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Immunoglobulin-like transcripts (ILTs) are immunoregulatory proteins that either activate or inhibit immune responses. ILT3 is inhibitory and is expressed preferentially by antigen-presenting cells. When its extracellular domain binds to an unidentified ligand of activated T cells, the T cell is silenced. Our objective was to study the expression of ILT3 on circulating monocytes in RRMS. Freshly isolated peripheral blood mononuclear cells were analyzed by multicolored flow cytometry. The proportion of ILT3(+)CD14(+) monocytes in blood, and ILT3 levels expressed by them, is lower in untreated multiple sclerosis in relapse than in: (1) untreated multiple sclerosis in remission (p < 0.009); (2) stable interferon beta-treated relapsing-remitting multiple sclerosis (p < 0.001) and; (3) healthy controls (p < 0.009). Glatiramer acetate-stimulated CD4( +) T cells, co-cultured with freshly isolated monocytes, proliferate significantly better (p = 0.0017 for multiple sclerosis; p = 0.0015 for controls) when T cell interaction with monocyte-expressed ILT3 is blocked by anti-ILT3 antibody. Interferon beta is beneficial in multiple sclerosis; why so remains unclear. Interferon beta-1b markedly increases ILT3 expression in vitro by monocytes from multiple sclerosis patients and controls. These findings identify a putative novel mechanism for the therapeutic benefit bestowed by Interferon beta and a new target for therapeutic intervention in relapsing-remitting multiple sclerosis.

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<p>Supplemental Figure 1. CD11b+ myeloid cells in glioma correlate to tumor grade. Supplemental Figure 2. Schematic depicted for bone marrow transplant of RCAS tumor bearing animals. Supplemental Figure 3. Analysis of tumor sections for necrosis and microvascular proliferation. Supplemental Figure 4. AZD1480 impairs phosphorylation of Stat3 but has no effect in vitro and IDH status</p>

<div>Abstract<p><b>Purpose:</b> While the tumor microenvironment has been known to play an integral role in tumor progression, the function of nonresident bone marrow–derived cells (BMDC) remains to be determined in neurologic tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas.</p><p><b>Experimental Design:</b> We analyzed human blood and tumor samples from patients with low- and high-grade gliomas. A spontaneous platelet-derived growth factor (PDGF) murine glioma model (RCAS) was utilized to recapitulate human disease progression. Levels of CD11b⁺/GR1⁺ BMDCs were analyzed at discrete stages of tumor progression. Using bone marrow transplantation, we determined the unique influence of BMDCs in the transition from low- to high-grade glioma. The functional role of these BMDCs was then examined using a JAK 1/2 inhibitor (AZD1480).</p><p><b>Results:</b> CD11b⁺ myeloid cells were significantly increased during tumor progression in peripheral blood and tumors of glioma patients. Increases in CD11b⁺/GR1⁺ cells were observed in murine peripheral blood, bone marrow, and tumors during low-grade to high-grade transformation. Transient blockade of CD11b⁺ cell expansion using a JAK 1/2 Inhibitor (AZD1480) impaired mobilization of these cells and was associated with a reduction in tumor volume, maintenance of a low-grade tumor phenotype, and prolongation in survival.</p><p><b>Conclusions:</b> We demonstrate that impaired recruitment of CD11b⁺ myeloid cells with a JAK1/2 inhibitor inhibits glioma progression <i>in vivo</i> and prolongs survival in a murine glioma model. <i>Clin Cancer Res; 23(12); 3109–19. ©2016 AACR</i>.</p></div>

<p>Supplemental Figure 1. CD11b+ myeloid cells in glioma correlate to tumor grade. Supplemental Figure 2. Schematic depicted for bone marrow transplant of RCAS tumor bearing animals. Supplemental Figure 3. Analysis of tumor sections for necrosis and microvascular proliferation. Supplemental Figure 4. AZD1480 impairs phosphorylation of Stat3 but has no effect in vitro and IDH status</p>

<div>Abstract<p><b>Purpose:</b> While the tumor microenvironment has been known to play an integral role in tumor progression, the function of nonresident bone marrow–derived cells (BMDC) remains to be determined in neurologic tumors. Here we identified the contribution of BMDC recruitment in mediating malignant transformation from low- to high-grade gliomas.</p><p><b>Experimental Design:</b> We analyzed human blood and tumor samples from patients with low- and high-grade gliomas. A spontaneous platelet-derived growth factor (PDGF) murine glioma model (RCAS) was utilized to recapitulate human disease progression. Levels of CD11b⁺/GR1⁺ BMDCs were analyzed at discrete stages of tumor progression. Using bone marrow transplantation, we determined the unique influence of BMDCs in the transition from low- to high-grade glioma. The functional role of these BMDCs was then examined using a JAK 1/2 inhibitor (AZD1480).</p><p><b>Results:</b> CD11b⁺ myeloid cells were significantly increased during tumor progression in peripheral blood and tumors of glioma patients. Increases in CD11b⁺/GR1⁺ cells were observed in murine peripheral blood, bone marrow, and tumors during low-grade to high-grade transformation. Transient blockade of CD11b⁺ cell expansion using a JAK 1/2 Inhibitor (AZD1480) impaired mobilization of these cells and was associated with a reduction in tumor volume, maintenance of a low-grade tumor phenotype, and prolongation in survival.</p><p><b>Conclusions:</b> We demonstrate that impaired recruitment of CD11b⁺ myeloid cells with a JAK1/2 inhibitor inhibits glioma progression <i>in vivo</i> and prolongs survival in a murine glioma model. <i>Clin Cancer Res; 23(12); 3109–19. ©2016 AACR</i>.</p></div>