PubMed Health⌕ Search

Biomedical subjects

Frank O Nestle

Publications and source records attributed to Frank O Nestle.

At least 19 recordsLinked to original sources
PubMed2007

The pathogenic role of tissue-resident immune cells in psoriasis.

Psoriasis is a common chronic inflammatory skin disease, the study of which might also be of considerable value to the understanding of other inflammatory and autoimmune-type diseases, such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and diabetes mellitus. There is clear evidence that T cells and dendritic cells have a central role in psoriasis. Based on recent data from humans and animal models, we propose that a psoriasis lesion can be triggered and sustained by the local network of skin-resident immune cells. This concept focuses attention on local, rather than systemic, components of the immune system for rationalized therapeutic approaches of psoriasis and possibly also other chronic inflammatory diseases.

Animals↗
PubMed2006

Animal models of psoriasis and psoriatic arthritis: an update.

Psoriasis is a chronic inflammatory skin disorder characterized by accelerated growth and altered differentiation of keratinocytes and angiogenesis with marked ectasia of blood vessels. It develops through interactions between the skin and immune system mediated by T cells, dendritic cells, and inflammatory cytokines. The understanding of the cellular and molecular alterations underlying the disease has advanced, yet the majority of factors leading to the initiation and maintenance of disease remain elusive. Researchers have attempted to reproduce psoriasis in genetically modified and xenotransplantation mouse models to gain insight into its pathogenesis, and they are beginning to use these models to test new therapeutic agents and define mechanisms of action. Every mouse model has strengths and weaknesses, with room for improvement. Still, these models will accelerate knowledge of psoriasis pathogenesis and aid in the development of new therapeutics.

Animals↗
PubMed2005

Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production.

Psoriasis is one of the most common T cell-mediated autoimmune diseases in humans. Although a role for the innate immune system in driving the autoimmune T cell cascade has been proposed, its nature remains elusive. We show that plasmacytoid predendritic cells (PDCs), the natural interferon (IFN)-alpha-producing cells, infiltrate the skin of psoriatic patients and become activated to produce IFN-alpha early during disease formation. In a xenograft model of human psoriasis, we demonstrate that blocking IFN-alpha signaling or inhibiting the ability of PDCs to produce IFN-alpha prevented the T cell-dependent development of psoriasis. Furthermore, IFN-alpha reconstitution experiments demonstrated that PDC-derived IFN-alpha is essential to drive the development of psoriasis in vivo. These findings uncover a novel innate immune pathway for triggering a common human autoimmune disease and suggest that PDCs and PDC-derived IFN-alpha represent potential early targets for the treatment of psoriasis.

Animals↗
PubMed2005

Dendritic-cell-based therapeutic vaccination against cancer.

Early clinical trials, in which over 1000 cancer patients received dendritic cell (DC) vaccines, tested different vaccine preparations, but they did not always induce sufficient acquired immunity or meet the expected level of tumor regressions. Current studies aim to improve the DC vaccine approach and capture the potential of these cells in order to gain access to lymphoid tissues and induce strong cell-mediated immunity. DC clinical trials are moving towards a more professional environment, in accordance with the latest quality standards. This explains the current need for innovative well designed trials with defined endpoints that induce robust anti-tumor immunity.

Animals↗
PubMed2004

Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha.

Psoriasis is a common T cell-mediated autoimmune disorder where primary onset of skin lesions is followed by chronic relapses. Progress in defining the mechanism for initiation of pathological events has been hampered by the lack of a relevant experimental model in which psoriasis develops spontaneously. We present a new animal model in which skin lesions spontaneously developed when symptomless prepsoriatic human skin was engrafted onto AGR129 mice, deficient in type I and type II interferon receptors and for the recombination activating gene 2. Upon engraftment, resident human T cells in prepsoriatic skin underwent local proliferation. T cell proliferation was crucial for development of a psoriatic phenotype because blocking of T cells led to inhibition of psoriasis development. Tumor necrosis factor-alpha was a key regulator of local T cell proliferation and subsequent disease development. Our observations highlight the importance of resident T cells in the context of lesional tumor necrosis factor-alpha production during development of a psoriatic lesion. These findings underline the importance of resident immune cells in psoriasis and will have implications for new therapeutic strategies for psoriasis and other T cell-mediated diseases.

Animals↗
PubMed2004

Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors.

