Dendritic Cell Interactions and Cytokine Production

Ricciardi-Castagnoli 4.1 Dendritic Cells Recognize Perturbations of the Immune System . . 63 4.2 Host-Pathogen Gene Profiling 66 4.3 Dendritic Cells and Pathogen Interaction 68 4.4 Dendritic Cells as Sensors of Infection 70 4.5 Dendritic Cell Transcriptional Profile Induced by Pathogens Include Cytokines and Chemokines 71 4.6 Activation of NK Cells by Dendritic Cells Is Mediated by Dendritic Cell-Derived IL-2 75 Abstract. The dendritic cell lineage comprises cells at...

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The MHC class II presentation pathway. MHC class II a p heterodimers assemble in the endoplasmic reticulum (ER) with the assistance of invariant chain (Ii). The cytoplasmic tail of Ii contains a motif that targets the MHC class II Ii complex to the endosomal lysosomal pathway. Maturation of the early endosomes leads to activation of lysosomal enzymes, including cysteinal proteases, which degrade endogenous and exogenous internalized proteins and Ii. Following Ii cleavage, the MHC class...

Induction of Immunity and Inflammation by Interleukin12 Family Members

Kleinschek, J. Knauer, P. Krumbholz, J. Richter, S. Schoeneberger, N. Schuetze, S. Schulz, K. Toepfer, R. Voigtlaender, J. Lehmann, U. Mueller 7.1 Structure of IL-12 Family Members 108 7.2 Expression of IL-12 Family Members and Their Receptors 109 7.3 Signal 7.4 Biology of IL-12 Family Members 112 7.5 Role of IL-12 Family Members in Host Defense 114 7.6 Antitumor Activity of IL-12 Family Members 116 7.7 Role of IL-12 Family Members in Organ-Specific Autoimmunity . 117...

Preface

Cytokines have been a focus of scientific interest at least since the 1980's. Analyzing their expression patterns has permitted a better understanding of the pathogenesis of various diseases, including the inflammatory dermatoses. Exploring T-cell mediated skin diseases such as psoriasis, atopic dermatitis, and allergic contact dermatitis in this context is of particular interest since the skin is becoming increasingly recognized as a visible immunological organ. These T-cell mediated diseases...

Regulatory T Cells in Psoriasis

Cooper 12.1.1 Psoriasis as a T Cell-Mediated Autoimmune Disease 194 12.2 T Cell Activation 196 12.3 T Regulatory Cells 197 12.3.1 Identifying Treg Cells 197 12.4 T Regulatory Cells in Psoriasis 199 12.4.2 Activity 200 12.4.4 Measuring Treg Cells in Skin 203 12.5 Therapy and the Treg Population The Example of Alefacept . . . 205 12.6 Conclusions and Implications 206 Abstract. Psoriasis is a chronic autoimmune disease in which T lymphocytes are thought to be...

TGFpMediated Immunoregulation

Li, R.A. Flavell 9.2 Materials and Methods 156 9.2.1 Transgenic Mice 156 9.2.2 Tumor 9.2.3 Infection Model 157 9.2.4 Diabetes Model 157 9.3.1 TGFP and Effector T Cells 157 9.3.2 TGFP and Regulatory T Cells 158 Abstract. T cell homeostasis is required for normal immune responses and prevention of pathological responses. Transforming growth factor (TGF ) plays an essential role in that regulation. Owing to its broad expression and inhibitory effects on...

TNF Blockade An Inflammatory Issue

Takada, D. Jackson-Bernitsas, K.S. Ahn, G. Sethi, H. Ichikawa 10.2 TNF Cell 10.3 Inhibitors of TNF Cell Signaling 166 10.3.1 NF-kB 10.3.2 AP-1 10.3.3 Suppression of TNF-Induced P38 MAPK Activation 168 10.3.4 Suppression of TNF-Induced JNK Activation 169 10.3.5 Suppression of TNF-Induced P42 p44 MAPK Activation 170 10.3.6 Suppression of TNF-Induced AKT Activation 171 10.4 Role of TNF in Skin Diseases 172 10.5 Bright Side of TNF 174 10.6 Dark Side of TNF Blockers...

