Use of yttrium-90-labeled anti-Tac antibody in primate xenograft transplantation.
The high-affinity interleukin-2 receptor (IL-2R) is expressed by T cells activated in response to foreign histocompatibility antigens but not by normal resting cells. Thus, blockade of the interaction of IL-2 with its receptor could achieve selective immunosuppression. Accordingly, anti-Tac, a murine IgG2a class monoclonal antibody specific to the IL-2R, was used alone or in a chelated form with yttrium-90 (90Y), a pure beta emitter, to inhibit rejection of cardiac xenografts from Macaca fascicularis (cynomolgus) donors transplanted to the cervical or abdominal region of Macaca mulatta (rhesus) recipients (n = 20). Animals received no immunosuppression (n = 3, group I, controls), unmodified anti-Tac (n = 5, 2 mg/kg q.o.d., group II), or 90Y-anti-Tac (n = 5, 16 mCi, group III). To distinguish the nonspecific immunosuppressive effect of radiation, 90Y was administered bound to UPC-10 (n = 4, 16 mCi, group IV), another murine monoclonal antibody that does not specifically recognize activated immunoresponsive cells. All immunosuppression was administered in divided doses during the first 2 weeks posttransplant. Group I animals rejected their grafts at 6.7 +/- 1 days and demonstrated a rise in soluble IL-2R levels at the time of rejection, indicating the generation of Tac-expressing and -releasing cells. Graft survival in group II was not prolonged compared with controls (mean survival 6.2 +/- 1 days; P greater than 0.05). In contrast, graft survival in animals that received the designed dosage of 90Y-anti-Tac was significantly prolonged to an average of 38.4 +/- 5 days compared with groups I and II (P less than 0.005 and P les sthan 0.0005, respectively). Prolongation of graft survival occurred in animals that received 90Y-UPC-10 (mean survival 21.3 +/- 5 days, P less than 0.05 versus group I, P less than 0.01 versus group II). However, 90Y-UPC-10 was significantly less effective in prolonging graft survival than 90Y-anti-Tac, in which one-half the per-kilogram dosage of radioactivity was delivered in specific fashion via anti-Tac (P less than 0.025). Reversible nonlethal bone marrow suppression occurred without associated nephro- or hepatotoxicity, and virtually all animals developed antibodies to the murine monoclonal. Thus, the approach used in the present study, IL-2R-directed therapy with 90Y-anti-Tac, may have potential applications in organ transplantation and in the treatment of Tac-expressing neoplastic diseases.
Cooper
M M
MM
Surgery Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
Robbins
R C
RC
Goldman
C K
CK
Mirzadeh
S
S
Brechbiel
M W
MW
Stone
C D
CD
Gansow
O A
OA
Clark
R E
RE
Waldmann
T A
TA
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D006084:Graft Rejection / Q000276:immunology / Q000528:radiation effects; D016027:Heart Transplantation / Q000276:immunology*; D007165:Immunosuppression Therapy; D007167:Immunotherapy; D000922:Immunotoxins; D008252:Macaca fascicularis; D008253:Macaca mulatta; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D014183:Transplantation, Heterologous; D016042:Transplantation, Heterotopic; D015021:Yttrium Radioisotopes / Q000494:pharmacology*
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D000922:Immunotoxins; D015375:Receptors, Interleukin-2; D015021:Yttrium Radioisotopes