T cell-activated macrophages are capable of both recognition and rejection of pancreatic islet xenografts.
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.
Yi
Shounan
S
National Pancreas Transplant Unit, University of Sydney at Westmead Hospital, Westmead, New South Wales, Australia.
Hawthorne
Wayne J
WJ
Lehnert
Anne M
AM
Ha
Hong
H
Wong
Jeferey Kwok Wah
JK
van Rooijen
Nico
N
Davey
Kelly
K
Patel
Anita T
AT
Walters
Stacey N
SN
Chandra
Abhilash
A
O'Connell
Philip J
PJ
D019264:Adoptive Transfer; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000637:transplantation; D002465:Cell Movement / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D005260:Female; D016332:Fetal Tissue Transplantation / Q000276:immunology / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D016130:Immunophenotyping; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015398:Signal Transduction / Q000276:immunology; D013552:Swine; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D019172:Transplantation Conditioning; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000473:pathology
D015415:Biomarkers