• 1
    Wilks AF. The JAK kinases: not just another kinase drug discovery target. Semin Cell Dev Biol 2008; 19: 31928.
  • 2
    Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, et al. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 1995; 377: 658.
  • 3
    Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ, et al. Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 1995; 270: 797800.
  • 4
    Kawamura M, McVicar MD, Johnston JA, Blake TB, Chen YQ, Lal BK, et al. Molecular cloning of L-JAK, a Janus family protein-tyrosine kinase expressed in natural killer cells and activated leukocytes. Proc Natl Acad Sci U S A 1994; 91: 63748.
  • 5
    Lai KS, Jin Y, Graham DK, Witthuhn BA, Ihle JN, Liu ET. A kinase-deficient splice variant of the human JAK3 is expressed in hematopoietic and epithelial cancer cells. J Biol Chem 1995; 270: 2502836.
  • 6
    Malaviya R, Uckun FM. Genetic and biochemical evidence for a critical role of Janus kinase (JAK)-3 in mast cell-mediated type I hypersensitivity reactions. Biochem Biophys Res Commun 1999; 257: 80713.
  • 7
    Roberts JL, Lengi A, Brown SM, Chen M, Zhou YJ, O'Shea JJ, et al. Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. Blood 2004; 103: 200918.
  • 8
    Neubauer H, Cumano A, Muller M, Wu H, Huffstadt U, Pfeffer K. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Cell 1998; 93: 397409.
  • 9
    Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, et al. Jak2 is essential for signaling through a variety of cytokine receptors. Cell 1998; 93: 38595.
  • 10
    Brennan FM, McInnes IB. Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 2008; 118: 353745.
  • 11
    Annunziato F, Cosmi L, Liotta F, Maggi E, Romagnani S. Type 17 T helper cells: origins, features and possible roles in rheumatic disease. Nat Rev Rheumatol 2009; 5: 32531.
  • 12
    Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum 2009; 60: 1895905.
  • 13
    Boy MG, Wang C, Wilkinson BE, Chow VF, Clucas AT, Krueger JG, et al. Double-blind, placebo-controlled, dose-escalation study to evaluate the pharmacologic effect of CP-690,550 in patients with psoriasis. J Invest Dermatol 2009; 129: 2299302.
  • 14
    Van Gurp E, Weimar W, Gaston R, Brennan D, Mendez R, Pirsch J, et al. Phase 1 dose-escalation study of CP-690,550 in stable renal allograft recipients: preliminary findings of safety, tolerability, effects on lymphocyte subsets and pharmacokinetics. Am J Transplant 2008; 8: 17118.
  • 15
    Changelian PS, Flanagan ME, Ball DJ, Kent CR, Magnuson KS, Martin WH, et al. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Science 2003; 302: 8758.
  • 16
    Jiang JK, Ghoreschi K, Deflorian F, Chen Z, Perreira M, Pesu M, et al. Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550). J Med Chem 2008; 51: 80128.
  • 17
    Kingsbury C, Ohlmeyer M, Paradkar VM, Park H, Quintero J, Shao Y. Preparation of 2,7,9-substituted purinone derivatives as selective Jak3 inhibitors useful for immunosuppression. PCT Int Appl 2009; Kingsbury C, Ohlmeyer M, Paradkar VM, Park H, Quintero J, Shao Y. WO 2009048474. URL:
  • 18
    Lin TH, Metzger A, Diller DJ, Desai M, Henderson I, Ahmed G, et al. Discovery and characterization of triaminotriazine aniline amides as highly selective p38 kinase inhibitors. J Pharmacol Exp Ther 2006; 318: 495502.
  • 19
    Ma HL, Liang S, Li J, Napierata L, Brown T, Benoit S, et al. IL-22 is required for Th17 cell-mediated pathology in a mouse model of psoriasis-like skin inflammation. J Clin Invest 2008; 118: 597607.
  • 20
    Li J, Tomkinson KN, Tan XY, Wu P, Yan G, Spaulding V, et al. Temporal associations between interleukin 22 and the extracellular domains of IL-22R and IL-10R2. Int Immunopharmacol 2004; 4: 693708.
