Combined donor specific transfusion and anti-CD154 therapy achieves airway allograft tolerance.
BACKGROUND
The state of tolerance allows long term graft survival without immunosuppressants. Lung transplantation tolerance has not been consistently achieved in either small or large animal models.


METHODS
The mechanisms and effectiveness of a tolerance induction protocol consisting of donor specific transfusion (DST; day 0) and a short course of co-stimulatory blockade (anti-CD154 antibody; days -7, -4, 0 and +4) were studied in the mouse heterotopic tracheal transplant model of chronic lung rejection. C57BL/6 mice received BALB/c tracheal grafts (day 0) and were treated with DST alone, anti-CD154 alone, the combination (DST/anti-CD154), or no treatment. No non-specific immunosuppressants were used.


RESULTS
DST/anti-CD154 in combination, but neither treatment alone, markedly prolonged the lumen patency and survival (>100 days) of fully histo-incompatible allografts (p<0.05 versus control allografts at every time point studied up to 16 weeks) without immunosuppression. This protocol was donor antigen specific as third party grafts (C3H) were promptly rejected. In addition, DST/anti-CD154 did not result in mixed chimerism but induced transplantation tolerance via a peripheral mechanism(s), which included significantly reduced cytotoxic T cell activity (p<0.001) and a significantly increased percentage of CD4+CD25+ cells (p = 0.03).


CONCLUSIONS
The DST/anti-CD154 protocol successfully induced and maintained long term, donor specific tolerance in the mouse heterotopic airway graft model of chronic lung rejection. This finding may lead us closer to successful tolerance induction in lung transplantation.
Chalermskulrat
W
W
Division of Pulmonary Diseases and Critical Care Medicine and Lung Transplantation Program, University of North Carolina, School of Medicine, CB #7020, Bioinformatics Building, Room 4131, Chapel Hill, NC 27599, USA.
McKinnon
K P
KP
Brickey
W J
WJ
Neuringer
I P
IP
Park
R C
RC
Sterka
D G
DG
Long
B R
BR
McNeillie
P
P
Noelle
R J
RJ
Ting
J P
JP
Aris
R M
RM
D000818:Animals; D023201:CD40 Ligand / Q000627:therapeutic use*; D005260:Female; D005452:Fluoresceins; D005456:Fluorescent Dyes; D006084:Graft Rejection / Q000517:prevention & control*; D007150:Immunohistochemistry; D016040:Lung Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D013388:Succinimides; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014132:Trachea / Q000637:transplantation*; D014184:Transplantation, Homologous
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D005452:Fluoresceins; D005456:Fluorescent Dyes; D013388:Succinimides; D023201:CD40 Ligand