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

Abstract

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.

CC chemokine receptor 5 deletion impairs macrophage activation and induces adverse remodeling following myocardial infarction

“…The decreased expression of proinflammatory and anti-inflammatory markers on macrophages could be the result of CCR5 effects on T-cell function. Previously, Yi and colleagues (33) demonstrated that CD4ϩ T-cell-activated macrophages recognize and reject xenografts in the absence of other immune effector cells. In a follow-up study to evaluate the signaling pathway, isolated CCR5-deficient macrophages from xenograft recipients showed an impaired activation phenotype, suggesting that CCR5 signaling mediates CD4ϩ Tcell-macrophage activation (34).…”

Activation of IκB Kinase β and NF-κB Is Essential for Helicobacter pylori -Induced Chronic Gastritis in Mongolian Gerbils

“…Clodronate liposomes were used to specifically deplete macrophages. A single injection of clodronate into mice was reported to induce depletion of macrophages within 2 days (27). Mongolian gerbils were given clodronate liposomes, and the degree of macrophage depletion was assessed by immunostaining with F4/80, a specific marker for resident tissue macrophages, 2 days after administration.…”

Monocyte Adhesion to Xenogeneic Endothelium during Laminar Flow Is Dependent on α-Gal-Mediated Monocyte Activation

“…Monocyte infiltration occurs early after xenografting in both rodent-and pig-to-primate combinations, although the kinetics and severity of monocyte accumulation are more variable in pig-toprimate than in rodent models (2, 4, 5, 9 -12). Several lines of evidence support the role of monocytes and NK cells as effectors of DXR: depletion of monocytes or NK cells in xenograft recipients delays the onset of DXR, adoptive transfer of activated monocytes from rejected xenografts accelerates rejection in newly transplanted animals, and NK cells directly recognize and lyse xenogeneic endothelial cells through Ab-independent cytotoxic pathways (13)(14)(15)(16)(17). Furthermore, monocytes recruited into the xenograft elaborate multiple proinflammatory cytokines and chemokines, such as TNF-␣, IFN-␥, and MCP-1, that amplify the inflammatory response (4,9,12,15).…”