INTERLEUKIN-33 PROLONGS ALLOGRAFT SURVIVAL DURING CHRONIC CARDIAC REJECTION

ACTIVATION AND ROLE OF T REGULATORY CELLS

S.M. Brunner¹, G. Schiechl¹, H.J. Schlitt², S. Fichtner-feigl^1
1Surgery, University Hospital Regensburg, Regensburg/GERMANY, ², Univ. Regensburg, Regensburg/GERMANY

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Introduction

IL-33 is a member of the IL-1 family of cytokines that stimulates the generation of cells, cytokines, and immunoglobulins characteristic of a type 2 immune response. IL-33 mediates signal transduction through ST2, a receptor expressed on Th2 and mast cells. In this study, we demonstrate the effect of IL-33 on allograft function during chronic cardiac rejection in mice.

Material and Methods

B6.C-H2bm12/KhEg (bm12) donor hearts were transplanted into wild type MHC class II-mismatched C57BL/6J recipient mice. Graft function was assessed by palpation of the abdomen and rejection was defined as cessation of cardiac contractions. Starting at day 5 IL-33 was administered i.p. daily. Cardiac allografts were harvested and graft infiltrating CD4+ T-cells were isolated and cytokine production was determined by ELISA. Cells isolated from cardiac allografts and spleens were examined with flow cytometry. Further H&E staining of cardiac allografts was performed.

Results

Allogeneic transplanted control animals receiving PBS showed progressive allograft rejection with reduced graft contractility starting on day 7 with complete allograft rejection within 22 days after transplantation. In contrast, the median allograft survival in animals treated with daily i.p. injections of IL-33 was extended to 48 days. This clinically obvious effect of reduced allograft rejection could also be verified by H&E staining of the cardiac allografts. The prolonged allograft survival following IL-33 treatment was due to significant changes in cytokine production by graft infiltrating CD4⁺ T-cells. We observed a significant decrease in the production of pro-inflammatory IL-17A and significantly increased levels of the Th2-cytokines IL-5 and IL-13. In addition, IL-33 treatment resulted in changes of the homeostasis of the lymphoid and myeloid compartment in both the cardiac allografts and in the periphery. Flow cytometric analyses demonstrated a relative reduction of CD4⁺ T-cells by 30% following IL-33 treatment, whereas the relative level of CD8⁺ T-cells remained unchanged. Amongst CD4⁺ T-cells a significant increase in CD4⁺ Foxp3⁺ Treg could be detected. Further, changes in the myeloid compartment were evident following IL-33 administration. A significant decrease in CD11b^high Gr1^high granulocytes coinciding with a significant increase in CD11b^high Gr1^intermediate myeloid cells could be observed in cardiac allografts, as well as in the periphery.

Conclusion

IL-33 treatment prolongs allograft survival after cardiac transplantation in mice. IL-33 induces changes in cytokine production of graft infiltrating cells and alters the composition of the lymphoid and myeloid compartment. Thus, IL-33 and its downstream effects need further evaluation as a possible therapeutic option for chronic allograft rejection.

Disclosure: All authors have declared no conflicts of interest.