title: CD4 mAb therapy modulates alloantibody production and intracardiac graft deposition in association with selective inhibition of Th1 lymphokines.
abstract: The accelerated (24 h) rejection of (LEWxBN)F1 cardiac allografts (Tx) in LEW rats sensitized with BN skin grafts, is abrogated with CD4 mAb (BWH-4) administration between skin (day -7) and heart (day 0) transplantation (Tx survival ca. 11 days, p < 0.0001). This study analyzed the effects of CD4-targeted therapy upon host IgG and IgM alloantibody (allo-Ab) within the serum by two-color flow cytometry, and within the Tx, by immunohistology. These data were correlated with mRNA and protein production profiles of Th1 (IL-2, IFN-gamma) vs Th2 (IL-4) specific cytokines (polymerase chain reaction and/or immunohistology). Skin grafts elicited a strong systemic IgM allo-Ab response, which peaked at the time of cardiac Tx rejection at 24 h. It was associated with extensive deposits of IgM on Tx endothelium. Treatment with BWH-4 mAb diminished circulating IgM allo-Ab levels, and only low levels of IgM could be detected at the Tx site. Conversely, the low circulating IgG allo-Ab levels during rejection at 24 h in untreated recipients were accompanied by a strong labeling for intra-Tx IgG. BWH-4 mAb therapy did not prevent totally the switch of the IgM to IgG, but the IgG allo-Ab response was earlier, less intense and more transient than in untreated recipients. Accelerated rejection triggered sequential lymphokine mRNA expression in cardiac Tx, with the peak of transcription for IL-2 (6-12 h) preceding that for IL-4 (24 h). Interestingly, although CD4 targeted therapy virtually ablated the induction of IL-2 mRNA, it preserved transcription of the IL-4 gene. BWH-4 mAb therapy decreased otherwise abundant intra-Tx IL-2 and IFN-gamma, but allowed a vigorous elaboration of IL-4, confirming the translation of mRNA to the protein in vivo. Thus, CD4 mAb-mediated abrogation of accelerated cardiac Tx injury correlates with suppression of Th1 responses (depressed IL-2 and IFN-gamma production), but sparing of the Th2 function (enhanced IL-4 elaboration). Indeed, CD4 mAb-induced allo-Ab depression and immunosuppressive effects may reflect selective targeting of proinflammatory Th1-like cells and the multifaceted effects of IL-4 produced by unopposed Th2-like cells.
authors.affiliation: Harvard Medical School, Department of Surgery, Boston, MA 02115.
authors.forename: J W
authors.initials: JW
authors.lastname: Kupiec-Weglinski
authors.forename: B
authors.initials: B
authors.lastname: Wasowska
authors.forename: I
authors.initials: I
authors.lastname: Papp
authors.forename: G
authors.initials: G
authors.lastname: Schmidbauer
authors.forename: M H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: W M
authors.initials: WM
authors.lastname: Baldwin
authors.forename: K J
authors.initials: KJ
authors.lastname: Wieder
authors.forename: W W
authors.initials: WW
authors.lastname: Hancock
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D015704:CD4 Antigens / Q000276:immunology*; D006084:Graft Rejection; D016027:Heart Transplantation; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007376:Interleukin-2 / Q000235:genetics; D015847:Interleukin-4 / Q000096:biosynthesis*; D007518:Isoantibodies / Q000096:biosynthesis*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007376:Interleukin-2; D007518:Isoantibodies; D012333:RNA, Messenger; D015847:Interleukin-4