BACKGROUND: It has been proposed that the innate immune system plays a central role in driving the autoimmune T-cell cascade leading to psoriasis; however, there is no direct evidence for this. OBSERVATIONS: We observed aggravation and spreading of a psoriatic plaque when treated topically with the toll-like receptor (TLR) 7 agonist imiquimod. The exacerbation of psoriasis was accompanied by a massive induction of lesional type I interferon activity, detected by MxA expression after imiquimod therapy. Since imiquimod induces large amounts of type I interferon production from TLR7-expressing plasmacytoid dendritic cell precursors (PDCs), the natural interferon-producing cells of the peripheral blood, we asked whether PDCs are present in psoriatic skin. We identified high numbers of PDCs in psoriatic skin lesions (up to 16% of the total dermal infiltrate) based on their coexpression of BDCA2 and CD123. By contrast, PDCs were present at very low levels in atopic dermatitis and not detected in normal human skin. CONCLUSIONS: This study shows that psoriasis can be driven by the innate immune system through TLR ligation. Furthermore, our finding that large numbers of PDCs infiltrate psoriatic skin suggests a role of lesional PDCs as type I interferon-producing targets for the TLR7 agonist imiquimod.

Administration, Topical↗
PubMed2004

Metastatic melanoma secreted IL-10 down-regulates CD1 molecules on dendritic cells in metastatic tumor lesions.

CD1 molecules are expressed by antigen-presenting cells such as dendritic cells and mediate primary immune responses to lipids and glycolipids which have been shown to be expressed by various tumors. Glycolipids are expressed by melanoma cells but, despite their immunogenicity, no efficient spontaneous immune responses are elicited. As IL-10 has previously been shown to down-regulate CD1a on dendritic cells and is known to be expressed by various melanoma cell lines, we investigated if melanoma-derived IL-10 could down-regulate CD1 molecule expression on dendritic cells as a possible way to circumvent immune recognition. We found that CD1a, CD1b, CD1c, and CD1d were significantly down-regulated on dendritic cells in metastatic (n = 10) but not in primary melanoma lesions (n = 10). We further detected significantly higher IL-10 protein levels in metastatic than in primary melanomas. Moreover, supernatants from metastatic melanomas were significantly more effective in down-regulating CD1 molecules on dendritic cells than supernatants from primary melanoma cultures. This effect was blocked using a neutralizing IL-10 antibody in a dose dependent manner. Our findings suggest that metastatic but not primary melanomas can down-regulate CD1 molecules on infiltrating dendritic cells by secreting IL-10 which may represent a novel way to escape the immune response directed against the tumor.

Antigens, CD1↗
PubMed2004

Nephrogenic fibrosing dermopathy treated with extracorporeal photopheresis.

Nephrogenic fibrosing dermopathy (NFD) is a rare fibrosing skin disease of unknown etiology occurring in patients with terminal renal disease. It was first described in the year 2000. The histology of NFD shows an increased number of dendritic cells, fibroblasts and thickened collagen fibers resembling scleromyxedema. It can be distinguished from scleromyxedema by a different distribution pattern of the skin lesions with indurated plaques mainly on the extremities and the absence of paraproteinemia. As yet, no treatment for NFD has been proven to be uniformly efficient. We describe the case of a 40-year old patient with renal insufficiency who was treated with hemodialysis and who had undergone kidney transplantation. Two years after transplantation, she developed sclerodermiform brownish plaques on her extremities. The induration improved significantly after 4 cycles of extracorporeal photopheresis.

Adult↗
PubMed2004

Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities.

Chronic and excessive inflammation in skin and joints causes significant morbidity in psoriasis patients. As a prevalent T lymphocyte-mediated disorder, psoriasis, as well as the side effects associated with its treatment, affects patients globally. In this review, recent progress is discussed in the areas of genetics, the immunological synapse, the untangling of the cytokine web and signaling pathways, xenotransplantation models, and the growing use of selectively targeted therapies. Since psoriasis is currently incurable, new management strategies are proposed to replace previous serendipitous approaches. Such strategic transition from serendipity to the use of novel selective agents aimed at defined targets in psoriatic lesions is moving rapidly from research benches to the bedsides of patients with this chronic and debilitating disease.

Animals↗
PubMed2003

Immune evasion by murine melanoma mediated through CC chemokine receptor-10.

