Interleukin-33 prolongs allograft survival during chronic cardiac rejection

Transpl Int. 2011 Oct;24(10):1027-39. doi: 10.1111/j.1432-2277.2011.01306.x. Epub 2011 Jul 28.


Interleukin-33 (IL-33) stimulates the generation of cells and cytokines characteristic of a Th2 immune response. We examined the effects of IL-33 on allografted heart tissue in a chronic cardiac rejection model, including analysis of the peripheral myeloid and lymphoid compartments. B6.C-H2bm12/KhEg hearts were transplanted into MHC class II-mismatched C57Bl/6J mice; IL-33 was administered daily. Cells from allografts and spleens were isolated for flow cytometry and cultured for cytokine production; some tissues were used for immunohistochemistry. Animals treated with IL-33 showed significantly longer allograft survival, which was associated with a distinct cytokine profile produced by graft-infiltrating cells. Proinflammatory IL-17A production was decreased with IL-33 treatment, while increased levels of IL-5, IL-10, and IL-13 were observed. After IL-33 therapy, flow cytometry showed a direct induction of CD4(+) Foxp3(+) Treg, whereas the number of B220(+) CD19(+) B cells, and circulating, as well as allograft deposited, alloantibodies was reduced. Following IL-33 treatment, a significant decrease in graft-infiltrating CD11b(high) Gr1(high) granulocytes coincided with a significant increase in CD11b(high) Gr1(intermediate) myeloid-derived suppressor cells (MDSC). In conclusion, IL-33 treatment in the setting of chronic rejection promotes the development of a Th2-type immune response that favors MDSC and Treg expansion, reduces antibody-mediated rejection (AMR), and ultimately, prolongs allograft survival.

MeSH terms

  • Animals
  • CD11b Antigen / metabolism
  • Female
  • Flow Cytometry / methods
  • Forkhead Transcription Factors / biosynthesis
  • Graft Rejection
  • Graft Survival
  • Green Fluorescent Proteins / metabolism
  • Heart / physiology*
  • Heart Transplantation / methods*
  • Interleukin-33
  • Interleukins / metabolism*
  • Isoantibodies / chemistry
  • Mice
  • Mice, Inbred C57BL
  • T-Lymphocytes, Regulatory / cytology


  • CD11b Antigen
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IL33 protein, human
  • Interleukin-33
  • Interleukins
  • Isoantibodies
  • Green Fluorescent Proteins