PENYAKIT YANG BERKAITAN DENGAN SITOKIN DAN APLIKASI TERAPINYA

wp-1558146855011..jpgPENYAKIT 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

PENYAKIT YANG BERKAITAN DENGAN SITOKIN DAN APLIKASI TERAPINYA

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 Terapi: Rheumatoid arthritis

Drugs: Recombinant nonglycosylated human IL-1Ra (anakinra)

Clinical trials: Type I diabetes, metabolic syndrome, hypersecretion, type 2 diabetes mellitus, HIV, neurologic disorders, heart failure, acute myocardial infarction, Kawasaki disease, cancer

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 Therapy: Asthma

Drugs: Humanized blocking mAbs specific for IL-5 (mepolizumab), mAbs targeting IL-5 receptor (MEDI-563/benralizumab), humanized mAbs (reslizumab)

Clinical trials: Hypereosinophilic syndrome, COPD, atopic dermatitis, asthma

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 Treatment: Psoriatic arthritis and severe plaque psoriasis

Approved drugs: Anti–IL-12/23 human IgG1 mAbs (ustekinumab), recombinant human IL-12 (NM-IL-12)

Clinical trials: Lymphoma, wound infection, cancer, leukemia, HIV, infectious disease, multiple sclerosis, Behçet disease, acute radiation syndrome, 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

  • Treatment: Hairy cell leukemia, malignant melanoma, AIDS-related Kaposi sarcoma, hepatitis C infections, multiple sclerosis, genital warts, hepatitis C with HIV coinfection, hepatitis B, general viral infections, myelogenous leukemia, cutaneous T-cell lymphoma, follicular non-Hodgkin lymphoma, renal cell carcinoma,

  • Drugs: IFN-α-con-1 (Infergen), IFN-α-n3 leukocyte derived (Alferon-N), Pegylated IFN-α-2a (Pegasys), Recombinant IFN-α-2a (Roferon-A), Recombinant IFN-α-2b (Intron A), PEG recombinant IFN-α-2b (PEG Intron)

  • Clinical trials: HIV infections, polycythemia vera, thrombocythemia, leukemia, myeloproliferative disorders, hepatocellular carcinoma, cancer, chronic myeloid leukemia, COPD, diabetes mellitus type 1

    IFN-β

  • Treatment: Clinically isolated syndrome, relapsing multiple sclerosis, early/relapsing multiple sclerosis

  • Drugs: IFN-β-1a (Avonex, Rebiferon), IFN-β-1b (Betasteron)

  • Clinical trials: Ulcerative colitis, asthma, respiratory disease syndrome, cancer, HTLV-I Infection

IFN-γ Susceptibility to intracellular pathogen infection and tumor development, type 1 diabetes, rheumatoid arthritis, atopic dermatitis, EAE Treatment: Chronic granulomatous disease, osteoporosis, autoimmune diseases (Crohn disease)

Drugs: Humanized anti–IFN-γ mAbs (fontolizumab), Bioengineered IFN-γ1b (Actimmune)

Clinical trials: HIV infection, Friedreich ataxia, glioblastoma, gliosarcoma, autosomal dominant osteopetrosis type 2, pulmonary fibrosis, sepsis, uveitis, inherited ophthalmic diseases, cancer

TGF-β Alzheimer disease, cardiovascular pathologies, cancer, allergic rhinitis, fibrosis Drugs: Synthetic antisense oligodeoxynucleotide (trabedersen/AP12009), human mAbs against TGF-β1, TGF-β2, and TGF-β3 (fresolimumab/GC1008); acetic salt of a 14mer peptide from human TGF-β1 type III receptor (P144); TβR-I inhibitor (Galunisertib/LY2157299)

Clinical trials: Anaplastic astrocytoma, glioblastoma, pancreatic neoplasms, melanoma, colorectal neoplasms, anaplastic astrocytoma, metastatic breast cancer, diffuse systemic sclerosis, primary focal segmental glomerulosclerosis, non–small cell lung cancer, primary brain tumors, skin fibrosis, hepatocellular carcinoma and non–small cell lung cancer (recurrent)

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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