Human melanoma cells frequently express CC chemokine receptor (CCR)10, a receptor whose ligand (CCL27) is constitutively produced by keratinocytes. Compared with B16 murine melanoma, cells rendered more immunogenic via overexpression of luciferase, B16 cells that overexpressed both luciferase and CCR10 resisted host immune responses and readily formed tumors. In vitro, exposure of tumor cells to CCL27 led to rapid activation of Akt, resistance to cell death induced by melanoma antigen-specific cytotoxic T cells, and phosphatidylinositol-3-kinase (PI3K)-dependent protection from apoptosis induced by Fas cross-linking. In vivo, cutaneous injection of neutralizing antibodies to endogenous CCL27 blocked growth of CCR10-expressing melanoma cells. We propose that CCR10 engagement by locally produced CCL27 allows melanoma cells to escape host immune antitumor killing mechanisms (possibly through activation of PI3K/Akt), thereby providing a means for tumor progression.

Aged↗
PubMed2003

Vaccination of patients with cutaneous T-cell lymphoma using intranodal injection of autologous tumor-lysate-pulsed dendritic cells.

Cutaneous T-cell lymphoma (CTCL) is a lymphoproliferative skin disease with limited therapeutic options. Ten CTCL patients were treated with once-weekly intranodal injection of 1 x 106 mature monocyte-derived dendritic cells (DCs) pulsed with 100 microg/mL tumor lysate protein equivalent and keyhole limpet hemocyanin (50 microg/mL). Tumor-specific delayed-type hypersensitivity (DTH) reactions developed in 8 of 8 patients challenged with tumor-lysate-pulsed DCs and in 3 of 8 patients challenged with tumor lysate alone. Three of 5 patients showed significant tumor-lysate-specific increases of in vitro peripheral blood lymphocyte proliferation coinciding with increased interferon-alpha (IFN-alpha) production. Five of 10 (50%) patients had objective responses. Four patients had partial responses (PRs). Two are still in PR, and the other 2 patients had a mean PR duration of 10.5 months. One patient had a complete response (CR) for 19 months that is ongoing. The remaining 5 patients had progressive disease. In the 5 responder patients, 6.8 +/- 1.4 vaccinations were necessary to induce an objective clinical response. Response was associated with low tumor burden. Continuation of vaccinations with new tumor lysate derived from progressive lesions reinduced treatment responses in 2 patients in PR. Selected patients had massive infiltration of CD8+ and TIA+ cytotoxic T cells at the site of regressing lesions and molecular remission after therapy. Intranodal injection of autologous tumor-lysate-pulsed DCs is well-tolerated and achieves immunologic and objective clinical responses in selected CTCL patients.

Aged↗
PubMed2003

Intranodal injection of semimature monocyte-derived dendritic cells induces T helper type 1 responses to protein neoantigen.

Dendritic cells (DCs) represent the most potent antigen-presenting cells of the immune system capable of initiating primary immune responses to neoantigens. Here we characterize the primary CD4 T-cell immune response to protein keyhole limpet hemocyanin (KLH) in 5 metastatic melanoma patients undergoing a tumor peptide-based dendritic cell vaccination trial. Monocyte-derived dendritic cells displaying a semimature phenotype, as defined by surface markers, were loaded ex vivo with antigen and injected intranodally at weekly intervals for 4 weeks. All patients developed a strong and long-lasting delayed-type hypersensitivity reactivity to KLH, which correlated with the induction of KLH-dependent proliferation of CD4 T cells in vitro. Secondary in vitro stimulation with KLH showed significant increase in interferon-gamma and interleukin-2 (IL-2) but not IL-4, IL-5, nor IL-10 secretion by bulk T cells. On the single-cell level, most TH1 cells among in vitro-generated KLH-specific T-cell lines confirmed the preferential induction of a KLH-specific type 1 T helper immune response. Furthermore, the induction of KLH-specific antibodies of the IgG2 subtype may reflect the induction of a type 1 cytokine profile in vivo after vaccination. Our results indicate that intranodal vaccination with semimature DCs can prime strong, long-lasting CD4 T-cell responses with a TH1-type cytokine profile in cancer patients.

Antibody Formation↗
PubMed2003

Dendritic cell-based cancer therapy.

Dendritic cell (DC)-based cancer immunotherapy has been shown to be safe and feasible. In clinical pilot studies, DCs primed with tumor antigens have successfully been used to induce tumor-specific immunity and obtain some clinical responses in cancer patients. Even though many advances have been achieved over the past years, we are still far from a unifying therapy concept. This review will discuss the current research driving the rapidly growing field of DC-based cancer immunotherapy and highlight some recent progress related to critical issues such as DC preparation, choice and loading of antigen, and the route of administration.

Animals↗