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The receptor-ligand pairs CD28-B7 and CD40-gp39 are essential for the initiation and amplification of T-cell-dependent immune responses. CD28-B7 interactions provide 'second signals' necessary for optimal T-cell activation and IL-2 production, whereas CD40-gp39 signals co-stimulate B-cell, macrophage, endothelial cell and T-cell activation. Nonetheless, blockade of either of these pathways alone is not sufficient to permit engraftment of highly immunogenic allografts. Here we report that simultaneous but not independent blockade of the CD28 and CD40 pathways effectively aborts T-cell clonal expansion in vitro and in vivo, promotes long-term survival of fully allogeneic skin grafts, and inhibits the development of chronic vascular rejection of primarily vascularized cardiac allografts. The requirement for simultaneous blockade of these pathways for effective inhibition of alloimmunity indicates that, although they are interrelated, the CD28 and CD40 pathways are critical independent regulators of T-cell-dependent immune responses.

A 3 1/2-year-old child had a murmur of pulmonary stenosis. Echocardiography and cardiac catheterization revealed a pulmonary infundibular obstruction. Magnetic resonance imaging of the heart demonstrated a mass in the interventricular septum. The mass was successfully resected and a pathologic diagnosis of capillary hemangioma was made. Only two previous cases of hemangioma causing right ventricular outflow obstruction have been reported; both of these cases involved adults. This case represents the first report of a hemangioma causing right ventricular outflow tract obstruction in a child. An exploratory operation with resection is the treatment of choice.

A pathogenetic mechanism for the formation of tetralogy of Fallot is postulated. We propose that the right ventricular ejection stream is divided into a transseptal aortic stream and an infundibular pulmonary stream during embryonic life before the ventricular septum is closed. The surgically unaltered hearts from 77 cases of tetralogy of Fallot were examined, and measurements made of certain morphologic features. A malformed, stenotic pulmonary valve was found in most all cases and accounts for a divided ejection stream. Infundibular stenosis is shown to be a postnatally acquired, progressive lesion. The detailed anatomic features of the heart and great vessels in tetralogy of Fallot are explained as a response of the developing heart and great vessels to the abnormal blood flow pattern of a divided right ventricular ejection stream. This pathogenetic mechanism, compared to previously proposed hypotheses, appears better able to account for the malformation complex of tetralogy of Fallot.