Tolerance in baboon kidney transplantation with total lymphoid irradiation (TLI) and anti-CD3/CD4-idarubicin conjugates.
BACKGROUND
We previously reported the induction of transplantation tolerance by a modified wide field method of pretransplant total lymphoid irradiation (TLI), cumulative dose 800 cGy, given as 80 or 100 cGy fractions twice/week, in approximately one-third of chacma baboons receiving liver or kidney allografts (1-4) and in vervet monkeys receiving baboon kidney xenografts (5). In this study, the effects of the administration of brief courses of anti-CD3 or CD4-Idarubicin conjugates on the frequency and predictability of tolerance induction by TLI were examined.


METHODS
TLI was administered pretransplant in doses of 800, 600, or 400 cGy. The conjugates were administered either after transplantation in doses of 0.25 mg/kg body weight, 3 times/week for 2 weeks, or as a single dose of 1.0 mg/kg body weight 24 hr before transplantation.


RESULTS
Operational tolerance, defined as normal graft function >1 year after transplantation, was obtained in one-half of six baboons receiving the single dose of 1 mg/kg of Idarubicin conjugate pretransplant after 800 cGy of TLI and also in one of four baboons treated with 400 cGy of TLI and a single dose of anti-CD3 conjugate before transplantation. By contrast, administration of the conjugated antibodies 3 times/week for 2 weeks after transplantation prevented tolerance induction in all animals, providing further evidence for the involvement of active mechanisms, capable of inhibition by immunosuppressive agents, in tolerance induction with TLI, and of relevance to our reported clinical experience with TLI (6).


CONCLUSIONS
These promising findings invite further studies with a larger number of animals and additional brief regimens of irradiation and antibody dosages and specificities.
Myburgh
J A
JA
Department of Surgery, Medical School, York Road, Parktown 2193, South Africa.
Smit
J A
JA
Pieterz
G A
GA
Ling
S
S
Sandrin
M S
MS
McKenzie
I F
IF
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D015255:Idarubicin / Q000627:therapeutic use*; D007108:Immune Tolerance / Q000187:drug effects; D000922:Immunotoxins / Q000627:therapeutic use*; D016030:Kidney Transplantation / Q000276:immunology*; D015182:Lymphatic Irradiation; D010215:Papio; D011182:Postoperative Care; D011300:Preoperative Care
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D015704:CD4 Antigens; D000922:Immunotoxins; D015255:Idarubicin