CD4 MAB THERAPY MODULATES ALLOANTIBODY PRODUCTION AND INTRACARDIAC GRAFT DEPOSITION IN ASSOCIATION WITH SELECTIVE-INHIBITION OF TH1 LYMPHOKINES

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) transpl antation (Tx survival ca. 11 days, p < 0.0001). This study analyzed th e 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 prote in production profiles of Th1 (IL-2, IFN-gamma) vs Th2 (IL-4) specific cytokines (polymerase chain reaction and/or immunohistology). Skin gr afts elicited a strong systemic IgM allo-Ab response, which peaked at the time of cardiac Tx rejection at 24 h. It was associated with exten sive deposits of IgM on Tx endothelium. Treatment with BWH-4 mAb dimin ished 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 accomp anied 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 res ponse was earlier, less intense and more transient than in untreated r ecipients. Accelerated rejection triggered sequential lymphokine mRNA expression in cardiac Tx, with the peak of transcription for IL-2 (6-1 2 h) preceding that for IL-4 (24 h). Interestingly, although CD4 targe ted 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 elaborat ion of IL-4, confirming the translation of mRNA to the protein in vivo . Thus, CD4 mAb-mediated abrogation of accelerated cardiac Tx injury c orrelates with suppression of Th1 responses (depressed IL-2 and IFN-ga mma production), but sparing of the Th2 function (enhanced IL-4 elabor ation). Indeed, CD4 mAb-induced allo-Ab depression and immunosuppressi ve effects may reflect selective targeting of proinflammatory Th1-like cells and the multifaceted effects of IL-4 produced by unopposed Th2- like cells.