Peritransplant tolerance induction with anti-CD3-immunotoxin: a matter of proinflammatory cytokine control.
BACKGROUND
Tolerance is gaining momentum as an approach to reduce lifelong immunosuppressive therapy while improving transplant longevity. Anti-CD3 immunotoxin (IT), FN18-CRM9, has potential to induce tolerance owing to its exceptional ability to deplete sessile lymph node T cells. However, if initiated at the time of transplantation, alpha-CD3-IT alone elicits a proinflammatory cytokine response, precluding establishment of tolerance.


METHODS
Four groups of rhesus monkeys received kidney allografts and immunosuppression. Three groups received alpha-CD3-IT alone or alpha-CD3-IT supplemented with 15-deoxyspergualin (DSG) and/or methylprednisolone (MP). One group received alpha-CD3-monoclonal antibody with DSG and MP. Cytokines were measured by enzyme-linked immunosorbent assay.


RESULTS
Supplementing peritransplant alpha-CD3-IT treatment with a brief course of DSG and MP promoted rejection-free kidney allograft acceptance in 75% of macaques followed for up to 550 days. Among those given alpha-CD3-IT alone or with MP, none were long-term survivors. Tolerance developed after alpha-CD3-IT, DSG, and MP treatment, but not when the unconjugated a-CD3 monoclonal antibody was substituted for IT. Systemic production of proinflammatory cytokines interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha induced after peritransplant alpha-CD3-IT was prevented only in animals given DSG. Despite high levels of interleukin (IL)-12 in the first month after transplant, tolerant recipients exhibited IL-12 resistance, as evidenced by baseline plasma levels of IFN-gamma but elevated IL-4. DSG was shown to inhibit IL-12-driven IFN-gamma production by a mechanism associated with inhibition of nuclear factor kappa-B.


CONCLUSIONS
In this model, peritransplant induction of tolerance is promoted by efficient elimination of sessile lymph node T cells and control of the proinflammatory IFN-gamma response by a mechanism that appears to involve resistance to IL-12.
Contreras
J L
JL
Department of Surgery and Transplant Center, University of Alabama at Birmingham, 35294, USA.
Wang
P X
PX
Eckhoff
D E
DE
Lobashevsky
A L
AL
Asiedu
C
C
Frenette
L
L
Robbin
M L
ML
Hubbard
W J
WJ
Cartner
S
S
Nadler
S
S
Cook
W J
WJ
Sharff
J
J
Shiloach
J
J
Thomas
F T
FT
Neville
D M
DM
Thomas
J M
JM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017252:CD3 Complex / Q000276:immunology*; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D006085:Graft Survival / Q000502:physiology; D006146:Guanidines / Q000494:pharmacology; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000494:pharmacology; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology; D016030:Kidney Transplantation; D008253:Macaca mulatta; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D010835:Phytohemagglutinins / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016207:Cytokines; D006146:Guanidines; D007166:Immunosuppressive Agents; D000922:Immunotoxins; D018836:Inflammation Mediators; D016328:NF-kappa B; D010835:Phytohemagglutinins; D018664:Interleukin-12; D007371:Interferon-gamma; C037258:gusperimus