Role of CD40-CD154 pathway in the rejection of concordant and discordant xenogeneic islets.
BACKGROUND
Costimulatory blockade has been shown to allow long-term survival of xenogeneic islets. The aim of the present study was to evaluate the role of recipient CD40 and CD154 in the rejection process of concordant and discordant islet xenotransplantation (Tx).


METHODS
Diabetic C57BL/6 mice, CD40- or CD154 knockout (KO) mice were transplanted with either concordant rat or discordant human islets.


METHODS
group 1, control (ie, C57BL/6 mice received islet Tx without therapy); group 2, C57BL/6 mice received islet Tx with anti-CD154 monoclonal Ab (mAb) therapy; group 3, CD40 KO mice; and group 4, CD154 KO mice were used as recipients without therapy. Mouse anti-rat mixed lymphocyte reactions (MLR) were performed using mouse splenocytes obtained from animals transplanted with rat islets in groups 1 to 4.


RESULTS
In group 2, short-term anti-CD154 mAb therapy significantly prolonged rat-to-mouse and human-to-mouse xenograft survival, compared to controls. In CD40-KO and CD154-KO recipients, survival of concordant or discordant islets was not prolonged significantly compared to control groups. Mouse anti-donor rat cellular responses were reduced approximately 50% in group 2 but remained unmodified in groups 3 and 4, when compared to group 1.


CONCLUSIONS
Improved graft survival and reduced MLR responses against donor cells in vitro among the anti-CD154 mAb-treated mice could be explained by specific targeting of activated T cells with subsequent inactivation by anergy and/or elimination by apoptosis, or complement- or cellular-mediated mechanisms. Rejection of xenografts and strong MLR responses against donor cells in vitro in CD40 or CD154 KO animals is possible through efficient activation of alternate pathways of costimulation.
Mai
G
G
Surgical Research Unit, Department of Surgery, University Hospital Geneva, Geneva, Switzerland.
Bucher
P
P
Morel
P
P
Mei
J
J
Bosco
D
D
Andres
A
A
Mathe
Z
Z
Wekerle
T
T
Berney
T
T
Bühler
L H
LH
D000818:Animals; D019013:CD40 Antigens / Q000235:genetics / Q000502:physiology*; D023201:CD40 Ligand / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D006084:Graft Rejection / Q000473:pathology*; D006801:Humans; D016381:Islets of Langerhans Transplantation / Q000473:pathology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D014183:Transplantation, Heterologous / Q000473:pathology
D019013:CD40 Antigens; D023201:CD40 Ligand