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T Cell-Activated Macrophages Are Capable of Both Recognition and Rejection of Pancreatic Islet Xenografts¹

Shounan Yi^*, Wayne J. Hawthorne^*, Anne M. Lehnert^*, Hong Ha^*, Jeferey Kwok Wah Wong^*, Nico van Rooijen, Kelly Davey^*, Anita T. Patel^*, Stacey N. Walters^*, Abhilash Chandra^* and Philip J. O’Connell^2,*

^* National Pancreas Transplant Unit, University of Sydney at Westmead Hospital, Westmead, New South Wales, Australia; and Department of Cell Biology, Free University, Amsterdam, The Netherlands

Macrophages have been proposed as the major effector cell in T cell-mediated xenograft rejection. To determine their role in this response, NOD-SCID mice were transplanted with fetal pig pancreas (FPP) before reconstitution with CD4⁺ T cells from BALB/c mice. Twelve days after CD4⁺ T cell reconstitution, purified macrophages (depleted of T cells) were isolated from CD4⁺ T cell-reconstituted FPP recipient mice and adoptively transferred to their nonreconstituted counterparts. After adoptive macrophage transfer, FPP recipient mice transferred with macrophages from CD4⁺ T cell-reconstituted mice demonstrated xenograft destruction along with massive macrophage infiltration at day 4 and complete graft destruction at day 8 postmacrophage transfer. By contrast, FPP recipients that received macrophages from nonreconstituted mice showed intact FPP xenografts with few infiltrating macrophages at both days 4 and 8 after macrophage transfer. The graft-infiltrating macrophages showed increased expression of their activation markers. Depletion of endogenous macrophages or any remaining CD4⁺ T cells did not delay graft rejection in the macrophage-transferred FPP recipients, whereas depletion of transferred macrophages with clodronate liposomes prevented graft rejection. Our results show that macrophages primed by FPP and activated by CD4⁺ T cells were attracted from the peripheral circulation and were capable of specific targeting and destruction of FPP xenografts. This suggests that in xenograft rejection, there are macrophage-specific recognition and targeting signals that are independent of those received by T cells.

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