title: Pretreatment with cyclosporine and anti-interleukin 2 receptor antibody abrogates the anti-idiotype response in rat recipients of cardiac allografts.
abstract: A 10-day course with ART-18, a mouse monoclonal antibody (mAb) directed against the rat interleukin 2 receptor (IL-2R), prolongs the survival of (LEW x BN)F1 cardiac allografts in LEW recipients to approximately 3 weeks (acute rejection = 8 days, P less than 0.001). We examined host responses against ART-18 idiotype (Id) and mouse immunoglobulin in recipients immunomodulated with ART-18 mAb. Treatment with ART-18 elicited high titers of anti-Id antibodies 14 days after transplantation. However, naive rats given ART-18 before transplantation showed strong anti-Id responses as early as day 4 after engraftment, coinciding with abrogation of the treatment effect (graft survival, approximately 10 days). Preimmunization with irrelevant mouse IgG, which elicited high titers of anti-IgG, did not influence the efficacy of ART-18 upon graft survival (17 days). The use of cyclosporin A (CsA) in conjunction with ART-18 prior to transplantation suppressed the anti-Id response and led to dramatic graft prolongation (greater than 58 days), with two of five grafts surviving indefinitely. This striking effect of CsA plus ART-18 pretreatment did not depend upon CsA per se, as grafts were rejected within 12 days in animals pretreated with CsA alone; in both groups CsA trough levels were comparable. Moreover, administration of CsA before transplantation in concert with control IgG (instead of ART-18) prompted rejection within 2-4 weeks. Thus, discrete interaction(s) between anti-IL-2R mAb and CsA prior to engraftment induces partial host unresponsiveness/tolerance to anti-IL-2R mAb treatment following transplantation and suppresses the neutralizing anti-Id responses, which results in long-term/permanent graft acceptance. This study provides a strategy to overcome the anti-Id response mounted by graft recipients that otherwise limits the efficacy of anti-IL-2R mAb treatment.
authors.affiliation: Harvard Medical School, Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115.
authors.forename: K
authors.initials: K
authors.lastname: Tanaka
authors.forename: N L
authors.initials: NL
authors.lastname: Tilney
authors.forename: K G
authors.initials: KG
authors.lastname: Stunkel
authors.forename: W W
authors.initials: WW
authors.lastname: Hancock
authors.forename: T
authors.initials: T
authors.lastname: Diamantstein
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D003524:Cyclosporins / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007130:Immunoglobulin Idiotypes / Q000032:analysis / Q000276:immunology*; D007165:Immunosuppression Therapy; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D015375:Receptors, Interleukin-2 / Q000276:immunology / Q000502:physiology*; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D003524:Cyclosporins; D007140:Immunoglobulin Fab Fragments; D007130:Immunoglobulin Idiotypes; D015375:Receptors, Interleukin-2