The Ultimate Immunology Study Guide Part 4

L. Cells of Innate Immunity 37 ● Macrophages, NK cells, neutrophils, eosinophils, dendritic cells a) Cytokine Mediators Cytokines Cell Source Cell Target Primary Effects IFN - , 18 Macrophage, fibroblasts all Antiviral, antiproliferation, inc. Class I TNF 17 Macrophage, T-cells, other Endothelial cells, neurons, liver, fat Inflammation, fever, catabolism, apoptosis IL-1 17 Macrophage, T-cells, Endothelial cells Endothelial cells, neurons, liver Inflammation, fever 8-10 Macrophage, T-cells, endothelial cells, fibroblasts, others leukocytes Chemotaxis, activation Chemokines Size (in kD) M. Effects of TNF on Vasculature 1. Increase vascular permeability ● Change cell shape ● Inc. pinocytotic vesicles & endocytosis ● Inc. nitric oxide production 2. Enhance tissue inflammation ● Upreg. of adhesion expression ● Induction of cytokine expression (IL-1, IL-8) ● Apoptosis 3. Enhance procoagulation activity ● Inc. PAI-1, dec. tPA ● Inc. tissue factor expression ● Dec. thrombomodulin production N. Chemokines: Chemotactic Cytokines *produced quickly ~ 1 hr … provide [] dependent gradient 1. Functions a) Homing: traffic, relocation, & recirculation of lymphocytes … differentiation, maturation b) Inflammation: activation of neutrophils, lymphocytes & stimulates production of inflammatory cytokines c) Angiogenesis: proliferation, migration of endothelial cell 2. Structure a) C x C - α chemokine b) C C - β chemokine c) x C - lymphotactin d) Cx 3 C - fractalkine (aka neurotactin) 3. CxC α-Chemokines a) GROα h) CxCR2 b) GROβ i) CxCR2 c) GROδ j) CxCR2 d) IL-8 k) CxCR1, CxCR2 e) IP-10 (CxCL-10) l) CxCR3 f) SDF-1 α/β m) CxCR4 g) BCA-1 n) CxCR5 IP-10 (CxCCL-10) MCP-1 MIP-1a & MIP-1b Rantes - Inhibits angiogenesis (stops premature blood vessel formation) - block fibroblast migration (anti-fibrotic - chemoattractant for monocytes, T-cells, NK cells - promotes adhesion to myocytes - major chemoattractant for monocytes - chemoattractant for monocytes, eosinophils, Th1 cells 38 agent) - induced by TNF O. CC β-Chemokines a. MCP-1 b. MIP-1 c. MIP-1β d. RANTES e. MCP-3 f. MCP-2 g. Eotaxin-1 h. MCP-4 i. MCP-2 j. MIP-3β k. MIP-3 P. Cytokines Linking Innate & Adaptive Immunity Cytokine s Size (in kD) l. m. n. o. p. q. r. s. t. u. v. CCR2 CCR1, CCR5 CCR5 CCR1, CCR3, CCR5 CCR1, CCR2, CCR5 CCR3 CCR3 CCR2, CCR3 CCR1, CCR3 CCR7 CCR6 Cell Source Cell Target Primary Effects Macrophage, dendritic cell, neutrophils T-cells, NK cells +TNF/IL-1 = IFN-g, induces GM-CSF, TNF Maintain Th1 cells Enhance CTL, NK cytotoxicity IL-12 35, 40 IL-18 18 Macrophages, dendritic cells, microglia, kufer cells, osteoblasts T-cells, NK cells Induces IFN-g in presence of IL-12 Activation: adhesion chemokines PMN activation TNF, IL-1, IL-8 IL-15 14 Macrophage, dendritic cell, fibroblast, BM stroma T-cells, B cells, NK cells NK maturation, T-cell proliferation, similar to IL-2 IL-6 26 Macrophage, T-cells, multiple cell types T-cells, B-cells, macrophages, multiple cell types Ab production, anti-inflammatory Q. IL-12 1. 2. Function a) Initiates Th1 response - induce IFN-g: rapid production b) Enhances generation of CTL & NK ● Transcription of perforin & granzymes ● Enhance adhesion of cells c) Synergetic w/ IL-2 for IFN-g production d) Maintains Th1 response ● Stabilizes IFN-g mRNA Regulation a) IL-10 blocks IL-12 transcription b) TGF-B inhibits IL-12 syn. (alters mRNA stability) c) IFN-a & b inhibits IL-12 production 39 R. IL-6 1. Function a) Pro-inflammatory ● Enhances humoral immunity - stimulated B-cell differentiation b) Anti-inflammatory ● Dec. adhesion molecules on endothelial cells, production of collagenase & MMPs, production of TNF ● Induces IL-1ra production, production of soluble TNF receptors S. Th 1 & Th 2 Cytokines Cytokine s Size (in kD) Cell Source Cell Target Primary Effects IL-2 14-17 T-cells T-, & NK cells Proliferation G ILN-g 21-24 T-, & NK cells T-, NK, endothelial cells, macrophages