Date: Sunday, May 3, 2015
Session Time: 5:30pm-6:30pm
Presentation Time: 5:30pm-6:30pm
Location: Exhibit Hall E
Purpose: Wider utilization of VCA is hampered by the need for long-term immunosuppression. Barriers to more targeted immunosuppression in VCA include (1) limited knowledge of the cells and cytokines mediating acute skin rejection, (2) high antigenicity of the skin component of VCA, and (3) lack of strategies to promote allograft tolerance. We aimed to address these challenges by more fully characterizing the rejection process and identifying novel targets for intervention. We particularly focused on CD4+ Th17 cells which mediate strong pro-inflammatory responses in skin during autoimmune disease and which have been implicated in chronic rejection in solid organ transplantation.
Methods: Orthotopic hindlimb transplants were performed between syngeneic or allogeneic mouse strain combinations. Animals were assessed daily for clinical signs of rejection and tissue biopsies were obtained at various time points to assess rejection kinetics. H&E histology, tissue homogenization and quantitative PCR as well as T cell tissue extraction for flow analysis were performed.
Results: Tissues transplanted across a full H-2 barrier displayed reproducible kinetics of rejection with animals reaching grade 1 rejection at day 4, grade 2 rejection at day 5, and grade 3 rejection between days 8-9. Histologically, rejection was characterized by a marked mononuclear cell infiltrate. Quantitative PCR and T Cell PRC on rejecting skin revealed striking infiltration with Th1 cells and upregulation of the Th1 genes T-bet (80 fold) and IFNg (20 fold) but not TH17 genes RoRγT or IL-17. The cognate transcription factor for Tregs, Foxp3, was also upregulated in rejecting skin, suggesting that an ineffectual tolerogenic response was mounted.
Conclusions: Orthotopic hindlimb transplantion between allogenic strain combinations of mice reveals predictable patterns of rejection, confirming the utility of this model in characterizing immunological aspects of VCA. The intense mononuclear infiltrate characteristic of rejection is predominated by Th1 but not Th17 polarized CD4+ T cells. The presence of Treg markers in allogeneic transplants suggests a latent capacity for transplant tolerance. We hope that this capacity can be augmented by further characterizing and altering the transplant cytokine milieu.
To cite this abstract in AMA style:Fryer M, Furtmùller G, Oh B, Reddy S, Sarhane K, Raimondi G, Brandacher G, Cooney D. Defining and Directing T Cell Subsets Involved in Rejection of Vascularized Composite Allografts [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/defining-and-directing-t-cell-subsets-involved-in-rejection-of-vascularized-composite-allografts/. Accessed February 26, 2020.
« Back to 2015 American Transplant Congress