  • 21
    Young DA, Hegen M, Ma HL, Whitters MJ, Albert LM, Lowe L, et al. Blockade of the interleukin-21/interleukin-21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis. Arthritis Rheum 2007; 56: 115263.
  • 22
    McKew JC, Lee KL, Shen MW, Thakker P, Foley MA, Behnke ML, et al. Indole cytosolic phospholipase A2 α inhibitors: discovery and in vitro and in vivo characterization of 4-{3-[5-chloro-2-(2-{[(3,4-dichlorobenzyl)sulfonyl]amino}ethyl)-1-(diphenylmethyl)- 1H-indol-3-yl]propyl}benzoic acid, efipladib. J Med Chem 2008; 51: 3388413.
  • 23
    Waldman TA. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nature Rev Immunol 2006; 6: 595601.
  • 24
    Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ, et al. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science 1994; 266: 10457.
  • 25
    Konforte D, Paige CJ. Identification of cellular intermediates and molecular pathways induced by IL-21 in human B cells. J Immunol 2006; 177: 838192.
  • 26
    De Groot RP, Coffer PJ, Koenderman L. Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family. Cell Signal 1998; 10: 61928.
  • 27
    Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 1998; 334: 297314.
  • 28
    Thornton S, Kuhn KA, Finkelman FD, Hirsch R. NK cells secrete high levels of IFN-γ in response to in vivo administration of IL-2. Eur J Immunol 2001; 31: 335560.
  • 29
    Lejeune D, Dumoutier L, Constantinescu S, Kruijer W, Schuringa JJ, Renauld JC. Interleukin-22 (IL-22) activated the JAK/Stat, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line. J Biol Chem 2002; 277: 3367682.
  • 30
    Dumoutier L, Van Roost E, Colau D, Renauld JC. Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor. Proc Natl Acad Sci U S A 2000; 97: 101449.
  • 31
    Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. IL-22 increases the innate immunity of tissues. Immunity 2004; 21: 24154.
  • 32
    Ramos AS, Schmidt CA, Andrade SS, Fronza M, Rafferty B, Dalmora SL. Biological evaluation of recombinant human erythropoietin in pharmaceutical products. Braz J Med Biol Res 2003; 36: 15619.
  • 33
    Ranson T, Vosshenrich CA, Corcuff E, Richard O, Mueller W, Di Santo JP. IL-15 is an essential mediator of peripheral NK-cell homeostasis. Blood 2003; 101: 488793.
  • 34
    Milici AJ, Kudlacz EM, Audoly L, Zwillich S, Changelian P. Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arthritis Res Ther 2008; 10: R14.
  • 35
    Yabu JM, Vincenti F. Novel immunosuppression: small molecules and biologics. Semin Nephrol 2007; 27: 47986.
  • 36
    Walker JG, Ahern MJ, Coleman M, Weedon H, Papangelis V, Beroukas D, et al. Changes in synovial tissue Jak-STAT expression in rheumatoid arthritis in response to successful DMARD treatment. Ann Rheum Dis 2006; 65: 155864.
  • 37
    Williams NK, Bamert RS, Patel O, Wang C, Walden PM, Wilks AF, et al. Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J Mol Biol 2009; 387: 21932.
  • 38
    O'Sullivan LA, Liongue C, Lewis RS, Stephenson SE, Ward AC. Cytokine receptor signaling through the Jak-Stat-Socs pathway in disease. Mol Immunol 2007; 44: 2497506.
  • 39
    Maini RN, Taylor PC, Szechinski J, Pavelka K, Broll J, Balint G, et al, for the CHARISMA Study Group. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006; 54: 281729.
  • 40
    Takagi N, Mihara M, Moriya Y, Nishimoto N, Yoshizaki K, Kishimoto T, et al. Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis. Arthritis Rheum 1998; 41: 211721.
  • 41
    Nakahara H, Nishimoto N. Anti-interleukin-6 receptor antibody therapy in rheumatic diseases. Endocr Metab Immune Disord Drug Targets 2006; 6: 37381.