Showing papers by "David Baltimore published in 2007"

MicroRNA-155 is induced during the macrophage inflammatory response

Abstract: The mammalian inflammatory response to infection involves the induction of several hundred genes, a process that must be carefully regulated to achieve pathogen clearance and prevent the consequences of unregulated expression, such as cancer. Recently, microRNAs (miRNAs) have emerged as a class of gene expression regulators that has also been linked to cancer. However, the relationship between inflammation, innate immunity, and miRNA expression is just beginning to be explored. In the present study, we use microarray technology to identify miRNAs induced in primary murine macrophages after exposure to polyriboinosinic:polyribocytidylic acid or the cytokine IFN-β. miR-155 was the only miRNA of those tested that was substantially up-regulated by both stimuli. It also was induced by several Toll-like receptor ligands through myeloid differentiation factor 88- or TRIF-dependent pathways, whereas up-regulation by IFNs was shown to involve TNF-α autocrine signaling. Pharmacological inhibition of the kinase JNK blocked induction of miR-155 in response to either polyriboinosinic:polyribocytidylic acid or TNF-α, suggesting that miR-155-inducing signals use the JNK pathway. Together, these findings characterize miR-155 as a common target of a broad range of inflammatory mediators. Importantly, because miR-155 is known to function as an oncogene, these observations identify a potential link between inflammation and cancer.

Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates.

Abstract: RNAi is a powerful method for suppressing gene expression that has tremendous potential for therapeutic applications. However, because endogenous RNAi plays a role in normal cellular functions, delivery and expression of siRNAs must be balanced with safety. Here we report successful stable expression in primates of siRNAs directed to chemokine (c-c motif) receptor 5 (CCR5) introduced through CD34+ hematopoietic stem/progenitor cell transplant. After hematopoietic reconstitution, to date 14 months after transplant, we observe stably marked lymphocytes expressing siRNAs and consistent down-regulation of chemokine (c-c motif) receptor 5 expression. The marked cells are less susceptible to simian immunodeficiency virus infection ex vivo. These studies provide a successful demonstration that siRNAs can be used together with hematopoietic stem cell transplant to stably modulate gene expression in primates and potentially treat blood diseases such as HIV-1.

MART-1 T cell receptors

Abstract: T-cell receptors that recognize MART-1 antigen are provided. The TCRs can be used, for example, to treat patients suffering from melanoma.

Targeted gene delivery for dendritic cell vaccination

Abstract: Methods and compositions are provided for delivery of a polynucleotide encoding a gene of interest, typically an antigen, to a dendritic cell (DC). The virus envelope comprises a DC-SIGN specific targeting molecule. The methods and related compositions can be used to treat patients suffering from a wide range of conditions, including infection, such as HIV/AIDS, and various types of cancers.

Modulation of innate immunity receptors' signaling by micrornas mir-146a and mir-146b

Abstract: The present disclosure relates to the finding that microRNA-146 plays a role modulating the innate immune response. Innate immunity receptor signaling can be modulated by delivery of microRNA-146 (miR-146) or antisense miR-146 to target immune cells. In some embodiments, IL-1 receptor associated kinase 1 (IRAK1) and TNF receptor associated factor 6 (TRAF6) expression levels are downregulated in a target cell by administering a miR-146 oligonucleotide. Modulation of the innate immune system through miR-146 can be used to treat a variety of diseases and disorders associated with activation of the innate immune system, such as sepsis and Crohn's disease.