PLASMACYTOID DENDRITIC CELLS SENSE SKIN INJURY AND PROMOTE WOUND HEALING THROUGH TYPE I INTERFERONS

Plasmacytoid dendritic cells (pDCs) are a rare population of circulating cells, which selectively express intracellular Toll-like receptors (TLR)-7 and TLR-9 and have the capacity to produce large amounts of type I IFNs (IFN-a/b) in response to viruses or host derived nucleic acid containing complexes. pDCs are normally absent in skin but accumulate in the skin of psoriasis patients where their chronic activation to produce IFN-a/b drives the disease formation. Whether pDCs and their activation to produce IFN-a/b play a functional role in healthy skin is unknown. Here we show that pDCs are rapidly and transiently recruited into healthy human and mouse skin upon epidermal injury. Infiltrating pDCs were found to sense nucleic acids in wounded skin via TLRs, leading to the production of IFN-a/b. The production of IFN-a/b was paralleled by a short lived expression of cathelicidins, which form complexes with extracellular nucleic acids and activated pDCs to produce IFN-a/b in vitro. In vivo, cathelicidins were sufficient but not necessary for the induction of IFN-a/b in wounded skin, suggesting redundancy of this pathway. Depletion of pDCs or inhibition of IFN-a/bR signaling significantly impaired the inflammatory response and delayed re-epithelialization of skin wounds. Thus we uncover a novel role of pDCs in sensing skin injury via TLR mediated recognition of nucleic acids and demonstrate their involvement in the early inflammatory process and wound healing response through the production of IFN-a/b.

Celebrandosi nel giorno XIX aprile MDCCCXLI da questa Comunità Israelitica con divote azioni di grazie ed analoghe preci nell'oratorio maggiore l'anniversario natalizio di sua maestà l'imperatore e re Ferdinando I

discorso ... Sabbato Graziadio Treves

Frank i frankiści polscy : 1726 - 1816 ; monografia historyczna osnuta na źródłach archiwalnych i re̜kopiśmiennych

przez Alexandra Kraushara

Ms. hebr. oct. 151 - Reḳanaṭi

Vorbesitzer: Abraham Merzbacher; vermutlich durch Paginierungsfehler fehlt Bl. 10

Libri de re rustica : M. Catonis, lib. I. M. Terentii Varronis lib. III. L. Iunii Moderati Columellae lib. XII. Eiusdem de arboribus liber separatus ab alijs ... Palladii lib. XIIII. De duobus dierum generibus simulq[ue] de vmbris [et] horis quae apud Pal

Lugares e imp. tomados de Short-title catalogue of books printed in the German-speaking countries and German Books printed in other countries from 1455 to 1600 now in the British Museum

Libri de re rustica : M. Catonis, lib. I. M. Terentii Varronis lib. III. L. Iunii Moderati Columellae lib. XII. Eiusdem de arboribus liber separatus ab alijs ... Palladii lib. XIIII. De duobus dierum generibus simulq[ue] de vmbris [et] horis quae apud Pal

Lugares e imp. tomados de Short-title catalogue of books printed in the German-speaking countries and German Books printed in other countries from 1455 to 1600 now in the British Museum

Descrittione del Regno di Napoli nella quale s'ha piena contezza, cosi' del sito d'esso, de'nomi delle prouintie antiche ... come de'monti, de'mari ... Et vi si fa mentione de i re, con la loro vita, & effigie, che l'han dominato ... le loro arme ... e con un preambolo de i re di Gierusalem, oue si dichiara perche i re di Napoli habbiano quel titolo : Con la tauola copiosissima, & altre cose notabili, che nella prima impressione non erano

Contiene con portada propia: Della descritione del Regno di Napoli ... Libro secondo. In Napoli : Nella Stamperia dello Stigliola à Porta Reale, 1597

Immune response in human melanoma after transfer of an allogeneic class I major histocompatibility complex gene with DNA–liposome complexes

Analysis of the antitumor immune response after gene transfer of a foreign major histocompatibility complex class I protein, HLA-B7, was performed. Ten HLA-B7-negative patients with stage IV melanoma were treated in an effort to stimulate local tumor immunity. Plasmid DNA was detected within treated tumor nodules, and RNA encoding recombinant HLA-B7 or HLA-B7 protein was demonstrated in 9 of 10 patients. T cell migration into treated lesions was observed and tumor-infiltrating lymphocyte reactivity was enhanced in six of seven and two of two patients analyzed, respectively. In contrast, the frequency of cytotoxic T lymphocyte against autologous tumor in circulating peripheral blood lymphocytes was not altered significantly, suggesting that peripheral blood lymphocyte reactivity is not indicative of local tumor responsiveness. Local inhibition of tumor growth was detected after gene transfer in two patients, one of whom showed a partial remission. This patient subsequently received treatment with tumor-infiltrating lymphocytes derived from gene-modified tumor, with a complete regression of residual disease. Thus, gene transfer with DNA–liposome complexes encoding an allogeneic major histocompatibility complex protein stimulated local antitumor immune responses that facilitated the generation of effector cells for immunotherapy of cancer.

Induction of topoisomerase I cleavage complexes by 1-β-d-arabinofuranosylcytosine (ara-C) in vitro and in ara-C-treated cells

1-β-d-Arabinofuranosylcytosine (Ara-C) is a nucleoside analog commonly used in the treatment of leukemias. Ara-C inhibits DNA polymerases and can be incorporated into DNA. Its mechanism of cytotoxicity is not fully understood. Using oligonucleotides and purified human topoisomerase I (top1), we found a 4- to 6-fold enhancement of top1 cleavage complexes when ara-C was incorporated at the +1 position (immediately 3′) relative to a unique top1 cleavage site. This enhancement was primarily due to a reversible inhibition of top1-mediated DNA religation. Because ara-C incorporation is known to alter base stacking and sugar puckering at the misincorporation site and at the neighboring base pairs, the observed inhibition of religation at the ara-C site suggests the importance of the alignment of the 5′-hydroxyl end for religation with the phosphate group of the top1 phosphotyrosine bond. This study also demonstrates that ara-C treatment and DNA incorporation trap top1 cleavage complexes in human leukemia cells. Finally, we report that camptothecin-resistant mouse P388/CPT45 cells with no detectable top1 are crossresistant to ara-C, which suggests that top1 poisoning is a potential mechanism for ara-C cytotoxicity.