PENYAKIT YANG BERKAITAN DENGAN SITOKIN DAN APLIKASI TERAPINYA
PENYAKIT YANG BERKAITAN DENGAN SITOKIN DAN APLIKASI TERAPINYA
Interleukins (IL) adalah sekelompok sitokin (protein yang disekresikan dan molekul sinyal) yang pertama kali diekspresikan oleh sel darah putih (leukosit). IL dapat dibagi menjadi empat kelompok besar berdasarkan fitur struktural yang membedakan. Namun, kesamaan urutan asam amino mereka agak lemah (biasanya 15-25% identitas). Genom manusia menyandi lebih dari 50 interleukin dan protein terkait.
Fungsi sistem kekebalan tubuh sebagian besar tergantung pada interleukin, dan kekurangan yang jarang dari beberapa dari mereka telah dijelaskan, semuanya menampilkan penyakit autoimun atau defisiensi imun. Mayoritas interleukin disintesis oleh helper limfosit T CD4, juga melalui monosit, makrofag, dan sel endotel. Mereka mempromosikan pengembangan dan diferensiasi limfosit T dan B, dan sel hematopoietik.
Reseptor interleukin pada astrosit di hippocampus juga diketahui terlibat dalam pengembangan memori spasial pada tikus.
Nama “interleukin” dipilih pada tahun 1979, untuk menggantikan berbagai nama yang berbeda yang digunakan oleh kelompok penelitian yang berbeda untuk menunjuk interleukin 1 (faktor pengaktif limfosit, protein mitogenik, faktor penggantian sel-T III, faktor pengaktifan sel-B, diferensiasi sel-B, diferensiasi sel-B faktor, dan “Heidikine”) dan interleukin 2 (TSF, dll.). Keputusan ini diambil selama Lokakarya Limfokin Internasional Kedua di Swiss (27-31 Mei 1979 di Ermatingen).
Istilah interleukin berasal dari (inter-) “sebagai sarana komunikasi”, dan (-leukin) “berasal dari kenyataan bahwa banyak dari protein ini diproduksi oleh leukosit dan bertindak atas leukosit”. Namanya adalah benda peninggalan; Sejak itu telah ditemukan bahwa interleukin diproduksi oleh berbagai macam sel tubuh. Istilah ini diciptakan oleh Dr Vern Paetkau, Universitas Victoria.
Beberapa interleukin diklasifikasikan sebagai limfokin, sitokin yang diproduksi limfosit yang memediasi respons imun.
Terapi
| Sitokin | Penyakit Terkait | Aplikasi terapi |
|---|---|---|
| IL-1α and IL-1β | Rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, psoriasis, inflammatory bowel disease, Graves disease, diabetes, cryopyrin-associated periodic syndromes, cancer, bacterial and viral infections, atopic dermatitis, asthma, osteoarthritis, chronic obstructive pulmonary disease, Alzheimer disease, atherosclerosis, myocardial infarction | Terapi: Cryopyrin-associated periodic syndromes, gout
Drugs: Human mAbs targeting only IL-1β (ILARIS/canakinumab), dimeric fusion protein consisting of human IL-1R (IL-1R1) and IL-1 receptor accessory protein (IL-1RAcP) linked with Fc region of human IgG1 that neutralizes IL-1 (IL-1 Trap/rilonacept) Clinical trials: Adult-onset Still disease, systemic juvenile idiopathic arthritis, Schnitzler syndrome, osteoarthritis, hereditary periodic fevers, atrial fibrillation, HIV, cardiovascular disease (see also IL-1Ra) |
| IL-1Ra (antagonist) | Rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, psoriasis, juvenile idiopathic arthritis, Still disease, type 1 diabetes, inflammatory bowel disease, atopic dermatitis, asthma | Rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, psoriasis, juvenile idiopathic arthritis, Still disease, type 1 diabetes, inflammatory bowel disease, atopic dermatitis, asthma |
| IL-2 | T cell–mediated autoimmune and inflammatory diseases, X-Linked severe combined immunodeficiency 1 | Terapi: Cancer, leukemia, and infectious diseases; use in bone marrow transplantation and to prevent kidney transplantation rejection
