title: Effect of DAB(389)IL-2 immunotoxin on the course of experimental autoimmune encephalomyelitis in Lewis rats.
abstract: Activated T cells express the high affinity interleukin 2 receptor (IL-2R also CD25) that binds interleukin 2 (IL-2) and transduces signals important for the proliferation and survival of these cells. We investigated the effect of the genetically engineered immunotoxin DAB(389)IL-2 on experimental autoimmune encephalomyelitis (EAE), an autoimmune disease of the central nervous system (CNS) mediated by activated myelin-reactive T cells. EAE is the most commonly used animal model of the human disease multiple sclerosis (MS). DAB(389)IL-2 is a recombinant fusion product made of a portion of diphtheria toxin, which contains binding and translocation components of the toxin linked to IL-2. The diphtheria toxin targets and kills cells expressing the high affinity IL-2 receptor and has been successfully used in several autoimmune and neoplastic conditions. We observed a significant suppression of guinea-pig spinal cord homogenate (gpSCH)-MBP induced active EAE in Lewis rats at 2 x 1,600 kU of DAB(389)IL-2 given on days 7 and 9 post-immunization and complete suppression with the same dose on days 7, 8 and 9 or 7, 8, 9 and 10 after immunization during the active disease period. There were reduced mononuclear cell infiltrates of CD4(+), CD8(+), CD25(+) and alphabetaTCR(+) T cells in the spinal cord of treated rats. However, treatment at day 11 or 12 post-immunization led to severe, fatal disease. The toxin added to cultures in vitro or injected in vivo suppressed antigen- and mitogen-induced T cell proliferation. DAB(389)IL-2 treatment in vivo or exposure of encephalitogenic T cells in vitro prior to transfer did have a significant inhibitory effect on adoptive transfer EAE. Our data demonstrate that DAB(389)IL-2 immunotoxin can suppress active and passive EAE if applied at specific, early time points, but can have negative consequences at later time points.
authors.affiliation: Department of Allergy and Immunology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: S Michael
authors.initials: SM
authors.lastname: Phillips
authors.forename: Mahendra K
authors.initials: MK
authors.lastname: Bhopale
authors.forename: Cris S
authors.initials: CS
authors.lastname: Constantinescu
authors.forename: Bogoljub
authors.initials: B
authors.lastname: Ciric
authors.forename: Brendan
authors.initials: B
authors.lastname: Hilliard
authors.forename: Elvira
authors.initials: E
authors.lastname: Ventura
authors.forename: Ehud
authors.initials: E
authors.lastname: Lavi
authors.forename: Abdolmohamad
authors.initials: A
authors.lastname: Rostami
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004167:Diphtheria Toxin / Q000235:genetics / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology*; D005260:Female; D006168:Guinea Pigs; D000922:Immunotoxins / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000235:genetics / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D009154:Mutation / Q000502:physiology; D004676:Myelin Basic Protein; D051381:Rats; D011917:Rats, Inbred Lew; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000627:therapeutic use; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects; D013997:Time Factors
chemical_list: D015703:Antigens, CD; D004167:Diphtheria Toxin; D000922:Immunotoxins; D007376:Interleukin-2; D004676:Myelin Basic Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox