Cytokines As Potential Therapeutic Targets for Inflammatory Skin Diseases

by Numerof, R.; Dinarello, Charles A.; Asadullah, K.

• ISBN13: 9783540254270
• ISBN10: 3540254277
• Format: Hardcover
• Copyright: 2005-11-15
• Publisher: Springer Verlag

Summary

Cytokines and cytokine receptors remain an area of great interest for the development of targeted therapies for cutaneous inflammatory diseases. Anti-TNF therapeutics have proven to be effective in the treatment of psoriasis, and clinical investigations have now begun for other cytokine-directed therapies, such as those targeting IFN-g, IL-12p40, and IL-18. In addition to therapeutics that target cytokines directly, strategies that target cytokine signaling pathways are in development. This book summarizes the findings of the 56th International Workshop of the Ernst Schering Research Foundation that focused on "Cytokines as Potential Therapeutic Targets for Inflammatory Skin Diseases".

Table of Contents

1 Inhibition of IFN-γ as a Method of Treatment of Various Autoimmune Diseases, Including Skin Diseases
B. Skurkovich, S. Skurkovich	1	(28)
1.1 Introduction	2	(2)
1.2 Treatment of Th-l-Mediated Autoimmune Diseases	4	(3)
1.2.1 Rheumatoid Arthritis	5	(1)
1.2.2 Multiple Sclerosis	5	(1)
1.2.3 Corneal Transplant Rejection	6	(1)
1.2.4 Type I Diabetes	6	(1)
1.2.5 Uveitis	7	(1)
1.3 Treatment of Th-1-Mediated Autoimmune Skin Diseases Using Anti-IFN-γ	7	(5)
1.3.1 Psoriasis Vulgaris	7	(2)
1.3.2 Alopecia Areata	9	(1)
1.3.3 Vitiligo	10	(1)
1.3.4 Acne Vulgaris	11	(1)
1.3.5 Herpes Simplex Virus Type 1	11	(1)
1.4 Genetic Skin Diseases in Which Cytokines May Be Involved	12	(1)
1.4.1 Dystrophic Epidermolysis Bullosa (DEB)	12	(1)
1.5 Other Th-1-Mediated Skin Diseases in Which Testing of Anticytokine Therapy Is Warranted	13	(1)
1.6 Beneficial Effect of Anti-IFN-7gamma; in Possibly Non-Th-1-Mediated Skin Diseases	14	(1)
1.6.1 Herpes Simplex Virus Type 2	14	(1)
1.7 Skin Diseases Involving Th-1/Th-2 Cytokines	14	(1)
1.8 Discussion	15	(4)
References	19	(10)
2 Cytokine Targeting in Psoriasis and Psoriatic Arthritis: Beyond TNFα
I.B. McInnes	29	(16)
2.1 Introduction	30	(1)
2.2 Interleukin- 15	31	(4)
2.2.1 Basic Biology	31	(2)
2.2.2 Immunologic Activities of IL-15	33	(2)
2.3 IL-15 in Chronic Inflammation	35	(2)
2.4 IL-15 in Psoriasis and Psoriatic Arthritis	37	(2)
2.5 Conclusion	39	(1)
References	40	(5)
3 Inhibitors of Histone Deacetylases as Anti-inflammatory Drugs
C.A. Dinarello	45	(16)
3.1 Introduction	46	(2)
3.1.1 HDAC Inhibitors as Anti-tumor Agents	47	(1)
3.1.2 HDAC Inhibition and Expression of Latent Viral Genes	47	(1)
3.2 HDAC Inhibitors in Models of Inflammatory Diseases	48	(3)
3.2.1 Models of Lupus Erythematosus	48	(2)
3.2.2 Graft-Versus-Host Disease	50	(1)
3.2.3 Models of Arthritis	50	(1)
3.2.4 Hepatitis Induced by Intravenous Con A	51	(1)
