Red-cell ICAM-4 is a ligand for the monocyte/macrophage integrin CD11c/CD18: characterization of the binding sites on ICAM-4.

Intercellular adhesion molecule 4 (ICAM-4) is a unique member of the ICAM family because of its specific expression on erythroid cells and ability to interact with several types of integrins expressed on blood and endothelial cells. The first reported receptors for ICAM-4 were CD11a/CD18 and CD11b/CD18. In contrast to these 2, the cellular ligands and the functional role of the third beta2 integrin, CD11c/CD18, have not been well defined. Here, we show that ICAM-4 functions as a ligand for the monocyte/macrophage-specific CD11c/CD18. Deletion of the individual immunoglobulin domains of ICAM-4 demonstrated that both its domains contain binding sites for CD11c/CD18. Analysis of a panel of ICAM-4 point mutants identified residues that affected binding to the integrin. By molecular modeling the important residues were predicted to cluster in 2 distinct but spatially close regions of the first domain with an extension to the second domain spatially distant from the other residues. We also identified 2 peptides derived from sequences of ICAM-4 that are capable of modulating the binding to CD11c/CD18. CD11c/CD18 is expressed on macrophages in spleen and bone marrow. Inhibition of erythrophagocytosis by anti-ICAM-4 and anti-integrin antibodies suggests a role for these interactions in removal of senescent red cells.

Z-100, an immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis strain Aoyama B, augments anti-tumor activities of X-ray irradiation against B16 melanoma in association with the improvement of type 1T cell responses.

In this study, the effects of combination therapy consisting of X-ray irradiation and Z-100 on the survival time of C57BL/6 mice inoculated with B16F10 melanoma were investigated. Survival time was significantly prolonged in B16F10 melanoma-bearing mice treated with the X-ray irradiation (5 Gy) and Z-100 (10 mg/kg s.c.) combination therapy compared with mice irradiated with X-rays alone. The weight of primary tumors and number of metastatic colonies were also significantly suppressed by the combination therapy compared with that in the X-ray irradiation group. These results indicated that Z-100 could enhance the anti-tumor effects of radiotherapy against B16F10 melanoma. On the other hand, the survival time of CD4 knockout mice bearing the same tumors was not prolonged by the combination therapy compared with mice irradiated with X-rays alone, suggesting that CD4+ cells are partly involved in augmentation of the anti-tumor effect of radiotherapy by Z-100. In addition, type 1 cytokine (IL-2, IFN-gamma) production was significantly increased and type 2 cytokine (IL-4, IL-10) production was significantly suppressed in the tumor-bearing mice treated with the combination therapy compared with the X-ray irradiation group. Moreover, interleukin-12 production by CD11c+ cells was also significantly increased in mice treated with the combination therapy compared with the X-ray irradiation group. These results indicate that Z-100 augmented the anti-tumor effects of X-ray irradiation. Moreover, we demonstrated that the effects of Z-100 were expressed at least in part, by the improvement of the T cell responses from type 2-dominant to type 1-dominant via up-regulation of IL-12 production.