Requirements for ICAM-1 immunogene therapy of lymphoma.

Intercellular cell adhesion molecule-1 (ICAM-1) is a cell-surface glycoprotein capable of eliciting bidirectional signals that activate signalling pathways in leukocytes, endothelial, and smooth muscle cells. Gene transfer of xenogeneic ICAM-1 into EL-4 lymphomas causes complete tumor rejection; however, it is unknown whether the mechanism responsible involves the "foreignness" of the ICAM-1 transgene, bidirectional signalling events, ICAM-1-receptor interaction, or a combination of the latter. To begin to address this question, we constructed four different therapeutic expression vectors encoding full-length ICAM-1, and forms in which the N-terminal ligand-binding domains and cytoplasmic tail had been deleted. Mouse EL-4 tumors (0.5 cm in diameter), which actively suppress the immune response, were significantly inhibited in their growth following injection of expression plasmids encoding either full-length xenogenic (human) ICAM-1, or a functional cytoplasmic domain-deficient form that retains ligand-binding activity. Efficacy of ICAM-1-mediated antitumor immunity was significantly augmented by administration of the antivascular drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA), which suppressed blood supply to the tumor, leading to enhanced leukocyte infiltration, and complete tumor eradication in a gene dosage and CD8(+) T cell and NK cell-dependent fashion. Generation of potent cytotoxic T cell (CTL)-mediated antitumor immunity was reflected by ICAM-1-facilitated apoptosis of tumor cells in situ. In contrast, nonfunctional ICAM-1 lacking the N-terminal ligand-binding Ig domain failed to generate antitumor immunity, even in the presence of DMXAA. These studies demonstrate that ICAM-1-stimulated antitumor immunity can overcome tumor-mediated immunosuppression, particularly when employed in combination with an attack on the tumor vasculature. The ligand-binding domain of ICAM-1 is essential for generating antitumor immunity, whereas the cytoplasmic domain and bidirectional activation of tumor signalling pathways are not essential.

'This is not our country': Declining diversity in the Islamic Republic of Iran

The expulsion of Christians from Mosul by the Islamic State (IS) in the summer of 2014 marked the first time in nearly 2000 years that the Iraqi city lacked a Christian population.1 Along with the conflict in Syria and the other upheavals that have accompanied the phenomenon variously known as the Arab Spring, al-thawra or the Islamic Awakening, the emigration of Christians from their homes has accelerated in recent years. The Roman Catholic Pope Francis mentioned this during his visit to the region in May 2014, noting that these historic communities, among the oldest in the world, are decreasing to the point where their long-term existence is uncertain. This is because Christians in more stable parts of the Middle East are also leaving. This paper discusses one such example: the continuing emigration of Armenian Christians from Iran. For Iranian Armenians, the main incentive for emigration is the feeling of exclusion and alienation from the wider society. This has largely come about by the Islamic Republic’s promotion of a Shi’a-based Iranian identity which does not count minorities as full citizens. This in turn has led to the development of a sense of foreignness in Iranian society among Armenian youth. The lack of belonging makes their ties to Iran much less solid, and therefore makes migration a much less painful process. Furthermore, their parents, who were raised in the more pluralistic Iran of the last Shah, find it easier to identify as Iranians than their children.