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.

Simultaneous blockade of the CD40 and CD28 costimulatory pathways is an effective treatment strategy to promote allograft acceptance but does not lead to indefinite allograft survival. The immune mechanisms responsible for costimulation-independent rejection are not defined. Here we have studied the rejection responses of murine C57BL/6 recipients, which we show to be relatively resistant to inhibition by combined CD40/CD28 blockade. We demonstrate that asialo GM1 + CD8 + cells play a critical role in this costimulation blockade-resistant rejection. These results provide new insights into the costimulatory requirements for T-cell subsets and demonstrate for the first time that combined blockade of the CD40 and CD28 pathways does not adequately inhibit CD8-mediated skin allograft rejection. Furthermore, we provide evidence that asialo GM1 is a potentially important therapeutic target for CD8-dependent immune responses.

Single-stage direct-to-implant reconstruction using a prepectoral approach appears to be a safe and effective means of breast reconstruction in many patients, assuming adequate skin perfusion is present.

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Studies in vivo have documented the importance of CD40-gp39 interactions in the development of T-dependent antibody responses to foreign and auto-antigens. In this report, we demonstrate that allograft rejection is also associated with strong induction of CD40 and gp39 transcripts. When treatment was initiated at the time of transplant, MR1, a mAb specific for gp39, induced markedly prolonged survival of fully disparate murine cardiac allografts in both naive and sensitized hosts. However, when therapy was delayed until postoperative day 5, anti-gp39 failed to prolong graft survival. Allografts from recipients treated with MR1 from the time of transplantation showed decreased expression of transcripts for the macrophage effector molecule, inducible nitric oxide synthase, but essentially unaltered expression of B7 molecules and T cell cytokine transcripts (interleukin [IL]-2, interferon-gamma, IL-10, and IL-4) relative to control allografts. In addition, alloantibody responses in the MR1-treated mice were profoundly inhibited. However, our studies using B cell-deficient mice indicated that the ability of MR1 to prolong allograft survival was not dependent on B cells. These data suggest that blockade of CD40-gp39 interactions may inhibit allograft rejection primarily by interfering with T cell help for effector functions, rather than by interference with T cell activation.