3.3 Reducing Cytokines by HDAC Inhibitors	51	(4)
3.3.1 Low Concentrations of HDAC Inhibitors are Anti-inflammatory Whereas High Concentrations Are Needed for Anti-tumor Effects	51	(1)
3.3.2 Effect of SAHA on Secretion of IL-1β	52	(1)
3.3.3 Other Cytokines	53	(1)
3.3.4 LPS-Induced Cytokines In Vivo	54	(1)
3.4 Mechanism of Action of HDAC Inhibition in Reducing Inflammation	55	(1)
References	56	(5)
4 Dendritic Cell Interactions and Cytokine Production
M. Foti, F. Granucci, P. Ricciardi-Castagnoli	61	(20)
4.1 Dendritic Cells Recognize Perturbations of the Immune System	63	(3)
4.2 Host–Pathogen Gene Profiling	66	(2)
4.3 Dendritic Cells and Pathogen Interaction	68	(2)
4.4 Dendritic Cells as Sensors of Infection	70	(1)
4.5 Dendritic Cell Transcriptional Profile Induced by Pathogens Include Cytokines and Chemokines	71	(4)
4.6 Activation of NK Cells by Dendritic Cells Is Mediated by Dendritic Cell-Derived IL-2	75	(1)
References	76	(5)
5 Lysosomal Cysteine Proteases and Antigen Presentation
A. Rudensky, C. Beers	81	(16)
5.1 Introduction	82	(1)
5.2 The MHC Class II Pathway	82	(3)
5.3 Lysosomal Cysteine Proteases	85	(2)
5.4 MHC Class II Invariant Chain Degradation by Lysosomal Cysteine Proteases	87	(2)
5.5 Role of Cathepsin S and L in Generation of MHC Class II-Bound Peptides	89	(1)
5.6 Regulation of Cathepsin S and L Activity and Their Role in Ii Degradation in Macrophages	90	(1)
5.7 Role of Cathepsin S and L in MHC Class II Presentation by Nonprofessional Antigen-Presenting Cells	91	(1)
References	92	(5)
6 DCs and Cytokines Cooperate for the Induction of Tregs
A.H. Enk	97	(10)
6.1 Interleukin-10 Modulates DCs for Tolerance Induction	98	(1)
6.2 IL-10-Dependent Feedback Mechanisms Between Treg and DCs	99	(1)
6.3 TNF&Ialpha; and "Semi-mature" DCs	100	(1)
6.4 Suppressive Effects Mediated by TGF-β	101	(2)
6.5 Pharmaceuticals Interfere with DC Maturation	103	(1)
References	103	(4)
7 Induction of Immunity and Inflammation by Interleukin-12 Family Members
G. Alber, S. Al-Robaiy, M. Kleinschek, J. Knauer, P. Krumbholz, J. Richter, S. Schoeneberger, N. Schuetze, S. Schulz, K. Toepfer, R. Voigtlaender, J. Lehmann, U. Mueller	107	(22)
7.1 Structure of IL-12 Family Members	108	(1)
7.2 Expression of IL-12 Family Members and Their Receptors	109	(2)
7.3 Signal Transduction	111	(1)
7.4 Biology of IL-12 Family Members	112	(2)
7.5 Role of IL-l2 Family Members in Host Defense	114	(2)
7.6 Antitumor Activity of IL-12 Family Members	116	(1)
7.7 Role of IL-12 Family Members in Organ-Specific Autoimmunity	117	(4)
7.7.1 Experimental Autoimmune Encephalomyelitis	118	(1)
7.7.2 Rheumatoid Arthritis	118	(1)
7.7.3 Psoriasis Vulgaris	119	(1)
7.7.4 Inflammatory Bowel Disease	120	(1)
7.7.5 Insulin-Dependent Diabetes Mellitus	121	(1)
References	121	(8)
