GARP inhibits allergic airway inflammation in a humanized mouse model.

BACKGROUND: Regulatory T cells (Treg) represent a promising target for novel treatment strategies in patients with inflammatory/allergic diseases. A soluble derivate of the Treg surface molecule glycoprotein A repetitions predominant (sGARP) has strong anti-inflammatory and regulatory effects on human cells in vitro as well as in vivo through de novo induction of peripheral Treg. The aim of this study was to investigate the immunomodulatory function of sGARP and its possible role as a new therapeutic option in allergic diseases using a humanized mouse model. METHODS: To analyze the therapeutic effects of sGARP, adult NOD/Scidγc(-/-) (NSG) mice received peripheral blood mononuclear cells (PBMC) derived from allergic patients with sensitization against birch allergen. Subsequently, allergic inflammation was induced in the presence of Treg alone or in combination with sGARP. RESULTS: In comparison with mice that received Treg alone, additional treatment with sGARP reduced airway hyperresponsiveness (AHR), influx of neutrophils and macrophages into the bronchoalveolar lavage (BAL), and human CD45(+) cells in the lungs. Furthermore, the numbers of mucus-producing goblet cells and inflammatory cell infiltrates were reduced. To elucidate whether the mechanism of action of sGARP involves the TGF-ß receptor pathway, mice additionally received anti-TGF-ß receptor II (TGF-ßRII) antibodies. Blocking the signaling of TGF-ß through TGF-ßRII abrogated the anti-inflammatory effects of sGARP, confirming its essential role in inhibiting the allergic inflammation. CONCLUSION: Induction of peripheral tolerance via sGARP is a promising potential approach to treat allergic airway diseases.

[Septic thrombosis of the cavernous sinus due to folliculitis]. / Disseminierte Follikulitiden. Ursache einer septischen Sinus-cavernosus-Thrombose.

Sinus thrombosis is an acute life-threatening disease. While cavernous sinus thrombosis secondary to facial infections is described in the literature, it is uncommon. The key clinical characteristics are a facial infection, headache, chemosis and edema of the eyelid. The main differential diagnostic consideration is meningoencephalitis. Early diagnosis by angiography, magnetic resonance imaging and examination of CSF is important as treatment should be initiated as soon as possible in order to decrease morbidity and mortality. The mainstays of therapy are heparinization and appropriate intravenous antibiotic therapy.

Priming of T cells with Ad-transduced DC followed by expansion with peptide-pulsed DC significantly enhances the induction of tumor-specific CD8+ T cells: implications for an efficient vaccination strategy.

In recent years, vaccination strategies using antigen-presenting cells (APC) have been under investigation. Antigen delivery using genetic immunization through ex vivo transduction of dendritic cells (DC) is supposed to enhance the induction of antitumor responses in humans by activating a broad range of peptide-specific CD8+ T cells. In this study, we compared the potential of adenoviral (Ad)-transduced versus peptide-pulsed DC to induce melanoma-antigen (Ag)-specific T-cell responses in vitro. Whereas gp100-peptide-pulsed DC induced long-lasting specific CD8+ T-cell responses against single peptides, Ad-transduced DC induced broad and strong, specific immunity against various peptides of the gp100-Ag. Surprisingly, several restimulations led to decreasing gp100-specific and in parallel to increasing anti-adenoviral T-cell responses. Nevertheless, those anti-adenoviral T-cell responses provided an "adjuvant" effect by inducing an early release of high amounts of IL-2/IFN-gamma, therewith enhancing CTL induction in the initiation phase. Based on these data, we suggest a prime/boost vaccination strategy in melanoma patients--combining the use of Ad-DC and peptide-pulsed DC--to obtain efficient and long-term antitumor T-cell responses.

A comparison of two types of dendritic cell as adjuvants for the induction of melanoma-specific T-cell responses in humans following intranodal injection.

Dendritic cells (DCs) elicit potent anti-tumoral T-cell responses in vitro and in vivo. However, different types of DC have yet to be compared for their capacity to induce anti-tumor responses in vivo at different developmental stages. Herein, we correlated the efficiencies of different types of monocyte-derived DC as vaccines on the resulting anti-tumor immune responses in vivo. Immature and mature DCs were separately pulsed with a peptide derived from tyrosinase, MelanA/MART-1 or MAGE-1 and a recall antigen. Both DC populations were injected every 2 weeks in different lymph nodes of the same patient. Immune responses were monitored before, during and after vaccination. Mature DCs induced increased recall antigen-specific CD4(+) T-cell responses in 7/8 patients, while immature DCs did so in only 3/8. Expansion of peptide-specific IFN-gamma-producing CD8(+) T cells was observed in 5/7 patients vaccinated with mature DCs but in only 1/7 using immature DCs. However, these functional data did not correlate with the tetramer staining. Herein, immature DCs also showed expansion of peptide-specific T cells. In 2/4 patients vaccinated with mature DCs, we observed induction of peptide-specific cytotoxic T cells, as monitored by chromium-release assays, whereas immature DCs failed to induce peptide-specific cytotoxic T cells in the same patients. Instead, FCS-cultured immature DCs induced FCS-specific IgE responses in 1 patient. Our data demonstrate that this novel vaccination protocol is an efficient approach to compare different immunization strategies within the same patient. Thus, our data define FCS-free cultured mature DCs as superior inducers of T-cell responses in melanoma patients.

Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood.

A subpopulation of peripheral human CD4(+)CD25(+) T cells that expresses CD45RO, histocompatibility leukocyte antigen DR, and intracellular cytotoxic T lymphocyte-associated antigen (CTLA) 4 does not expand after stimulation and markedly suppresses the expansion of conventional T cells in a contact-dependent manner. After activation, CD4(+)CD25(+) T cells express CTLA-4 on the surface detectable for several weeks. These cells show a G1/G0 cell cycle arrest and no production of interleukin (IL)-2, IL-4, or interferon (IFN)-gamma on either protein or mRNA levels. The anergic state of CD4(+)CD25(+) T cells is not reversible by the addition of anti-CD28, anti-CTLA-4, anti-transforming growth factor beta, or anti-IL-10 antibody. However, the refractory state of CD4(+)CD25(+) T cells was partially reversible by the addition of IL-2 or IL-4. These data demonstrate that human blood contains a resident T cell population with potent regulatory properties.