Peritransplant tolerance induction in macaques: early events reflecting the unique synergy between immunotoxin and deoxyspergualin.
BACKGROUND
Day of transplant T cell depletion with anti-CD3 immunotoxin or F(Ab)2 immunotoxin induces stable tolerance to renal allografts in rhesus monkeys given 15-deoxyspergualin (DSG), a NF-kappaB inhibitor that suppresses proinflammatory cytokine (PC) production. Because PC and NF-kappaB are involved in dendritic cell (DC) maturation, we asked if impaired DC maturation and Th2-type cytokine deviation might be related to the synergistic effect of DSG in this novel model.


METHODS
Immunosuppression was initiated 4 hr before transplanting a major histocompatibility complex mismatched renal allograft. Some groups received a supplemental 5-day course of cyclosporine A or DSG or a 15-day course of DSG. Peripheral lymph nodes were sequentially examined for presence of mature DC. In vitro effects of DSG on PC-induced maturation of DC were also examined.


RESULTS
Allografts survived without rejection in 87% of recipients given immunotoxin or F(Ab)2 immunotoxin with DSG x 15 days, in 50% with DSG x 5 days, and 0% with cyclosporine A. The longest DSG survivors are >1000 days with normal graft function and tolerance validated, including acceptance of challenge second donor kidneys without treatment. DSG-treated recipients were unique in developing polarized Th2-type plasma cytokines. In DSG recipients, mature DC were significantly reduced in day +5 lymph node biopsies, with complete repopulation by 30 days. In vitro studies verified an inhibitory effect of DSG on DC maturation.


CONCLUSIONS
The study suggests DSG arrests DC maturation. The unusual synergy of immunotoxin and DSG apparently involves coincidental reduction in lymph node T cell mass and mature DC, a transient circumstance favoring development of stable tolerance.
Thomas
J M
JM
Department of Surgery, University of Alabama at Birmingham, 35294, USA.
Contreras
J L
JL
Jiang
X L
XL
Eckhoff
D E
DE
Wang
P X
PX
Hubbard
W J
WJ
Lobashevsky
A L
AL
Wang
W
W
Asiedu
C
C
Stavrou
S
S
Cook
W J
WJ
Robbin
M L
ML
Thomas
F T
FT
Neville
D M
DM
D000818:Animals; D017252:CD3 Complex; D002452:Cell Count; D016922:Cellular Senescence / Q000187:drug effects; D002678:Chimera; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000502:physiology; D006085:Graft Survival / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology*; D007108:Immune Tolerance; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D000922:Immunotoxins / Q000494:pharmacology*; D016030:Kidney Transplantation / Q000276:immunology*; D008198:Lymph Nodes / Q000473:pathology; D008253:Macaca mulatta; D008297:Male; D013234:Stem Cells / Q000276:immunology / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000473:pathology
D017252:CD3 Complex; D016207:Cytokines; D006146:Guanidines; D007140:Immunoglobulin Fab Fragments; D007166:Immunosuppressive Agents; D000922:Immunotoxins; C037258:gusperimus