Organ and tissue transplantation are frequently life-extending procedures for patients with end-stage organ disease or hematological malignancies; however, the success of transplantation of organs and tissues to a recipient from a genetically non-identical donor is limited by immune-mediated complications, including rejection, graft dysfunction, graft-versus-host-disease, and the side-effects of preventing rejection. Despite over 100 years of research in this area, we are just now beginning to develop an in-depth understanding of the immune mechanisms that determine the success of allotransplantation. A detailed understanding of transplantation immunology will allow for better selection of donor/recipient pairs, the development of novel therapeutic strategies and, ultimately, better outcomes. Reviews in this series explore the role of cytokines in both acute and chronic graft-versus-host disease, the effects of sterile inflammation, danger signals, and the inflammasome in solid organ transplantation, the mechanisms of humoral and cellular rejection, cell-based therapies to combat rejection and transplantation-associated infections, and the effects of both host intrinsic and extrinsic factors in transplantation outcomes.
Endogenous danger signals, or damage-associated molecular patterns (DAMPs), are generated in response to cell stress and activate innate immunity to provide a pivotal mechanism by which an organism can respond to damaged self. Accumulating experimental and clinical data have established the importance of DAMPs, which signal through innate pattern recognition receptors (PRRs) or DAMP-specific receptors, in regulating the alloresponse to solid organ transplantation (SOT). Moreover, DAMPs may incite distinct downstream cellular responses that could specifically contribute to the development of allograft fibrosis and chronic graft dysfunction. A growing understanding of the role of DAMPs in directing the immune response to transplantation has suggested novel avenues for the treatment or prevention of allograft rejection that complement contemporary immunosuppression and could lead to improved outcomes for solid organ recipients.
Jamie L. Todd, Scott M. Palmer
Although gene-environment interactions have been investigated for many years to understand people’s susceptibility to autoimmune diseases or cancer, a role for environmental factors in modulating alloimmune responses and transplant outcomes is only now beginning to emerge. New data suggest that diet, hyperlipidemia, pollutants, commensal microbes, and pathogenic infections can all affect T cell activation, differentiation, and the kinetics of graft rejection. These observations reveal opportunities for novel therapeutic interventions to improve graft outcomes as well as for noninvasive biomarker discovery to predict or diagnose graft deterioration before it becomes irreversible. In this Review, we will focus on the impact of these environmental factors on immune function and, when known, on alloimmune function, as well as on transplant fate.
Leonardo V. Riella, Jessamyn Bagley, John Iacomini, Maria-Luisa Alegre
An increasing number of older people receive organ transplants for various end-stage conditions. Although organ transplantation is an effective therapy for older patients (i.e., older than 65 years of age), such as in end-stage renal disease, this therapy has not been optimized for older patients because of our lack of understanding of the effect of aging and the immune response to organ transplantation. Here, we provide an overview of the impact of aging on both the allograft and the recipient and its effect on the immune response to organ transplantation. We describe what has been determined to date, discuss existing gaps in our knowledge, and make suggestions on necessary future studies to optimize organ transplantation for older people.
Monica M. Colvin, Candice A. Smith, Stefan G. Tullius, Daniel R. Goldstein