8 The Role of TNFa and IL-17 in the Development of Excess IL-1 Signaling-Induced Inflammatory Diseases in IL-1 Receptor Antagonist-Deficient Mice
H. Ishigame, A. Nakajima, S. Saijo, Y. Komiyama, A. Nambu, T. Matsuki, S. Nakae, R. Horai, S. Kakuta, Y Iwakura	129	(26)
8.1 Introduction	130	(3)
8.2 The Roles of TNFα and IL-17 in the Development of Arthritis	133	(7)
8.2.1 Development of Autoimmune Arthritis in IL-1Ra–/– Mice	133	(2)
8.2.2 The Role of TNFα in the Development of Arthritis	135	(3)
8.2.3 The Role of IL-17 in the Development of Arthritis	138	(2)
8.3 The Roles of TNFα and IL-17 in the Development of Aortitis	140	(4)
8.3.1 Development of Aortitis in IL-1Ra–/– Mice	140	(2)
8.3.2 The Roles of TNFα and IL-17 in the Development of Aortitis	142	(2)
8.4 The Role of TNFα in the Development of Dermatitis	144	(2)
8.4.1 Development of Psoriasis-Like Dermatitis in IL-1Ra–/– Mice	144	(1)
8.4.2 The Role of TNFα in the Development of Dermatitis	145	(1)
8.5 Conclusion	146	(1)
References	147	(8)
9 TGFβ-Mediated Immunoregulation
Y. Peng, L. Gorelik, Y. Laouar, M.O. Li, R.A. Flavell	155	(6)
9.1 Introduction	156	(1)
9.2 Materials and Methods	156	(1)
9.2.1 Transgenic Mice	156	(1)
9.2.2 Tumor Model	156	(1)
9.2.3 Infection Model	157	(1)
9.2.4 Diabetes Model	157	(1)
9.3 Results	157	(2)
9.3.1 TGFβ and Effector T Cells	157	(1)
9.3.2 TGEβ and Regulatory T Cells	158	(1)
9.4 Conclusions	159	(1)
References	160	(1)
10 TNF Blockade: An Inflammatory Issue
B.B. Aggarwal, S. Shishodia, Y. Takada, D. Jackson-Bernitsas, K.S. Ahn, G. Sethi, H. Ichikawa	161	(26)
10.1 Introduction	162	(1)
10.2 TNF Cell Signaling	162	(4)
10.3 Inhibitors of TNF Cell Signaling	166	(6)
10.3.1 NF-kappaB Blockers	166	(2)
10.3.2 AP-1 Blockers	168	(1)
10.3.3 Suppression of TNF-Induced P38 MAPK Activation	168	(1)
10.3.4 Suppression of TNF-Induced JNK Activation	169	(1)
10.3.5 Suppression of TNF-Induced P42/p44 MAPK Activation	170	(1)
10.3.6 Suppression of TNF-Induced AKT Activation	171	(1)
10.4 Role of TNF in Skin Diseases	172	(2)
10.5 Bright Side of TNF	174	(1)
10.6 Dark Side of TNF Blockers	174	(4)
10.7 Identification of Novel Blockers of TNF	178	(2)
10.8 Conclusions	180	(1)
References	180	(7)
11 IL-1 Family Members in Inflammatory Skin Disease
J. Sims, J. Towne, H. Blumberg	187	(6)
References	190	(3)
12 Regulatory T Cells in Psoriasis
M.H. Kagen, T.S. McCormick, K.D. Cooper	193	(18)
12.1 Introduction	194	(2)
12.1.1 Psoriasis as a T Cell-Mediated Autoimmune Disease	194	(2)
12.2 T Cell Activation	196	(1)
12.3 T Regulatory Cells	197	(2)
12.3.1 Identifying Treg Cells	197	(2)
12.4 T Regulatory Cells in Psoriasis	199	(6)
12.4.1 Numbers	200	(1)
12.4.2 Activity	200	(3)
12.4.3 Tissue	203	(1)
12.4.4 Measuring Treg Cells in Skin	203	(2)
12.5 Therapy and the Treg Population: The Example of Alefacept	205	(1)
12.6 Conclusions and Implications	206	(1)
References	207	(4)
Previous Volumes Published in This Series	211