Session Time: 2:30pm-4:00pm
Presentation Time: 2:54pm-3:06pm
Location: Room 606/607
Purpose: Interleukin-33 (IL-33) is an “alarmin”, or a self-derived molecule that triggers pleotropic immune responses after release from damaged tissue. Yet, how IL-33 shapes alloresponses or outcome after solid organ transplantation is poorly understood. Using a pre-clinical mouse model, we demonstrate that IL-33 in heart transplants is critical to restrain infiltrating myeloid cells from differentiating into pro-inflammatory cells after transplantation and thus limit the subsequent development of chronic rejection.
Methods: Wild type BALB/c, il33+/+ Bm12, il33-/- Bm12 hearts were heterotopically transplanted into WT or il33-/- B6 mice. In some groups, IL-33 was restored locally using extracellular matrix-based hydrogel at the time of transplantation. At days 3 to 7, or 100 to 120 post heart transplant (HTx) isolated grafts were stained with H+E or Trichrome. In addition to qRT-PCR and Western blot, IHC staining was used to define differences in cytokine expression and leukocyte infiltration. Leukocytes isolated from the HTx and recipient spleen were compared at various time points through flow cytometry.
Results: Surgery, acute, and chronic rejection increased IL-33 in HTx fibroblasts, vascular smooth muscle cells, and endothelial cells. HTx deficient in IL-33 displayed dramatically increased chronic rejection-associated fibrosis (% fibrotic: 58±6. vs. 42±1; P=0.002) and vasculopathy (% occlusion: 98±3 vs. 87±3; P=0.02). HTx deficient in IL-33 had increased CD3+ (281±35 cell/mm2 vs. 529±25; P=0.0004) areas of vascular cuffing. Characterization of the myeloid compartment in the HTx at day 3 post surgery revealed that transplants lacking IL-33 had significantly increased frequency of pro-inflammatory macrophages (CD11b+ Ly6Chi F4-80+) and cDC (CD11b+ CD11c+ CD80hi). Local delivery of IL-33 reduced these pro-inflammatory immune cells in the graft.
Conclusions: Our findings demonstrate that IL-33 is a regulatory alarmin after HTx and functions to control the generation of local inflammatory myeloid cells. Local IL-33 was critical to limit chronic rejection. We thus establish an unappreciated, yet fundamental role for upregulated IL-33 in heart allograft protection.
CITATION INFORMATION: Zhang Z., Liu Q., Hussey G., Dziki J., Mathews L., Dai H., Dwyer G., Lucas A., Oberbarnscheidt M., Badylak S., Turnquist H. Upregulated IL-33 in Heart Transplants Modulates Local Myeloid Populations to Protect against Chronic Allograft Rejection Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:Zhang Z, Liu Q, Hussey G, Dziki J, Mathews L, Dai H, Dwyer G, Lucas A, Oberbarnscheidt M, Badylak S, Turnquist H. Upregulated IL-33 in Heart Transplants Modulates Local Myeloid Populations to Protect against Chronic Allograft Rejection [abstract]. https://atcmeetingabstracts.com/abstract/upregulated-il-33-in-heart-transplants-modulates-local-myeloid-populations-to-protect-against-chronic-allograft-rejection/. Accessed November 13, 2019.
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