Immunosuppressive and trafficking properties of donor splenic and bone marrow dendritic cells.
BACKGROUND
Infusion of donor dendritic cells (DC) has been shown to prolong allograft survival in a number of models. However, many regimens that utilize donor DC do not consistently produced tolerance or long-term allograft survival. We hypothesized that one factor limiting the therapeutic effect of donor DC is their relative inability to traffic to recipient peripheral lymph nodes and inhibit the function of resident alloreactive T cells.


METHODS
Donor strain DC isolated from the spleens or bone marrow of Flt3L-treated mice were transferred intravenously into recipients at the time of skin grafting. Where indicated, recipients were treated with an anti-CD40L antibody and CTLA4-Ig.


RESULTS
Infusion of donor DC together with costimulatory blockade promoted donor-specific prolongation of skin allograft survival in mice. Perhaps due to their more immature phenotype, bone marrow DC trafficked more effectively to the spleen, bone marrow, and thymus and were associated with significantly longer allograft survival than were splenic DC. Neither population of DC trafficked well to peripheral lymph nodes. Consistent with our hypothesis, splenic but not lymph node T cells from DC-treated recipients displayed donor-specific hyporesponsiveness in vitro.


CONCLUSIONS
These data suggest that one factor contributing to rejection following treatment with donor DC plus costimulation blockade is the persistence of donor-reactive T cells within the recipient's secondary lymphoid structures. Strategies to improve DC trafficking to these structures may enhance their therapeutic effect.
Emory Transplant Center and Department of Surgery, Emory School of Medicine, Emory University, Atlanta 30322, GA.
Nikos
N
Emmanouilidis
Zhong
Z
Guo
Ying
Y
Dong
Marvin
M
Newton-West
Andrew B
AB
Adams
Eun D Han
ED
Lee
Jun
J
Wang
Thomas C
TC
Pearson
Christian P
CP
Larsen
Kenneth A
KA
Newell
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation*; D006082:Graft Enhancement, Immunologic; D006084:Graft Rejection / Q000628:therapy*; D006085:Graft Survival / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
D007519:Isoantigens