Obat: Recombinant human IL-2 (Proleukin, Interking), recombinant protein combining IL-2 and diphtheria toxin (Denileukin Diftitox), humanized IL-2Rα chain blocking mAbs (daclizumab, basiliximab) Clinical trials: Cancer, chronic graft-versus-host disease, multiple sclerosis, type I diabetes, thrombocytopenia, ulcerative colitis, Sjögren syndrome, different autoimmune and inflammatory diseases |
| IL-3 | Allergic asthma, cancer, lymphocytic and acute myeloid leukemias, inflammatory arthritis | Obat: atalytic and translocation domains of diphtheria toxin (DT388) linked to IL-3 (DT388Il3), recombinant human IL-3 (IL-3)
Clinical trials: Breast neoplasms, leukemia, myelodysplastic syndromes, blastic plasmacytoid DC neoplasm, HIV infections; cytopenias |
| IL-4 | Allergic asthma, allergic rhinitis, diabetes mellitus, parasite infection, chronic lymphocytic leukemia | Terapi: Asthma
Drugs: Soluble recombinant human IL-4 receptor (pitrakinra), humanized blocking mAbs specific for IL-4 (pascolizumab) Clinical trials: tuberculosis |
| IL-5 | Asthma, atopic dermatitis, chronic obstructive pulmonary disease, eosinophilic gastrointestinal diseases, hypereosinophilic syndrome, Churg-Strauss syndrome and eosinophilic nasal polyposis | Terapi: Asma
Obat-obatan: Human blocking mAbs khusus untuk IL-5 (mepolizumab), mAbs yang menargetkan reseptor IL-5 (MEDI-563 / benralizumab), mAb yang dimanusiakan (reslizumab) Uji klinis: sindrom Hypereosinophilic, COPD, dermatitis atopik, asma |
| IL-6 | Systemic lupus erythematosus, psoriasis, rheumatoid arthritis, juvenile idiopathic arthritis, B-cell malignancy, Castleman disease, pulmonary fibrosis, chronic inflammatory diseases, plasmacytoma/multiple myeloma, cardiac myxoma, asthma | Terapi: Rheumatoid arthritis, systemic juvenile idiopathic arthritis, Castleman disease
Drugs: Humanized mAbs targeting IL-6R (Actemra/tocilizumab) Clinical trials: Acute graft-versus-host disease, type 1 diabetes mellitus, dermatomyositis, schizophrenia, sclerosis, hemophagocytic lymphohistiocytosis, myocardial infarction, diabetic macular edema, arthritis, cardiovascular disease, primary Sjögren syndrome, leukemia |
| IL-7 | Multiple sclerosis, type 1 diabetes, rheumatoid arthritis, primary biliary cirrhosis, inflammatory bowel disease, atopic dermatitis, inhalation allergy, sarcoidosis, graft-versus-host disease | Drugs: Human recombinant IL-7 (CYT107)
Clinical trials: Cancer treatment, improving recovery after allogeneic stem cell transplantation, HIV therapy, sepsis, lymphopenia, cancer |
| IL-8 | Rheumatoid arthritis, psoriasis, bacterial and viral infections, chronic obstructive pulmonary disease, cystic fibrosis; cancer, acute myeloid leukemia, myelodysplastic syndromes, HIV infection | Drugs: Full human mAbs targeting IL-8 (HuMax-IL-8, ABX-IL-8)
Clinical trials: Pustulosis palmoplantaris, cancer, chronic bronchitis and COPD |
| IL-9 | Helminth infections, Hodgkin lymphoma, asthma and food allergy | Drug: Humanized mAbs specific for IL-9 (MEDI-528)
Tested in clinical trials: Asthma treatment |
| IL-10 | Systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus, inflammatory bowel disease, allergic asthma, allergic rhinitis, atopic dermatitis, bee venom allergy, contact dermatitis, cancer | Drugs: Human recombinant IL-10 (Tenovil), fusion protein consisting of targeting antibody and IL-10 (Dekavil/F8-IL-10)
Clinical trials: Rheumatoid arthritis |
| IL-11 | Allergic asthma and cancer | Drugs: Recombinant human IL-11 (oprelvekin)
Clinical trials: Chemotherapy-induced thrombocytopenia, leukemia, hemostatic disorders |
| IL-12 (p35/p40) | Bacterial infections, inflammatory bowel disease, psoriasis, cancer | Pengobatan: Artritis psoriatik dan psoriasis plak parah
Obat yang disetujui: Anti-IL-12/23 manusia IgG1 mAbs (ustekinumab), IL-12 manusia rekombinan (NM-IL-12) Uji klinis: Limfoma, infeksi luka, kanker, leukemia, HIV, penyakit menular, sklerosis multipel, penyakit Behçet, sindrom radiasi akut, CVID |
