Modification of nitroxyl contrast agents with multiple spins and their proton T1 relaxivity

The purpose of this study is to test the performance of multi-spin nitroxyl contrast agents for improving the sensitivity of MR detection for nitroxyl contrast agents. The relation between T1 relaxivity and the number of paramagnetic centers in a molecule was investigated. Compound-1 is a single molecule of methoxycarbonyl-PROXYL (MC-PROXYL). Two and three MC-PROXYL molecules were chemically coupled to obtain compounds-2 and -3, which have two and three nitroxyl spins in the molecule. A good linear relation, the slope of which increased depending on the number of nitroxyl spins in the molecule, was obtained between T1-weighted (FLASH) MR image contrast enhancement at 7 T and the concentration of nitroxyl contrast agents. T1-weighted MR image contrast enhancement and T1-relaxivity levels of nitroxyl contrast agents were increased depending on the number of nitroxyl spins in the molecule. Multi-coupling nitroxyl molecules can enhance the T1-weighted contrast effect, while maintaining the quantitative behavior of the molecule for up to three spins

CD137 agonist antibody prevents cancer recurrence: contribution of CD137 on both hematopoietic and nonhematopoietic cells

Antigen-specific memory T cells (Tms) are essential in the immune surveillance of residual and metastatic tumors. Activation of Tms requires designing vaccines based on tumor rejection antigens, which are often not available to cancer patients. Therefore, it is desirable to have a general applicable approach to activate Tms without extensive knowledge of tumor antigens. Here, we report that activation of antigen-specific Tms could be achieved by the administration of agonistic anti-CD137 monoclonal antibody without additional tumor vaccination, leading to the prevention of recurrence and metastases after surgical resection of primary tumors in mouse models. By reconstitution with CD137-deficient Tms, we demonstrate that expression of CD137 on antigen-specific Tms is only partially required for the effect of anti-CD137 antibody. Other host cells, including those from hematopoietic and nonhematopoietic origins, are also important because ablation of CD137 from these cells partially but significantly eliminates antitumor effect of anti-CD137 antibody. Our findings implicate a potential new approach to prevent recurrence and metastases in cancer patients

B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance

T-cell tolerance is the central program that prevents harmful immune responses against self-antigens, in which inhibitory PD-1 signal given by B7-H1 interaction plays an important role. Recent studies demonstrated that B7-H1 binds CD80 besides PD-1, and B7-H1/CD80 interaction also delivers inhibitory signals in T cells. However, a role of B7-H1/CD80 signals in regulation of T-cell tolerance has yet to be explored. We report here that attenuation of B7-H1/CD80 signals by treatment with anti–B7-H1 monoclonal antibody, which specifically blocks B7-H1/CD80 but not B7-H1/PD-1, enhanced T-cell expansion and prevented T-cell anergy induction. In addition, B7-H1/CD80 blockade restored Ag responsiveness in the previously anergized T cells. Experiments using B7-H1 or CD80-deficient T cells indicated that an inhibitory signal through CD80, but not B7-H1, on T cells is responsible in part for these effects. Consistently, CD80 expression was detected on anergic T cells and further up-regulated when they were re-exposed to the antigen (Ag). Finally, blockade of B7-H1/CD80 interaction prevented oral tolerance induction and restored T-cell responsiveness to Ag previously tolerized by oral administration. Taken together, our findings demonstrate that the B7-H1/CD80 pathway is a crucial regulator in the induction and maintenance of T-cell tolerance