Introduction

Anticytokine therapy was pioneered by S. Skurkovich, who in 1974 published in Nature the proposal that the hyperproduction of interferon (IFN) (a cytokine) can bring autoimmune disease and that neutralization of IFN could be therapeutic (Skurkovich et al. 1974). This proposal was based on data describing the mechanism of IFN action (Skurkovich et al.1973). It was postulated that IFN production was a part of the immune response and that any disturbance of IFN production could lead to immune...

Info

We pioneered anticytokine therapy (ACT) for autoimmune diseases (ADs). In 1974, we proposed that hyperproduced interferon (IFN) can bring AD and anti-IFN can be therapeutic. In 1989, we proposed removing tumor necrosis factor (TNF)-a together with certain types of IFN to treat various ADs. We found IFN in patients with different ADs and conducted the first clinical trial of ACT in 1975. Anti-IFN-y and anti-TNF-a work in similar ways, but the latter brings serious complications in some...

Contents

1 Inhibition of IFN-y as a Method of Treatment of Various Autoimmune Diseases, Including Skin Diseases B. Skurkovich, S. Skurkovich 1 2 Cytokine Targeting in Psoriasis and Psoriatic Arthritis Beyond TNFa I.B. McInnes 29 3 Inhibitors of Histone Deacetylases as Anti-inflammatory Drugs 45 4 Dendritic Cell Interactions and Cytokine Production M. Foti, F. Granucci, P. Ricciardi-Castagnoli 61 5 Lysosomal Cysteine Proteases and Antigen Presentation A. Rudensky, C. Beers 81 6 DCs and Cytokines...

Cs and Cytokines Cooperate for the Induction of Tregs

6.1 Interleukin-10 Modulates DCs for Tolerance Induction 98 6.2 IL-10-Dependent Feedback Mechanisms Between Treg and DCs . 99 6.3 TNFa and Semi-mature DCs 100 6.4 Suppressive Effects Mediated by TGF-P 101 6.5 Pharmaceuticals Interfere with DC Maturation 103 Abstract. Regulatory T cells (Treg) in broader terms consist of different subsets of T cells that are characterized by their ability to suppress proliferation of conventional effector T cells by various means. To date, three main groups of...

Discussion

IFN-y is a cytokine released mainly by certain T cells and natural killer cells. It drives the immune response by directing CD4+ T cells toward a Th-1 phenotype, activating macrophages to kill pathogens, enhancing or inducing MHC class I and class II molecules and stimulating B cells to mature and secret antibodies (Snapper 1996). In many autoimmune diseases, IFN-y appears to play a key role in activating autoreactive T cells (Buntinx et al. 2002). Thus different clinical manifestations of...

Cytokine Targeting in Psoriasis and Psoriatic Arthritis Beyond TNFa

2.2.1 Basic 2.2.2 Immunologic Activities of IL-15 33 2.3 IL-15 in Chronic Inflammation 35 2.4 IL-15 in Psoriasis and Psoriatic Arthritis 37 Abstract. Targeting TNFa provided proof of concept for the role of proinflammatory cytokines in promoting cutaneous inflammation, particularly psoriasis. Recent studies have elucidated the presence of numerous cytokine and chemokine activities in psoriatic skin and synovium. There is considerable interest in the potential of such activities as novel...

Treatment of Th1Mediated Autoimmune Diseases

We conducted the first anti-IFN-y therapy in Th-1-mediated diseases together with several clinics using a polyclonal anti-IFN-y antibody (both IgG and F(ab')2 antibody fragments) and in some cases, for comparison, a polyclonal anti-TNF-a. The antibodies were given intramuscularly once or twice daily for 5-6 days. Our studies include placebo-controlled, double-blind studies in patients with rheumatoid arthritis unresponsive to standard treatments (Sigidin et al. 2001) and in patients with...

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Isomallotochromanol and isomallotochromene Luteolin Rocaglamides Sanggenon C Sphondin Silymarin Saucerneols Sauchinone and Manassantins Wedelolactone Yakuchinones A and B Benzopyrene Rotenone Chlorophyll catabolite Pheophorbide A Iridoid glycoside Aucubin Others a-Lipoic acid Astaxanthin Germinated barley S-allylcysteine Vitamin C Vitamin E Oxoacanthospermoldes Parthenolide Pristimerin Triptolide (PG 490) Ursolic acid Alkaloids Cepharanthine Conophylline Morphine and its analogs Tetrandine...