| IL-13 | Asthma, allergic rhinitis, and fibrosis | Drugs: Humanized mAbs specific for IL-13 (lebrikizumab), soluble IL-13Rα2–Fc fusion protein (QAX576, IMA638), human anti–IL-13 mAbs (tralokinumab)
Clinical trials: Asthma, atopic dermatitis, idiopathic pulmonary fibrosis, COPD |
| IL-14 | Systemic lupus erythematosus, Sjögren syndrome, lymphoma | |
| IL-15 | Rheumatoid arthritis, psoriasis, diabetes mellitus, autoimmune vasculitis, systemic lupus erythematosus, pemphigus vulgaris, multiple sclerosis, celiac disease, Behçet disease, asthma, sarcoidosis, inflammatory bowel diseases, inflammatory synovitis | Drugs: Recombinant human IL-15 (rhIL-15), fusion protein IL-15N72D:IL-15RαSu/Fc (ALT-803), human mAbs against IL-15 (AMG-714)
Clinical trials: AML, cancer, HIV infection (as adjuvant), cancer, rheumatoid arthritis, celiac disease |
| IL-16 | Atopic dermatitis, allergic asthma, Crohn disease, rheumatoid arthritis, HCV, tuberculosis, HIV, multiple sclerosis, cancer, multiple myeloma | |
| IL-17A | Rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, psoriasis, allergic asthma, atopic dermatitis, contact hypersensitivity, graft-versus-host-disease | Treatment: Severe plaque psoriasis
Drugs: Human mAb binding to IL-17A (secukinumab/AIN457) Clinical trials: Psoriatic arthritis, rheumatoid arthritis, nail psoriasis, ankylosing spondylitis, chronic plaque-type psoriasis |
| IL-17B, C, D | Rheumatoid arthritis, allergic asthma, inflammatory cardiomyopathy, Wegener granuloma, multiple sclerosis, psoriasis | |
| IL-17F | Inflammatory bowel disease, psoriasis, allergic asthma, rheumatoid arthritis, Crohn disease | |
| IL-18 | Bacterial and viral infections, rheumatoid arthritis, psoriasis, multiple sclerosis, type I diabetes, Crohn disease, Alzheimer disease, allergic rhinitis, atopic dermatitis, asthma | Drugs: Recombinant human IL-18 (SB-485232, Tadekinig alfa)
Clinical trials: Cancer and lymphoma (in combination with other therapies), psoriasis, Still disease |
| IL-19 | Psoriasis, asthma, atopic dermatitis, arthritis, cancer | |
| IL-20 | Psoriasis, rheumatoid arthritis, obesity, atherosclerosis, ulcerative colitis, asthma, cancer, osteoporosis | |
| IL-21 | Cancer, systemic lupus erythematous, rheumatoid arthritis, EAE, Behçet disease | Drugs: Recombinant human IL-21 (Denenicokin/BMS-982470), IL-21–specific mAbs (NNC0114-0006)
Clinical trials: Cancer, lymphoma, leukemia, rheumatoid arthritis, diabetes mellitus (type 1), Crohn disease |
| IL-22 | Psoriasis, inflammatory bowel disease, cancer | Drugs: Recombinant protein containing a human IL-22 dimer (F652), human mAbs specific for IL-22 (fezakinumab/ILV-094)
Clinical trials: Acute graft-versus-host disease, atopic dermatitis, rheumatoid arthritis, psoriasis |
| IL-23 (p19+p40) | Exacerbate organ-specific autoimmune inflammation, Crohn disease, and psoriasis | Drugs: Human mAbs directed against IL-12 and IL-23 (Ustekinumab), mAbs against IL-23 (LY 3074828, guselkumab, tildrakizumab)
Clinical trials: Systemic lupus erythematosus, graft-versus-host disease, axial spondyloarthritis psoriasis, colitis, Crohn disease, type 1 diabetes mellitus, dermatitis, Behçet disease, CVID, multiple sclerosis |
| IL-24 | Melanoma, psoriasis | |
| IL-25 (IL-17E) | Gastrointestinal disorders, chronic rhinosinusitis, atopic dermatitis, allergic asthma | |
| IL-26 | Inflammatory bowel disease | |
| IL-27 (p28+EBI3) | Immune pathology caused by uncontrolled inflammatory response, Crohn disease or ulcerative colitis, asthma, and HIV | |
| IL-28A/B/IL29 (IFN-λ family) | Allergy (IgE-mediated food allergy, atopic dermatitis) and atopic asthma, autoimmune diseases, HBV, HCV, and cancer | Drugs: Pegylated interferon Lambda-1a (pegIFNλ), pegylated recombinant IL-29 (PEG-rIL-29)
