IL-2/IL-2 Ab Complex Leads to Long-Term Tolerance in a Treg Dependent DST Model of Skin Allograft Transplantation in Which DST and Timing of the Antibody Complex Are Crucial

G. Zhang,¹ Y. Wang,¹ M. Hu,¹ A. Sawyer,¹ J. Zhou,¹ S. Grey,² S. Alexander.¹

¹Children's Hospital at Westmead, Sydney, Australia
²Garvan Institute, Sydney, Australia.

Meeting: 2015 American Transplant Congress

Abstract number: 243

Keywords: Donor specific transfusion, Mice, Skin transplantation, Tolerance

Session Information

Session Name: Concurrent Session: Transplant Tolerance: Animal Models I

Session Type: Concurrent Session

Date: Monday, May 4, 2015

Session Time: 2:15pm-3:45pm

Presentation Time: 2:39pm-2:51pm

Location: Room 121-C

Background: In vivo Treg expansion using IL2 complexed with anti-IL2 antibody has been demonstrated to be effective in the induction of long-term acceptance of islet allografts. In this study, we investigated the effects of administration of IL2 complex in stringent skin allograft models. Method: 5 groups of B6 mice received a bm1 skin graft. bm1 is a MHC Class I mutant strain of B6. Group1: received IL2 complex 3 days before skin grafting. Group2: skin graft only control. Group3: received IL2 complex at Day -3, donor specific transfusion (DST) at Day0 and then skin grafting at Day7. Group4: DST at Day0, IL2 complex at Day4 and skin grafting at Day7. Group 5: DST at Day0 and skin grafting at Day7. IL2 complex was injected for 3 consecutive days.

Results: IL2 complex induced a 7.5-fold increase of Foxp3 Tregs in peripheral blood 4days after injection. Despite the substantial Treg expansion, B6 acutely rejected bm1 skin grafts at similar rate as the no IL2 complex control. DST prolonged survival of subsequent skin grafting but failed to induce long-term graft acceptance (MST=50). IL2 complex injection after DST moderately accelerated the graft rejection (MST=33). In contrast, administration of IL2 complex before DST rendered long-term graft acceptance (MST=100). In MLR, comparing the IL2 complex post-DST with pre-DST groups, splenocytes from the IL2 complex pre-DST group showed significantly reduced responses to bm1 stimulators while maintaining equivalent responses to third party stimulators. IFN-g ELISPOT showed a similar pattern of response to MLR. Compared with DST control, administration of IL2 complex after DST up-regulated CD25 expression on Foxp3- CD4+ (from 5.5% +/- 0.51 to 17% +/- 2.3) and on CD8+cells (from 0.74% +/- 0.32 to 2.73% +/- 0.92), and CD69 expression on Foxp3- CD4+cells (from 3.8% +/- 1.4 to 11.8% +/- 3.2).

Conclusion: IL-2 complex in combination with DST when given prior to DST leads long term tolerance, both timing of the IL-2 complex and the DST are essential for the development of tolerance as shown by the control groups of late IL-2 complex and IL-2 complex without DST. These results are consistent with the complex enhancing donor specific Tregs induced by the DST but in the absence of the DST these are not found. Similarly the late IL-2 complex appears to activate effector cells limiting tolerance.

To cite this abstract in AMA style:

Zhang G, Wang Y, Hu M, Sawyer A, Zhou J, Grey S, Alexander S. IL-2/IL-2 Ab Complex Leads to Long-Term Tolerance in a Treg Dependent DST Model of Skin Allograft Transplantation in Which DST and Timing of the Antibody Complex Are Crucial [abstract]. Am J Transplant. 2015; 15 (suppl 3). https://atcmeetingabstracts.com/abstract/il-2il-2-ab-complex-leads-to-long-term-tolerance-in-a-treg-dependent-dst-model-of-skin-allograft-transplantation-in-which-dst-and-timing-of-the-antibody-complex-are-crucial/. Accessed May 9, 2025.

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