The mechanism of synergistic interaction between anti-interleukin 2 receptor monoclonal antibody and cyclosporine therapy in rat recipients of organ allografts.
Untreated anephric LEW rats die ca. 9 days following transplantation of LBNF1 kidney allografts. Although treatment with ART-18, a mouse antirat IL-2R mAb (300 micrograms/kg/day x 10 days), prolonged graft survival to ca. 3 weeks, the severely impaired renal function was comparable to untreated controls (creatinine levels 3-5 mg/dl). In contrast, simultaneous infusion of ART-18 and a very low dose of CsA (0.75 mg/kg x 10 days), marginally effective on its own, resulted in survival of greater than 45 days; the grafts exhibited relatively good function comparable to that in rats treated with full-dose (15 mg/kg/day) CsA. This beneficial biological effect did not depend upon elevated CsA trough levels in animals conditioned with both modalities. The CD4:CD8 ratio at the graft site was lowest (0.3-0.4) in recipients treated with ART-18 + CsA. Synergy between the two agents has been demonstrated by adoptive transfer studies in which nonspecific suppression has been conferred selectively by cells infiltrating kidney grafts in rats given ART-18 and CsA in concert but not separately (LBNF1 and WF test cardiac allograft survival ca. 12 days). In contrast, suppression in the recipient spleens was donor-specific; both CD4 and CD8 cells prolonged test graft survival. Immunohistological evaluation of renal allografts revealed that therapy with ART-18 or low-dose CsA alone failed to deplete IL-2R+ cells and prevent production of IL-2, IFN-g, and TNF. In contrast, the frequency of infiltrating IL-2R+ cells and elaboration of endogenous cytokines in non-uremic hosts receiving combination therapy was greatly depressed, stressing again synergistic interaction between ART-18 and CsA. Additionally, markedly reduced class II antigen induction, XL-fibrin deposition, and glomerulitis may also contribute to prolonged survival and satisfactory function of kidney allografts in this animal group.
Ueda
H
H
Surgical Research Laboratory, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts.
Hancock
W W
WW
Cheung
Y C
YC
Diamantstein
T
T
Tilney
N L
NL
Kupiec-Weglinski
J W
JW
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D003404:Creatinine / Q000097:blood; D003524:Cyclosporins / Q000097:blood / Q000494:pharmacology*; D006085:Graft Survival; D016219:Immunotherapy, Adoptive; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D015375:Receptors, Interleukin-2 / Q000032:analysis / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014181:Transplantation Immunology / Q000187:drug effects; D014184:Transplantation, Homologous
D000911:Antibodies, Monoclonal; D003524:Cyclosporins; D015375:Receptors, Interleukin-2; D003404:Creatinine