Clinical trials: Hepatitis C infection |
| IL-30 (p28 subunit of IL-27) | ||
| IL-31 | Atopic dermatitis, allergic contact dermatitis, prurigo nodularis, chronic spontaneous urticaria, nonatopic eczema, asthma, and other inflammatory disorders | Drugs: Anti–IL-31 mAbs (BMS-981164)
Tested in clinical trials: Atopic dermatitis |
| IL-32 | Autoimmune diseases, such as rheumatoid arthritis, inflammatory bowel disease, Crohn disease, chronic rhinosinusitis, atopic dermatitis, asthma, cancer | |
| IL-33 | Autoimmune and cardiovascular diseases, asthma, rheumatoid arthritis, gastrointestinal tract and lung disorders, parasite infections | |
| IL-34 | Synovitis, rheumatoid arthritis, Sjögren syndrome | |
| IL-35 (p35+EBI3) | Tumor pathogenesis, asthma, atopic dermatitis, allergic rhinitis and celiac disease | |
| IL-36 | Psoriasis, asthma | |
| IL-37 | Rheumatoid arthritis, systemic lupus erythematosus, atopic dermatitis | |
| IL-38 | Systemic lupus erythematosus | |
| IFN-α, IFN-β | Viral infections, systemic lupus erythematosus, polymyositis, rheumatoid arthritis, multiple sclerosis, asthma | IFN-α
Pengobatan: Leukemia sel berbulu, melanoma ganas, Kaposi sarkoma terkait AIDS, infeksi hepatitis C, sklerosis multipel, kutil kelamin, hepatitis C dengan koinfeksi HIV, hepatitis B, infeksi virus umum, leukemia myelogenous, limfoma sel T kulit, limfoma sel kulit, folikel non- Limfoma Hodgkin, karsinoma sel ginjal, Obat-obatan: IFN-α-con-1 (Infergen), leukosit IFN-α-n3 yang diturunkan (Alferon-N), IFN-α-2a (Pegasys) pegilasi, IFN-α-2a rekombinan (Roferon-A), IFN rekombinan -α-2b (Intron A), PEG IFN-α-2b rekombinan (Intron PEG) Uji klinis: infeksi HIV, polisitemia vera, trombositemia, leukemia, kelainan mieloproliferatif, karsinoma hepatoseluler, kanker, leukemia myeloid kronis, PPOK, diabetes mellitus tipe 1 IFN-β Pengobatan: Sindrom yang terisolasi secara klinis, relaps sklerosis multipel, sklerosis multipel dini / relaps Obat-obatan: IFN-β-1a (Avonex, Rebiferon), IFN-β-1b (Betasteron) Uji klinis: Kolitis ulserativa, asma, sindrom penyakit pernapasan, kanker, Infeksi HTLV-I |
| IFN-γ | Susceptibility to intracellular pathogen infection and tumor development, type 1 diabetes, rheumatoid arthritis, atopic dermatitis, EAE | Pengobatan: Penyakit granulomatosa kronis, osteoporosis, penyakit autoimun (penyakit Crohn)
Obat-obatan: Anti-IFN-γ mAbs yang dimanusiakan (fontolizumab), Bioengineered IFN-Bio1b (Actimmune) Percobaan klinis: infeksi HIV, ataksia Friedreich, glioblastoma, gliosarcoma, osteopetrosis dominan tipe 2, fibrosis paru, sepsis, uveitis, penyakit opthalmik bawaan, kanker |
| TGF-β | Alzheimer disease, cardiovascular pathologies, cancer, allergic rhinitis, fibrosis | Obat-obatan: Sintetis oligodeoxynucleotide (trabedersen / AP12009), mAb manusia terhadap TGF-β1, TGF-β2, dan TGF-β3 (fresolimumab / GC1008); garam asetat dari 14mer peptida dari reseptor TGF-β1 tipe III manusia (P144); Inhibitor TβR-I (Galunisertib / LY2157299)
Uji klinis: Anaplastik astrositoma, glioblastoma, neoplasma pankreas, melanoma, neoplasma kolorektal, astrositoma anaplastik, kanker payudara metastatik, sklerosis sistemik difus primer, glomerulosklerosis segmental fokal primer, kanker paru-paru sel non-sel kecil, tumor otak primer, dan fibrosis sel – kanker paru-paru sel kecil (berulang) |
| TNF-α | Psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile arthritis, ankylosing spondylitis, inflammatory bowel disease, Crohn disease, ulcerative colitis, systemic sclerosis, systemic lupus erythematosus, pulmonary diseases, allergic diseases (asthma, allergic rhinitis, and atopic dermatitis), insulin resistance, depression, cancer, vascular diseases, neurological diseases |
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