Antiviral, activation Th1, Co-stim. - TNF, IL-1, downreg. IL-4, IL-10, & Th2, class I & II expressed Cytokines Size (in kD) 1 S, activation IFN, magnitude of IR Cell Source Cell Target Primary Effects IL-4, IL-13 20 T-cells T-, B-cells, macrophages, multiple cell type B-cell proliferation, isotype switch, IgE, IgG3, proliferation: Th2, downreg. IFN-g IL-5 40 T-cells, eosinophils Eosinophils, basophils Eiosino, maturtion, chemotaxis, helminth infection, allergic response T. Cytokines w/ Suppressive Activity 40 Cytokine s Size (in kD) IL-10 18.5 TGF 25 Cell Source Cell Target Primary Effects Macrophage, Th2 cells Macrophages, T-, B-cells, epithelium, PMNs Inhibits IFN-g, stimulates B-cells, suppresses APC & inflammation, promotes Th2 T-, B-, dendritic cells, macrophage, platelets Immune & tumor cells, multiple cell types Immune suppressor & activator, angiogenic factor, tumor promoter U. IL-10 Induced Suppression ● Inhibits production of IL-12 ● Prevents monocyte differentiation to DC ● Enhances IL-1 ra & sol TNF-a receptor production ● Dec. class II expression ● Downreg. Th1 ● Blocks PMN cytokines production & activity V. TGF 1. Functions Early Response -- [low] Late Response -- [high] Chemoattractants for PMNs, macrophages, CD4, CD8 Inhibits T-cell proliferation Stimulates innate immune cells Inhibits cytotoxic T-cells Induces IL-2 production Inhibits Th1 & Th2 cell activation Induces proinflammatory cytokines (IL-1) Inhibits TNF, IFN-g, IL-12 Causes chronic inflammation Inhibits IL-1 ra *Tumor cells produce large amounts of TGF 2. Effects in Cancer a) Early tumor development : immune response suppressed enhancing tumor growth b) Tumor growth & metastase : inc. angiogenesis, enhances tumor cell invasion, tumor cells proliferate in response to TGF → Proliferate = inc. rapidly in #; multiply W. Multiple Sclerosis = immune system disease that eats away @ protective covering of nerves 1. Characteristics ● Demyelination of central nervous stem & formation of sclerotic plaques 2. ● ● ● Cause ● ● ● 41 Major cause of neurological disability in young adults Chronic recurrent &/ progressive course Predominantly affecting females Autoimmune disease Highest incidence in temperate climates Genetic disposition - HLA Dr15, DQ6, Dw2 ○ Monozygotic twins show 27% concordance rate of MS ○ Dizygotic twins show 2.4% concordance rate of MS Viral infection ● *Oligodendroglia produce myelin X. MS Plaque 1. Active MS Plaque a) @ site of plaque ● Class II expression on activated microglia ● Olgio degeneration, axonal loss ● Edge has area of remyelination ● Center of plaque has olgio precursors (balance b/w oligo death & remyelination) 2. Immune Response ● Break down BBB ● Transmigration of autoreactive T-cells into tissues ● 3. Cytokines in MS a. TNF : upreg. In brain tissue, serum, CSF of MS patients & cytotoxic to oligodendroglial cells b. IFN- : systemic administration exacerbates disease & inc. production precedes replace (i) Effects ● Stimulate production of TNF & IFN● Promotes expansion of Th1 cells ● Downreg. TGF & IL-10 *IL-12 not good for MS patients (ii) Current MS Therapy ● Effects: reduces frequency of clinical exacerbations & progression of disability ● Mechanisms: inhibits IL-12 production, dec. Th1 response, induces IL-10 & TGF production & influx of T-regulatory cells into CNS (T-regs produce IL-10 & TGF) & (copolymer 1 induces T-regs) 4. IL-12 : upreg. In brain tissue, serum, CSF of MS patients & IL-12 KO mice resistant to disease a) Functions Y. Cytokine Therapies in Clinical Use Agent Nature of Agent Clinical Application Enbrel Soluble TNF-receptor Rheumatoid arthritis Remicade moAb to TNF receptor Rheumatoid arthritis IFN-B Th1 immune suppressive Multiple sclerosis G-CSF Stimulated PMN Neupogen Z. TGF-B Target for Cancer Therapy Drug Type Target Stage AP-11014 Oligonucleotide (anti-sense) TGF-β1 Preclinical Metelimumab Antibody TGF-β1 Phase II 42 Ly573636S VI. Small-molecule