title: Interleukin-33 prolongs allograft survival during chronic cardiac rejection.
abstract: 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.
authors.affiliation: Department of Surgery, University Medical Center Regensburg, Regensburg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Brunner
authors.forename: Gabriela
authors.initials: G
authors.lastname: Schiechl
authors.forename: Werner
authors.initials: W
authors.lastname: Falk
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schlitt
authors.forename: Edward K
authors.initials: EK
authors.lastname: Geissler
authors.forename: Stefan
authors.initials: S
authors.lastname: Fichtner-Feigl
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D006084:Graft Rejection; D006085:Graft Survival; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006321:Heart / Q000502:physiology*; D016027:Heart Transplantation / Q000379:methods*; D000067596:Interleukin-33; D007378:Interleukins / Q000378:metabolism*; D007518:Isoantibodies / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000166:cytology
chemical_list: D039481:CD11b Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C506536:IL33 protein, human; D000067596:Interleukin-33; D007378:Interleukins; D007518:Isoantibodies; D049452:Green Fluorescent Proteins