title: alpha/beta-T cell receptor-directed therapy in rat allograft recipients. Long-term survival of cardiac allografts after pretreatment with R73 mAb is associated with upregulation of Th2-type cytokines.
abstract: Rejection of vascularized allografts still poses the major problem in organ transplantation. Therefore, transplant rejection of cardiac allografts was investigated in a rat model (BN-to-LEW) under alpha/beta-TCR (R73) mAb-targeted therapy. Two protocols were studied: posttransplant ("immunosuppressive") and pretransplant conditioning therapy. In posttransplant therapy over a wide dose range, R73 mAb only marginally improved cardiac allograft survival (7.8 +/- 0.8 days vs. 12.5 +/- 0.8 days at 0.1 mg/kg for 7 days). In contrast, conditioning treatment with low-dose (0.1 mg/kg) anti-alpha/beta-TCR mAb given 3 to 7 days prior to organ transplantation was highly effective and resulted in 50% permanent acceptance of cardiac allografts. R73 mAb-treated rats were monitored with respect to peripheral lymphocyte populations and intragraft cytokine levels. A temporary, incomplete reduction (CD5+ cells) and partial modulation (alpha/beta-TCR/CD5 double+ cells) in the peripheral blood was observed. In contrast to untreated controls, intragraft production of IL-2 and IFN-gamma at the mRNA and protein level was abolished in both post- and pretreated recipients. Interestingly, pretransplant mAb application was associated with augmented in situ elaboration of the Th2-type cytokines, IL-4 and IL-10, together with up-regulated TGF-beta and PGE. Increased expression of IL-4 and IL-10 continued to be observed in long-term surviving allografts. In conclusion, the mechanism of conditioning therapy with alpha/beta-TCR mAb prior to alloantigen exposure appears to be a switch from Th1 to Th2 response allowing long-term acceptance of allogeneic grafts.
authors.affiliation: Department of Surgery, Technische Universität München, Germany.
authors.forename: C D
authors.initials: CD
authors.lastname: Heidecke
authors.forename: W W
authors.initials: WW
authors.lastname: Hancock
authors.forename: S
authors.initials: S
authors.lastname: Westerholt
authors.forename: T
authors.initials: T
authors.lastname: Sewczik
authors.forename: F
authors.initials: F
authors.lastname: Jakobs
authors.forename: N
authors.initials: N
authors.lastname: Zantl
authors.forename: A
authors.initials: A
authors.lastname: Varzaru
authors.forename: A
authors.initials: A
authors.lastname: Siegling
authors.forename: R
authors.initials: R
authors.lastname: Kurrle
authors.forename: K
authors.initials: K
authors.lastname: Deusch
authors.forename: H D
authors.initials: HD
authors.lastname: Volk
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018956:CD5 Antigens / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000235:genetics; D003864:Depression, Chemical; D015870:Gene Expression; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology*; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D016133:Polymerase Chain Reaction; D011300:Preoperative Care; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000187:drug effects* / Q000276:immunology*; D018417:Th1 Cells / Q000187:drug effects / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D018956:CD5 Antigens; D016207:Cytokines; D016693:Receptors, Antigen, T-Cell, alpha-beta