inhibitor TGF-βRI kinase Phase II Transplantation; Cancer → Transplantation = transferring cells, tissues, or organs from 1 site to another - Kidney, pancera, heart, lung, liver, bone marrow, cornea, etc A. Host & Graft Autograft = 1 body site to another in same individual (skin; blood vessel) Isograft = b/w genetically identical individuals Allograft = b/w genetically diff. Xenograft members of same species = b/w diff. species → Histocompatible = tissues that are antigenically similar → HLA Typing = performed prior translation *Even if MHC identical, rejection rxn will take place due to difference in numerous minor histocompatibility Ag -- mild & suppressed by drugs B. Graft Rejection 1. Sensitization Stage : T-cells recognize alloAg on graft & proliferate ● Diff. pop. of cells within graft can function as APCs -- dendritic cells of graph (passenger leukocytes) ● Langerhans cells & endothelial cells of graft blood vessel - both types express MHC II ● APCs of host can migrate into graft (endocytose foregin Ag) & present to host T-cells 2. Effector Stage : C. Overcoming HVG 1. Privileged Sites (absence of lymphatic vessels) : cornea, brain (Parkinson’s), Islet cells + semipermeable membrane (diabetes) 2. Immunosuppression : short term, nonspecific: radiation, cytotoxic drugs, corticosteroids ● Cyclosporin A, FK506, rapamycin: fungal metabolites -specific suppressor of T-cell response ● Specific: monoclonal Abs against cell surface molecules ● Okt-4,8 (ortho kang T-cell) - blocks T-cell response D. Cancer ● Chemical, physical, viruses, mutations 43 → Immune Surveillance Theory = malignant tumors arise only if immune system is impaired/tumor cells lose immunogenicity - Poissily carried out by NK cells, CTL, & macrophages a) Immunotherapy = treatment of disease by activating/suppressing immune system Chemotherapies = blocks DNA Hormonal Therapies = syn. & cell division interfere w/ tumor-cell growth ○ Targeted Therapy = small inhibitors of cancer Immunotherapies = induces/enhance antitumor immune response Monoclonal Ab can be targeted to tumor cells Successes: i. Treatment of terminal B-cell lymphoma w/ anti-idiotype mAb ii. mAb against CD20 B-cell maker (Rituximab) for non-Hodgkin’s lymphoma iii. Imunotoxins coupling toxic molecules w/ mAb iv. mAb against HER2 receptor in breast cancer b) Anticancer Immunotherapy ● Cytokines: IFNα, β ,γ , IL-1, IL-2, IL-4, IL-5, IL-12, GM-CSF, TNF (a) Lymphokine-Activated Killer (LAC) T-cells : incubate T w/ x-irradiated tumor + IL-2 & inject back w/ IL-2 ○ Side Effects: Vascular leak syndrome = emigration of leukocyte & plasma from blood (b) Tumor-Infiltrating Lymphocytes (TIL) : remove tumor w/ T-cells ○ Culture 4-6 weeks w/ IL-2 proliferation ○ Back to patient w/ IL-2 Magic Bullet : treatment for syphilis 2. Vaccine 44 VII. Immunization; Autoimmunity; AIDS A. Passive Immunization = treatment that provides immunity through transfer of Ab obtained from immune individual - Naturally by transfer of maternal Ab across placenta to protect fetus - Fast, but temporary protection (can induce hypersensitivity III response) B. Active Immunization = induction of immunity after exposure to Ag - Attenuated (live): Tb - BCG; measles, mumps, polio -sabin, chickenpox, yellow fever - Inactivated (dead): cholera, plague, flu, polio-salk, rubella - Pureed Ag: diphtheria, tetanus, strep, Hep B 45 C. HIV - 2 RNA strands - ~9,200 bp HIV reverse transcriptase - not accurate: 1 mutation in 2,000 nt - drug resistance (azt) Vaccine resistant! Integrase not activated in inactive T-cells - cyclosporine? Unintegrated HIV DNA - unstable After integration - provirus => permanent infection HIV provirus latent will pass daughter ells, but not expressed unless activated Protease = enzyme breaks down protein & peptides Fusion protein - gp120 (gp41) Gp41-120 may detach & bind to healthy T h -- destroyed by T c Secretes cytokines (TNF) & trigger apoptosis of other cells (dementia)