Donor HO-1 expression inhibits intimal hyperplasia in unmanipulated graft recipients: a potential role for CD8+ T-cell modulation by carbon monoxide.
BACKGROUND
Induction of heme oxygenase (HO)-1 expression protects transplanted organs from humoral rejection and ischemia-reperfusion injury, but induction in recipient immune cells also has direct immunomodulatory effects. Although many studies have examined the impact of HO-1 after transplantation, it is still unclear whether HO-1 expression solely in the donor tissue can influence the recipient T-cell response.


METHODS
Donor mice were treated with hemin to transiently upregulate HO-1. Control or HO-1-expressing aortas were transplanted into fully mismatched, completely unmanipulated recipients, and harvested at 6 weeks to assess neointimal area and T-cell infiltration. T cells were isolated from draining lymph nodes to assess cytokine production. In vitro, T-cell proliferative and cytokine responses to allogeneic donor dendritic (DC) and endothelial cells expressing HO-1 were examined.


RESULTS
Neointimal area was significantly (P<0.01) reduced in HO-1-expressing grafts. Hemin pretreated endothelial cells significantly inhibited proliferation (P<0.01) and interferon (IFN)-gamma production (P =0.01) in allogeneic CD8 T cells. This effect was mimicked by a carbon monoxide-releasing molecule. No phenotypic or functional changes were observed after incubation of T cells with hemin-treated dendritic cells. T-cell infiltration of HO-1-expressing donor aortas was significantly reduced (P<0.001), but proportions of IFN-gamma-producing T cells harvested from regional lymph nodes were similar.


CONCLUSIONS
Organs expressing cytoprotective HO-1 have a direct influence on the recipient immune response. Given the important role of CD8 T cells and IFN-gamma in chronic rejection, these data suggest that donor HO-1 expression may be useful to augment other immunosuppressive therapies to prolong graft survival and inhibit intimal hyperplasia.
Clarke
Helen M
HM
Department of Immunology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
Shrivastava
Seema
S
Motterlini
Roberto
R
Sawle
Philip
P
Chen
Daxin
D
Dorling
Anthony
A
D000818:Animals; D001011:Aorta / Q000637:transplantation*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D006965:Hyperplasia; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015427:Reperfusion Injury; D014180:Transplantation / Q000379:methods*
D007371:Interferon-gamma; D051547:Heme Oxygenase-1