Tolerability and side effects of anti-CD3-immunotoxin in preclinical testing in kidney and pancreatic islet transplant recipients.
BACKGROUND
Anti-CD3-immunotoxin (alpha-CD3-IT) promotes allograft tolerance in nonhuman primates owing to efficient depletion of sessile and circulating T cells. Common side effects of vascular leak syndrome, hepatotoxicity, and nephrotoxicity have limited tolerability of other immunotoxins. We report on preclinical studies of alpha-CD3-IT-related side effects.


METHODS
Normal rhesus monkeys received a kidney transplant and alpha-CD3-IT alone (on day -to +2) or in combination with brief peritransplant adjunctive immunosuppressive therapy. Some received donor CD34+ cells. Blood chemistries, complete blood count, weight, liver, and kidney biopsies were examined for immunotoxin-related changes. Five spontaneously diabetic primates also received alpha-CD3-IT, three of whom had a pancreas islet transplant.


RESULTS
The main side effect of alpha-CD3-IT, vascular leak syndrome, was entirely prevented by adjunctive immunosuppressive therapy. Renal and liver function tests and biopsies revealed a lack of nephrotoxicity and hepatotoxicity. All had transient weight loss (14+/-5%). Without infusion of donor CD34+ cells, 97% had full weight recovery. Of those given donor CD34+ cells, 50% were euthanized for wasting.


CONCLUSIONS
Side effects of alpha-CD3-IT are manageable and should not prevent therapeutic application.
Contreras
J L
JL
Division of Transplantation Immunology, University of Alabama at Birmingham, 35294, USA.
Eckhoff
D E
DE
Cartner
S
S
Frenette
L
L
Thomas
F T
FT
Robbin
M L
ML
Neville
D M
DM
Thomas
J M
JM
D000818:Animals; D017252:CD3 Complex / Q000276:immunology*; D019559:Capillary Leak Syndrome / Q000209:etiology / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury; D016572:Cyclosporine / Q000008:administration & dosage; D007108:Immune Tolerance; D000922:Immunotoxins / Q000009:adverse effects; D016381:Islets of Langerhans Transplantation; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008111:Liver Function Tests; D008253:Macaca mulatta; D008297:Male; D008775:Methylprednisolone / Q000008:administration & dosage; D019172:Transplantation Conditioning
D017252:CD3 Complex; D000922:Immunotoxins; D016572:Cyclosporine; D008775:Methylprednisolone