Modulation of CLA, IL-12R, CD40L, and IL-2Ralpha expression and inhibition of IL-12- and IL-23-induced cytokine secretion by CNTO 1275.
Cytokines interleukin (IL)-12 and IL-23 are implicated in the pathogenesis of psoriasis. IL-12 causes differentiation of CD4+ T cells to interferon-gamma (IFN-gamma)-producing T helper 1 (Th1) cells, while IL-23 induces differentiation to IL-17-producing pathogenic Th17 cells. The effects of the monoclonal antibody to IL-12/23 p40 subunit (CNTO 1275) on IL-12 receptor (IL-12R) expression, markers associated with skin homing, activation, and cytokine secretion were investigated in vitro using human peripheral blood mononuclear cells (PBMCs) from healthy donors. PBMCs were activated in the presence or absence of recombinant human (rh) IL-12 or rhIL-23, with or without CNTO 1275. CNTO 1275 inhibited upregulation of CLA, IL-12R, IL-2Ralpha and CD40L expression and also inhibited IL-12- and IL-23-induced IFN-gamma, IL-17A, tumor necrosis factor (TNF)-alpha, IL-2, and IL-10 secretion. Thus, the therapeutic effect of CNTO 1275 may be attributed to the IL-12/23 neutralization, resulting in decreased expression of skin homing and activation markers, and IL-12- and IL-23-induced cytokine secretion.
Reddy
Manjula
M
Department of Clinical Pharmacology and Experimental Medicine, Centocor, Inc., Malvern, PA, USA. MReddy@CNTUS.JNJ.COM
Davis
Cuc
C
Wong
Jackson
J
Marsters
Paul
P
Pendley
Charles
C
Prabhakar
Uma
U
D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D023201:CD40 Ligand / Q000187:drug effects / Q000378:metabolism*; D018929:Cell Culture Techniques; D016207:Cytokines / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D053711:Interleukin-12 Receptor beta 1 Subunit / Q000235:genetics / Q000378:metabolism; D053712:Interleukin-12 Receptor beta 2 Subunit / Q000235:genetics / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000187:drug effects / Q000378:metabolism*; D053707:Receptors, Interleukin-12 / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000069549:Ustekinumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000945:Antigens, Differentiation, T-Lymphocyte; D000951:Antigens, Neoplasm; C063419:CTAGE1 protein, human; D016207:Cytokines; D007155:Immunologic Factors; D053711:Interleukin-12 Receptor beta 1 Subunit; D053712:Interleukin-12 Receptor beta 2 Subunit; D053762:Interleukin-12 Subunit p40; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma; D000069549:Ustekinumab