorer prognosis. Further investigation on the role of complement cleavage products and other factors that influence the composition graft infiltrating cells may help define the mechanisms involved in these distinct forms of rejection and suggest more specific and effective therapeutic approaches. The role of the NK cell response in organ allograft rejection also warrants further investigation. While rodent models indicate that NK cells are unlikely to be sufficient to independently reject a nonhematopoietic allograft, it is likely that in some settings NK cell responses may influence or play an important role in the rejection response. NK cells have been observed to infiltrate both cardiac and renal allografts and to produce or promote the release of effector molecules (granzymes), cytokines (IFNγ), and chemokines that regulate the adaptive immune response. While it is clear that MHC matching influences clinical renal allograft survival, relatively little is known about the rules that govern NK cell recognition of allogeneic MHC molecules via their inhibitory and activatory receptors. It is possible that certain MHC disparities may elicit either greater or lesser activation of NK cells and that this may in turn influence the degree to which NK cells participate in the rejection process in a given donor-recipient pair. This review has focused on the effects of innate immunity on transplants in the perioperative period. This is the time when the transplanted organ is most vulnerable and visible to innate and adaptive immune response elements because of the physiological insults incurred from harvesting, transportation, and transplantation. It should be emphasized that these early events have long-term consequences. Renal transplants with delayed graft function and acute rejections have a greater incidence of chronic dysfunction. These long-term consequences may be related to decreased functional reserves or increased antigen sensitization. Innate immunity can also be of consequence at later times after transplantation, such as during infectious episodes. CMV infections, for example, frequently trigger coincident rejection episodes. In the future, multiple aspects of organ allograft injury (including some of the adaptive immune responses to organ allografts) may be modified by inhibiting selected components of innate immunity.

Original languageEnglish (US)
Pages (from-to)369-376
Number of pages8
JournalImmunity
Volume14
Issue number4
DOIs
StatePublished - Apr 2001

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases
  • Immunology

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