alpha/beta-T cell receptor-directed therapy in rat cardiac allograft recipients. Treatment prior to alloantigen exposure prevents sensitization and abrogates accelerated rejection.
An mAb directed to the alpha/beta-heterodimer of the rat T cell receptor was used to prevent rejection of cardiac allografts in sensitized (accelerated rejection) recipients. Over a wide dose range, alpha/beta-TCR-directed therapy abrogated accelerated rejection at 24-36 hr and extended cardiac allograft survival in a dose-dependent fashion, both when given after heart transplantation as well as during or before the sensitizing skin transplants (8.9 +/- 1.0 days, 12.7 +/- 0.6 days, or 8.7 +/- 1.5 days, respectively). Pretreatment with R73 completely abrogated host sensitization induced by skin grafting. As a result, post-heart transplant cyclosporine course (15 mg/kg for 7 day) has led to long-term graft acceptance (> 90 days vs. 15.2 +/- 1.6 days with postoperative CsA therapy alone). Administration of R73 mAb produced incomplete depletion (CD5+ cells) and partial modulation (alpha/beta-TCR/CD5 double-positive cells) in the peripheral blood. It suppressed in situ protein expression of many cytokines to background levels, in particular that of IL-2 and IFN-gamma, both when given after as well as before cardiac transplantation. However, only pretransplant mAb application was associated with augmented in situ elaboration of IL-4. alpha/beta-TCR-directed therapy induced strong host anti-idiotypic and, to a lesser degree, anti-isotypic antibody responses. Taken together, these results provide the rationale for a novel immunosuppressive strategy involving induction of hyporesponsiveness by alpha/beta-TCR-directed therapy before the alloantigenic exposure.
Heidecke
C D
CD
Department of Surgery, Technische Universität München, Germany.
Hancock
W W
WW
Jakobs
F
F
Zantl
N
N
Kurrle
R
R
Westerholt
S
S
Sewczik
T
T
Deusch
K
K
Kupiec-Weglinski
J
J
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D016027:Heart Transplantation / Q000276:immunology*; D007150:Immunohistochemistry; D008297:Male; D009206:Myocardium / Q000473:pathology; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D014184:Transplantation, Homologous
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D016693:Receptors, Antigen, T-Cell, alpha-beta