Anti-CD28 antibodies modify regulatory mechanisms and reinforce tolerance in CD40Ig-treated heart allograft recipients.
Blockade of CD40-CD40 ligand (CD40L) costimulation has been shown to synergize with that of CTLA4/CD28-B7 to promote transplant tolerance. To date, however, CD28-B7 interactions have been prevented using B7-blocking reagents like CTLA4-Ig that inhibit CD28-B7 together with CTLA4-B7 interactions. In this study, we have tested anti-CD28 Abs to prevent selectively CD28-B7 interactions while preserving CTLA4-B7 in addition to CD40-CD40L blockade. In the LEW.1W to LEW.1A rat combination, interfering with CD40-CD40L interactions by CD40Ig administration through gene transfer resulted in indefinite heart allograft survival due to the appearance of clonotypic CD8+CD45RClow regulatory T cells that were capable of transferring the tolerant state to naive animals. However, cardiac transplants in these recipients systematically developed chronic rejection lesions. Whereas anti-CD28 Ab monotherapy only delayed acute rejection and failed to induce tolerance, coadministration of anti-CD28 Abs and CD40Ig resulted in the long-term acceptation of allografts without chronic rejection lesions in 60% of the recipients, reduced the level of intragraft mRNA transcripts for cytokines and immune factors, and fully abrogated alloantibody production. In addition, the nature of regulatory cells was modified: the CD8+CD45RClow clonotypic T cells described in the CD40Ig-treated animals could not be found in cotreated animals, and the other CD8+CD45RClow cells had no regulatory activity and a different cytokine expression profile. Instead, in cotreated recipients we found IDO-dependent non-T cells with regulatory activity in vitro. Thus, the addition of a short-term anti-CD28 treatment with CD40Ig resulted in decreased heart allograft chronic rejection lesions, complete inhibition of Ab production, and modified regulatory mechanisms.
Institut National de la Santé et de la Recherche Médicale, Unité 643, Centre Hospitalier de l'Université Nantes, Institut de Transplantation et de Recherche en Transplantation, Université de Nantes, Faculté de Médecine, Nantes, France.
Carole
C
Guillonneau
Céline
C
Séveno
Anne-Sophie
AS
Dugast
Xian-Liang
XL
Li
Karine
K
Renaudin
Fabienne
F
Haspot
Claire
C
Usal
Joëlle
J
Veziers
Ignacio
I
Anegon
Bernard
B
Vanhove
D019264:Adoptive Transfer; D000818:Animals; D020296:Animals, Congenic; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D018106:CD28 Antigens / Q000187:drug effects*; D016827:CD8 Antigens / Q000032:analysis; D002999:Clone Cells; D016207:Cytokines / Q000378:metabolism; D006084:Graft Rejection / Q000517:prevention & control*; D016027:Heart Transplantation; D007108:Immune Tolerance; D017493:Leukocyte Common Antigens / Q000032:analysis; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000637:transplantation
D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; C499839:CD40Ig protein, recombinant; D016827:CD8 Antigens; D016207:Cytokines; D011993:Recombinant Fusion Proteins; D017493:Leukocyte Common Antigens