Prolonged acceptance of concordant and discordant xenografts with combined CD40 and CD28 pathway blockade.
BACKGROUND
The prompt and vigorous immune response to xenogenic tissue remains a significant barrier to clinical xenotransplantation. Simultaneous blockade of the CD28 and CD40 costimulatory pathways has been shown to dramatically inhibit the immune response to alloantigen.


METHODS
. In this study, we investigated the ability of simultaneous blockade of the CD28 and CD40 pathways to inhibit the immune response to xenoantigen in the rat-to-mouse and pig-to-mouse models.


RESULTS
Simultaneous blockade of the CD28 and CD40 pathways produced marked inhibition of the cellular response to xenoantigen in vivo and produced long-term acceptance of xenogeneic cardiac and skin grafts (rat-to-mouse), and markedly suppressed an evoked antibody response to xenoantigen. In addition, this strategy significantly prolonged the survival of pig skin on recipient mice.


CONCLUSIONS
Long-term hyporesponsiveness to xenoantigen across both a concordant and discordant species barrier, measured by the stringent criterion of skin grafting, can be achieved using a noncytoablative treatment regimen.
Elwood
E T
ET
Department of Surgery, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Larsen
C P
CP
Cho
H R
HR
Corbascio
M
M
Ritchie
S C
SC
Alexander
D Z
DZ
Tucker-Burden
C
C
Linsley
P S
PS
Aruffo
A
A
Hollenbaugh
D
D
Winn
K J
KJ
Pearson
T C
TC
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D060908:CTLA-4 Antigen; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007108:Immune Tolerance / Q000502:physiology*; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000276:immunology; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D015778:Minor Histocompatibility Antigens; D051381:Rats; D017207:Rats, Sprague-Dawley; D016038:Skin Transplantation / Q000276:immunology* / Q000473:pathology; D013552:Swine; D014183:Transplantation, Heterologous / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C556708:Ctla4 protein, rat; D015395:Histocompatibility Antigens Class I; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D015778:Minor Histocompatibility Antigens; C490628:Mr1 protein, mouse; C490627:Mr1 protein, rat; D000069594:Abatacept