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Histological examination of the skin in IL-1Ra- - mice. A Hematoxylin and eosin staining of the ear pinna of a normal 20-week-old WT mouse. B An affected IL-1Ra- - mouse at 20 weeks of age. The epidermis becomes thickened and hypertrophic associated with hyperkeratosis of the skin. Massive infiltration of neutrophils into the epidermis and dermis are observed in IL-1Ra- - mouse Fig. 6. Histological examination of the skin in IL-1Ra- - mice. A Hematoxylin and eosin staining of the ear...

IL15 in Psoriasis and Psoriatic Arthritis

IL-15 exhibits a plausible bioactivity profile in skin inflammation and has been detected in high levels in a range of inflammatory dermatoses. Thus, keratinocytes express both IL-15 and IL-15Ra, suggesting a role in autocrine regulation of keratinocytes in dermal inflammatory responses (Ruckert et al. 2000). Dermal IL-15 is upregulated by UVB irradiation and overexpression is associated with cutaneous malignancy (Mohamadzadeh et al. 1995). IL-15 has also been reported in bullous lesions,...

Other Th1Mediated Skin Diseases in Which Testing of Anticytokine Therapy Is Warranted

Other skin diseases that appear to involve a Th-1-mediated immune response include seborrheic dermatitis (SD), rosacea, oral lichen planus, and dermatophytosis. SD has upregulated expression of proinflamma-tory cytokines in skin biopsies of SD lesions (Molinero et al. 2003). T-cell subsets are also found in the dermal infiltrates of rosacea lesions (Rufli and Buchner 1984), and IFN-y-producing cells are found in dermatophytosis (Koga et al. 2001). In oral lichen planus, mononuclear cells...

References

Albers R, Bol M, Bleumink R, Willems AA, Pieters RH (2003) Effects of supplementation with vitamins A, C, and E, selenium, and zinc on immune function in a murine sensitization model. Nutrition 19 940-946 Arca E, Musabak U, Akar A, Erbil AH, Tastan HB (2004) Interferon-gamma in alopecia areata. Eur J Dermatol 14 33-36 Aurelian L, Ono F, Burnett J (2003) Herpes simplex virus (HSV)-associated erythema multiforme (HAEM) a viral disease with an autoimmune component. Dermatol Online J 9 1 Barker JN,...

Treatment of Th1Mediated Autoimmune Skin Diseases Using AntiIFNy

Anti Interferon Gamma Treatment

We used anti-IFN-y in patients with psoriasis vulgaris, alopecia areata, vitiligo, acne vulgaris, and herpes simplex type 1, and plan to expand the trials using a humanized monoclonal antibody. Trials are also planned for testing the treatment in other Th-1-mediated skin diseases, including seborrheic dermatitis, rosacea, oral lichen planus, and dermatophyto-sis, which are discussed in the following sections. In most cases, we used two methods of delivery of the antibody intradermal injection...

HDAC Inhibitors in Models of Inflammatory Diseases 321 Models of Lupus Erythematosus

An unexpected finding of HDAC inhibitors was the reduction in disease severity of models of murine autoimmune disease. The mouse model for systemic lupus erythematosus is the lpr lpr mouse that develops a spontaneous disease characterized by nephritis, proteinuria and early death. Trichostatin A was injected into these mice before the onset of significant disease for 5 weeks. Because trichostatin A in water is insoluble, the vehicle was also used for 5 weeks of treatment. Trichostatin A...

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Although TNF is a potent activator of AP-1, no specific blocker of AP-1 activation has yet been described. However, most phytochemicals that suppress NF-kB activation also suppress AP-1 activation (Manna and Aggarwal 2000 Manna et al. 2000 Torii et al. 2004). 10.3.3 Suppression of TNF-Induced P38 MAPK Activation TNF is one of the most potent activators of p38 MAPK (Lee et al. 1994). This activation is specifically inhibited by SB203580 (Henry et al. 1998 Kumar et al. 1997). Campbell et al....