title: Blockade of CD127 Exerts a Dichotomous Clinical Effect in Marmoset Experimental Autoimmune Encephalomyelitis.
abstract: Non-human primate models of human disease have an important role in the translation of a new scientific finding in lower species into an effective treatment. In this study, we tested a new therapeutic antibody against the IL-7 receptor α chain (CD127), which in a C57BL/6 mouse model of experimental autoimmune encephalomyelitis (EAE) ameliorates disease, demonstrating an important pathogenic function of IL-7. We observed that while the treatment was effective in 100 % of the mice, it was only partially effective in the EAE model in common marmosets (Callithrix jacchus), a small-bodied Neotropical primate. EAE was induced in seven female marmoset twins and treatment with the anti-CD127 mAb or PBS as control was started 21 days after immunization followed by weekly intravenous administration. The anti-CD127 mAb caused functional blockade of IL-7 signaling through its receptor as shown by reduced phosphorylation of STAT5 in lymphocytes upon stimulation with IL-7. Group-wise analysis showed no significant effects on the clinical course and neuropathology. However, paired twin analysis revealed a delayed disease onset in three twins, which were high responders to the immunization. In addition, we observed markedly opposite effects of the antibody on pathological changes in the spinal cord in high versus low responder twins. In conclusion, promising clinical effect of CD127 blockade observed in a standard inbred/SPF mouse EAE model could only be partially replicated in an outbred/non-SPF non-human primate EAE model. Only in high responders to the immunization we found a positive response to the treatment. The mechanism underpinning this dichotomous response will be discussed.
authors.affiliation: Department of Immunobiology, Biomedical Primate Research Centre, P.O. Box 3306, 2280, GH, Rijswijk, The Netherlands.|MS Centre Erasmus, Rotterdam, The Netherlands.|Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.|Department of Neuroscience, University Groningen, University Medical Center, Groningen, The Netherlands.
authors.forename: Jordon
authors.initials: J
authors.lastname: Dunham
authors.affiliation: Department of Experimental Medicine, Rinat, Pfizer Inc, South San Francisco, CA, USA.
authors.forename: Li-Fen
authors.initials: LF
authors.lastname: Lee
authors.affiliation: Department of Immunobiology, Biomedical Primate Research Centre, P.O. Box 3306, 2280, GH, Rijswijk, The Netherlands.
authors.forename: Nikki
authors.initials: N
authors.lastname: van Driel
authors.affiliation: Department of Neuroscience, University Groningen, University Medical Center, Groningen, The Netherlands.
authors.forename: Jon D
authors.initials: JD
authors.lastname: Laman
authors.affiliation: Department of Protein Engineering, Rinat, Pfizer Inc, South San Francisco, CA, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Ni
authors.affiliation: Department of Protein Engineering, Rinat, Pfizer Inc, South San Francisco, CA, USA.
authors.forename: Wenwu
authors.initials: W
authors.lastname: Zhai
authors.affiliation: Department of Experimental Medicine, Rinat, Pfizer Inc, South San Francisco, CA, USA.
authors.forename: Guang-Huan
authors.initials: GH
authors.lastname: Tu
authors.affiliation: Department of Experimental Medicine, Rinat, Pfizer Inc, South San Francisco, CA, USA.
authors.forename: John C
authors.initials: JC
authors.lastname: Lin
authors.affiliation: Center for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Jan
authors.initials: J
authors.lastname: Bauer
authors.affiliation: Department of Immunobiology, Biomedical Primate Research Centre, P.O. Box 3306, 2280, GH, Rijswijk, The Netherlands.|MS Centre Erasmus, Rotterdam, The Netherlands.|Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.|Department of Neuroscience, University Groningen, University Medical Center, Groningen, The Netherlands.
authors.forename: Bert A
authors.initials: BA
authors.lastname: 't Hart
authors.affiliation: Department of Immunobiology, Biomedical Primate Research Centre, P.O. Box 3306, 2280, GH, Rijswijk, The Netherlands. kap@bprc.nl.|MS Centre Erasmus, Rotterdam, The Netherlands. kap@bprc.nl.
authors.forename: Yolanda S
authors.initials: YS
authors.lastname: Kap
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002144:Callithrix; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology*; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D015851:Interleukin-7 / Q000276:immunology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000037:antagonists & inhibitors*; D016133:Polymerase Chain Reaction
chemical_list: D000911:Antibodies, Monoclonal; D015851:Interleukin-7; D053699:Interleukin-7 Receptor alpha Subunit
keywords: Autoimmunity; B cell; CD132; Common gamma chain; Immunotherapy; Lymphopoiesis; T cell