Cytokine inhibitors

Cytokine Inhibitors......Page 1
Contents......Page 6
Preface......Page 3
Contributors......Page 8
Introduction......Page 14
Contents......Page 0
Why Inhibit Il-1?......Page 18
Il-1ra In Patients With Rheumatoid Arthritis......Page 19
Il-1  Versus Il-1......Page 21
Gene Expression And Synthesis Of Il-1......Page 22
Proteinase-3 And Extracellular Cleavage Of Proil-1......Page 25
Ice And Il-18......Page 27
Present Understanding Of The Il-18 Receptor Complex......Page 29
Il-1rrp Is The Binding Component Of The Il-18 Receptor Complex......Page 30
Il-18 Signal Transduction Is Similar To That Of Il-1......Page 31
Inhibition Of Ice And Effect On Il-18......Page 34
Conclusions......Page 35
References......Page 36
Introduction......Page 46
Regulation Of Il-10 Production......Page 48
Immune-mediated In.ammation......Page 50
Microbial Pathogens And Endotoxin......Page 52
Noninfectious In.ammatory Disease......Page 53
Il-10 Production In Inflammatory Diseases In Humans......Page 54
Effects Of Il-10 In Human Volunteers......Page 55
Il-10 As A Therapeutic Agent......Page 56
References......Page 57
Introduction......Page 65
Natural Antibodies To Cytokines......Page 68
Ifn-......Page 69
Il-2......Page 72
Il-1......Page 73
Tumor Necrosis Factor And Lymphotoxin......Page 76
Il-6......Page 77
Chemokines......Page 80
Il-10......Page 82
Colony-stimulating Factors......Page 83
Other Cytokines And Soluble Cytokine Receptors......Page 84
Cytokine Antibodies In Normal Human Immunoglobulin......Page 85
Interferons......Page 86
Il-2......Page 89
Colony-stimulating Factors......Page 90
Methodological Problems......Page 92
Passive Immunization......Page 93
Conclusions......Page 94
References......Page 95
Tnf-......Page 108
Role Of Tnf- In Disease......Page 111
Rheumatoid Arthritis......Page 112
Anti – Tnf- Monoclonal Antibody (infliximab, Remicade)......Page 113
Clinical Pharmacology Results......Page 114
Treatment Of Crohn’s Disease With In.iximab......Page 115
Treatment Of Ra With In.iximab......Page 123
Malignancies......Page 131
Infusion Reactions......Page 132
Autoantibodies: Antinuclear Antibodies And Antibody Against Double-stranded Dna (anti-dsdna)......Page 133
Humanized Anti-tnf Monoclonal Antibody......Page 134
Recombinant Human Soluble P75 Tnf Receptor Fusion Protein (etanercept)......Page 135
Conclusions......Page 136
References......Page 137
Introduction......Page 143
Current Approaches In Anti-tnf- Design......Page 145
Blocking Biosynthesis Of Tnf-......Page 146
Macromolecular Inhibitors Of Tnf-......Page 147
Rational Design Of Small Molecule Anti-tnf-......Page 148
Structure Of Immunoglobulins......Page 149
Structure Of Receptors......Page 150
General Strategy In The Design Of Peptidomimetics......Page 151
Design Of A Tnf- Inhibitor......Page 153
References......Page 162
Introduction......Page 172
In Vitro Screening Of Enzyme Activity......Page 173
Cell-based Assays......Page 174
In Vivo Testing Of Tace Inhibitors......Page 175
Inhibitors And Sar......Page 176
Conclusions......Page 181
References......Page 183
Introduction......Page 186
Identification Of The Chemokine Receptors As The Hiv Coreceptor......Page 187
Chemokine Receptors Explain Hiv Tropism......Page 188
Interaction Of Viral Envelope And The Chemokine Receptor......Page 189
The Chemokine Family......Page 190
What Controls Specificity In Vivo?......Page 192
Validation Of Chemokines As Therapeutic Targets For Inflammation......Page 193
Modified Chemokines — An Effective Receptor Blockade Strategy......Page 195
Inhibition Of Hiv Infection Through Chemokine Receptor Ligands......Page 198
Small Molecule Inhibitors Of Coreceptors — The Pharmaceutical Ideal......Page 200
References......Page 202
Creation Of Receptor Antagonists By Modifying Cytokines......Page 210
Receptor Assembly......Page 212
Biological Activity Of Gp130 Cytokines — The Case For Antagonists......Page 213
Overview Of Receptor Binding Sites On Gp130 Cytokines......Page 215
Receptor Structure......Page 216
Rational Design Of Receptor Antagonists......Page 217
Assembly Of Il-6 Receptor Complexes......Page 218
Creation Of Il-6r Antagonists By Disruption Of Site 2......Page 220
Creation Of Superantagonists With Enhanced Binding To Il-6r......Page 221
Creation Of Il-6r Antagonists By Disruption Of Site 3......Page 223
Specificity Of Il-6r Antagonists......Page 225
Gp130 Antagonists......Page 226
Il-11r Antagonists......Page 227
Gp130 Cytokines Bind To Lif-r Through Residues In Site 3......Page 228
Creation Of A Lif-r Antagonist By Disruption Of Site 2 Of Hlif......Page 229
Assembly Of Cntf Receptor Complexes......Page 231
Creation Of Cntfr Antagonist By Disruption Of Site 3......Page 232
Mechanism: Do Receptor Antagonists Always Work As Competitive Antagonists?......Page 234
In Vitro Applications Of Il-6r And Lif-r Antagonists......Page 235
Difficulties To Overcome......Page 236
Gm-csfr Antagonist In Juvenile Myelomonocytic Leukemia......Page 237
Vaccination Of Mice With An Il-6r Antagonist To Neutralize Il-6......Page 238
Conclusions......Page 239
References......Page 240
Introduction......Page 250
Signal Transduction Mediated By Janus Kinase......Page 251
Mechanisms Of Negative Cytokine Regulation......Page 252
Protein Inhibitor Of Activated Stat......Page 253
Ssi Family......Page 254
Cis1 (cytokine-inducible Sh2-containing Protein 1)......Page 255
Ssi-1......Page 256
Ssi-3......Page 260
Ssi-1 – Deficient Mice......Page 261
References......Page 264
Introduction......Page 270
Jak Kinases......Page 271
Stat Transcription Factors......Page 273
Suppressors Of Cytokine Signaling......Page 275
Shp-1......Page 280
Protein Inhibitor Of Activated Stat......Page 281
Phosphatases And Degradation......Page 282
Conclusions......Page 283
References......Page 284
Introduction......Page 293
Scf Receptor C-kit......Page 294
Malignancies......Page 298
Receptors......Page 304
Ligands......Page 306
Biology......Page 308
Inflammation......Page 309
Cardiovascular Diseases......Page 310
Cancer And Tumor Angiogenesis......Page 311
Synthetic Tyrosine Kinase Inhibitors......Page 312
Vegfr Tyrosine Kinase Inhibitors......Page 313
Scf Receptor Inhibitors......Page 317
Conclusions......Page 318
References......Page 319
References To Patent Literature......Page 336
Introduction......Page 337
Identification Of P38 Mitogen-activated Protein Kinase As A Target For Inhibition Of Il-1 And Tnf......Page 338
Multiple Isoforms Of P38 Map Kinase......Page 339
Comparison Of P38 To Other Map Kinases......Page 341
Activation Stimuli For P38 And Its Homologs......Page 342
Inhibitors Compete With Atp For Binding To P38......Page 344
Selectivity Of Inhibitors......Page 345
Why P38 Inhibitors Are Selective......Page 346
Use Of Sb203580 To Determine Role Of P38......Page 347
Substrates For P38......Page 348
Role Of P38 In Regulation Of Gene Expression......Page 350
Role Of P38 In Production Of Cytokines And Inflammatory Mediators......Page 351
Role Of P38 In Cell Proliferation And Apoptosis......Page 352
Role Of P38 In Cell Morphology, Aggregation, And Migration......Page 353
P38 As A Therapeutic Target......Page 354
References......Page 356