title: Modulation of accelerated rejection of cardiac allografts in sensitized rats by anti-interleukin 2 receptor monoclonal antibody and cyclosporine therapy.
abstract: LBNF1 cardiac allografts (Tx) are rejected within 36 hr in LEW rats sensitized with BN skin Tx 7 days earlier, compared to 8-day rejection in unmodified hosts. Treatment with cyclosporine or ART-18, an anti-interleukin 2 receptor (IL-2[R]) mAb monoclonal antibody, abrogates accelerated rejection and prolongs mean Tx survival to 42 days and 16 days, respectively. ART-18 given in concert with subtherapeutic dose of CsA extends survival to 25 days. These studies were designed to dissect the early mechanisms leading to ART-18 and/or CsA-mediated abrogation of accelerated Tx injury. No effect of concomitant mAb administration upon CsA through levels was noted in Tx recipients conditioned with both modalities. The beneficial effect of ART-18+CsA treatment was also unrelated to CsA-induced diminished host responses to mAb, as shown by ELISA. In the biodistribution studies 125I-labeled ART-18 accumulated preferentially into host lymphoid tissues and Tx itself and away from the blood. In animals that were concomitantly given "cold" CsA, the clearance of labeled ART-18 from the blood increased further, as did mAb sequestration into the Tx. The sensitized hosts developed high titers of complement-dependent cytotoxic (CDC) antibodies, which peaked at the time of actual Tx loss. ART-18 or CsA alone inhibited CDC, whereas combined therapy decreased further the humoral effects of sensitization. The cell-mediated lymphocytotoxicity assay revealed a similar pattern. CsA, ART-18, and combination therapy each modulated the deposition of IgG, IgM, and C3 in Tx, as shown by immunohistology. However, only CsA or ART-18+CsA therapy abolished or markedly decreased elaboration of IL-2, interferon gamma, and tissue necrosis factor alpha.
  
  
  CONCLUSIONS
  (1) the adjunctive low dose of CsA potentiates the inhibitory effects of ART-18 upon humoral and cellular responses, leading to accelerated rejection of cardiac Tx in presensitized rats; (2) the synergistic interaction between both modalities that results in the inhibition of lymphokine production is critical and correlates with long-term Tx survival; (3) the biodistribution patterns of mAb are important--an increased blood level of mAb does not necessarily translate into its higher therapeutic efficacy.
authors.affiliation: Surgical Research Laboratory, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.forename: T
authors.initials: T
authors.lastname: Sablinski
authors.forename: W W
authors.initials: WW
authors.lastname: Hancock
authors.forename: R
authors.initials: R
authors.lastname: Di Stefano
authors.forename: G
authors.initials: G
authors.lastname: Mariani
authors.forename: C T
authors.initials: CT
authors.lastname: Mix
authors.forename: N L
authors.initials: NL
authors.lastname: Tilney
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D003524:Cyclosporins / Q000097:blood / Q000494:pharmacology*; D006084:Graft Rejection / Q000187:drug effects*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007109:Immunity; D007111:Immunity, Cellular; D007518:Isoantibodies / Q000276:immunology; D007958:Leukocyte Count; D007959:Lymphocyte Culture Test, Mixed; D016131:Lymphocyte Subsets / Q000276:immunology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D015375:Receptors, Interleukin-2 / Q000276:immunology* / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D003524:Cyclosporins; D007518:Isoantibodies; D015375:Receptors, Interleukin-2