Modulation of accelerated rejection of cardiac allografts in sensitized rats by anti-interleukin 2 receptor monoclonal antibody and cyclosporine therapy

Transplantation. 1991 Feb;51(2):300-5. doi: 10.1097/00007890-199102000-00004.


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.

In conclusion: (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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / biosynthesis
  • Antibodies, Monoclonal / therapeutic use
  • Cyclosporins / blood
  • Cyclosporins / pharmacology*
  • Graft Rejection / drug effects*
  • Graft Survival
  • Heart Transplantation / immunology*
  • Immunity
  • Immunity, Cellular
  • Isoantibodies / immunology
  • Leukocyte Count
  • Lymphocyte Culture Test, Mixed
  • Lymphocyte Subsets / immunology*
  • Male
  • Rats
  • Rats, Inbred Strains
  • Receptors, Interleukin-2 / immunology*
  • Receptors, Interleukin-2 / pharmacokinetics
  • Tissue Distribution


  • Antibodies, Anti-Idiotypic
  • Antibodies, Monoclonal
  • Cyclosporins
  • Isoantibodies
  • Receptors, Interleukin-2