Subject(s)
DNA Copy Number Variations/genetics , Genetic Markers/genetics , Genetic Predisposition to Disease , Germ-Line Mutation/genetics , Inheritance Patterns/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Lymphoproliferative Disorders/genetics , Female , Genome, Human , Humans , Male , Oligonucleotide Array Sequence Analysis , Pedigree , Polymorphism, Single Nucleotide/genetics , PrognosisABSTRACT
As increasing numbers of elderly patients require solid organ transplantation, the need to better understand how aging modifies alloimmune responses increases. Here, we examined whether aged mice exhibit augmented, donor-specific memory responses prior to transplantation. We found that elevated donor-specific IL-17, but not IFN-gamma, responses were observed in aged mice compared to young mice prior to transplantation. Further characterization of the heightened IL-17 alloimmune response with aging demonstrated that memory CD4(+) T cells were required. Reduced IL-2 alloimmune responses with age contributed to the elevated IL-17 phenotype in vitro, and treatment with an anti-IL-17 antibody delayed the onset of acute allograft rejection. In conclusion, aging leads to augmented, donor-specific IL-17 immune responses that are important for the timing of acute allograft rejection in aged recipients. IL-17 targeting therapies may be useful for averting transplant rejection responses in older transplant recipients.
Subject(s)
Aging/immunology , Interleukin-17/immunology , Animals , CD4-Positive T-Lymphocytes/immunology , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Graft Rejection/immunology , Immunologic Memory , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Skin Transplantation/immunology , Spleen/cytology , Spleen/immunology , Spleen/metabolismABSTRACT
Dendritic cells (DCs) play a key role in initiating alloimmunity yet the substances that activate them during the host response to transplantation remain elusive. In this study we examined the potential roles of endogenous innate immune agonists in activating dendritic cell-dependent alloimmunity. Using a murine in vitro culture system, we show that 135 KDa fragments of the extracellular matrix glycosaminoglycan hyaluronan induce dendritic cell maturation and initiate alloimmunity. Priming of alloimmunity by hyaluronan-activated DCs was dependent on signaling via TIR-associated protein, a Toll-like receptor (TLR) adaptor downstream of TLRs 2 and 4. However, this effect was independent of alternate TLR adaptors, MyD88 or Trif. Using an in vivo murine transplant model, we show that hyaluronan accumulated during skin transplant rejection. Examination of human lung transplant recipients demonstrated that increased levels of intragraft hyaluronan were associated with bronchiolitis obliterans syndrome. In conclusion, our study suggests that fragments of hyaluronan can act as innate immune agonists that activate alloimmunity.