Overview: Studies have found administration of IL-33 triples the survival of MHC-mismatched murine heart transplants (HTx) in the absence of any immunosupression. These data are consistent with earlier identified direct cardiovascular protective properties of IL-33 and its receptor, ST2. IL-33 promotes survival following myocardial infarction through ST2-dependent protection of cardiac myocytes. Likewise, local IL-33 limits ventricular dysfunction following cardiac hypertrophy. However, the impact that allograft expression of ST2 has on heart transplant outcome, particularly the development of allograft vasculopathy (AV), was undefined.

Methods: ST2 and IL-33 expression within syngeneic (C57BL/6; B6; H-2b) or allogeneic (BALB/c; H-2d) cardiac grafts was determined by Western blotting 5 or 10 days after transplantation into B6 recipients. To assess the role of ST2 on the development of AV, minor mismatched male wild type (WT) or St2-/- BALB/c (H-2d) hearts were transplanted into WT BALB/c females. WT BALB/c female hearts were transplanted into female WT BALB/c recipients as controls. HTx were assessed daily by palpation and rejection defined as cessation of detectable HTx contraction. In separate experiments, WT or St2-/- BALB/c aortic allografts were transplanted (ATx) into WT B6 recipients. Additional B6 mice received syngeneic control grafts. At post-operative day (POD) 28 (ATx) or 100 (HTx), transplants were explanted and assessed following H&E, Masson’s trichrome, or Verhoeff-van Gieson staining. To quantitate infiltrating CD3+ cells, immunohistochemical staining was also completed.

Results: HTx exhibit loss of ST2 and induced expression of the IL-33 antagonist, sST2 by 10 days post transplant. Both BALB/c WT and St2-/- male HTx into female BALB/c exhibited long-term survival (survival >100 days). However, at 100 POD, St2-/- HTx grafts display increased CD3+ cell infiltrate and exhibit indications of augmented development of AV. Relatedly, compared to WT BALB/c ATx, St2-/- ATx displayed profound intimal proliferation, deposition of connective tissue, and thus significantly increased percentage of luminal occlusion.

Conclusion:ST2 is lost during rejection and the absence of ST2 in both HTx and ATx increased immune infiltration and accelerated development of AV. Our data identify an unappreciated direct protective role for local IL-33 and graft ST2 following transplant of cardiovascular tissue.

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