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Interleukin 5 (IL-5) Treatment Prevents Chronic Allograft Rejection by Promoting IL-5 Receptor Expressing CD4 + CD25 + T Regulatory Ts2 Cells

Hall, Bruce M.1,4; Hall, Rachel M.1; Verma, Nirupama D.1,4; Robinson, Catherine M.1,4; Wilcox, Paul1; Tran, Giang T.1,4; Wang, Chuanmin2,3; Sharland, Alexandra2,3; Hodgkinson, Suzanne J.1,4

doi: 10.1097/

1Immune Tolerance Group, INGHAM Institute, Liverpool, Australia; 2Australian National Liver Transplantation Unit, Royal Prince Alfred Hospital, Sydney, Australia; 3Department of Surgery, University of Sydney, Sydney, Australia; 4South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Sydney, Australia.

Background: Our group has described a Th2 cytokine driven pathway of activation of naïve CD4+CD25+FOXP3+Treg (tTreg). tTreg are activated and proliferate to alloantigens if rIL-4 is present. IL-4 induces alloantigen-specific Treg that express IL-5Rα, the specific IL-5 receptor. These IL-4 activated Treg we call Ts2 cells. Ts2 cells suppress rejection and MLC proliferation in an alloantigen-specific manner. Ts2 cells response to specific-alloantigen is enhanced by IL-5.

Aim: To examine if IL-5 can activate alloAg-specific Ts2 cells and prevent chronic rejection.

Methods: Rats (F344) with adult Lewis heterotopic heart allografts received 5000units rIL-5 i.p. either daily for 10d or 50d from 7d after grafting (n = 5-6/grp). Graft survival was scored on a semi-quantitative scale. Host’s CD4+CD25+T cells were examined for cell numbers, in vitro response to donor antigen with IL-5, and cytokine and cytokine receptor expression by RT-PCR.

Results: Untreated controls totally rejected by 28d(n = 5). IL-5 prevented rejection until cessation of rIL-5 (p < 0.01 vs sham) at 18d. After rIL-5 treatment ceased, a rejection crisis occurred but all grafts recovered and survived for 60d with good function. In groups where rIL-5 treatment after 18d was continued three times a week, the rejection was milder and all grafts survived with good function for 60d. Pre-treatment with anti-CD25 or anti-IL-4 abolished benefit of rIL-5, consistent with the need for activation of host CD25+Tcells by IL-4 and alloantigen to induce Ts2 cells dependent on IL-5. After 10d of rIL-5 treatment, host CD4+CD25+FOXP3+ Treg increased in numbers (6-8% in IL-5 vs 3-4% in control), expressed IL-5Ra and proliferated to specific-donor antigen but not to self or third-party in MLC showing activation of alloAg-specific Treg by IL-5 treatment. CD4+CD25+T cells from rats treated for 50d with rIL-5 had their response to Lewis, but not to third-party, alloantigen enhanced by IL-5, consistent with a Ts2 cell response. RT-PCR of CD4+CD25+T cells found IL-5 treated groups had more IL-5Rα and FOXP3 than controls.

Conclusions: IL-5 treatment prevented allograft rejection by activation of CD4+CD25+FOXP3+Treg that had been activated by host IL-4 and donor alloAg to Ts2 cells. This approach of enhancing Th2 cytokine induced alloantigen-specific Treg may provide a new therapy for clinical chronic rejection.

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