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Journal of Neuroimmune Pharmacology

, Volume 11, Issue 1, pp 73–83 | Cite as

Blockade of CD127 Exerts a Dichotomous Clinical Effect in Marmoset Experimental Autoimmune Encephalomyelitis

  • Jordon Dunham
  • Li-Fen Lee
  • Nikki van Driel
  • Jon D. Laman
  • Irene Ni
  • Wenwu Zhai
  • Guang-Huan Tu
  • John C. Lin
  • Jan Bauer
  • Bert A. ‘t Hart
  • Yolanda S. KapEmail author
ORIGINAL ARTICLE

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.

Keywords

Lymphopoiesis Autoimmunity Immunotherapy T cell B cell CD132 Common gamma chain 

Abbreviations

ABL

Abelson

ALN

Axillary lymph node

CLN

Cervical lymph node

CNS

Central nervous system

cpm

Counts per minute

EAE

Experimental autoimmune encephalomyelitis

IFA

Incomplete freunds adjuvant

ILN

Inguinal lymph node

LLN

Lumbar lymph nodes

MNC

Mononuclear cells

MS

Multiple sclerosis

PBMC

Peripheral blood mononuclear cells

PD1

Programmed death receptor 1

PLP

Proteolipid protein

rhMOG

Recombinant human myelin oligodendrocyte glycoprotein

SLO

Secondary lymphoid organ

SPF

Specific-pathogen free

Notes

Acknowledgments

The authors like to thank Henk van Westbroek (BPRC) for the artwork and Dr. Ed Remarque (BPRC) for statistical advice. Jordon Dunham was funded by the European Union with a Marie Curie Fellowship (ITN NeuroKine; 316722), and the authors are grateful for this support.

Conflict of Interest

Li-Fen Li, Irene Ni, Wenwu Zhai, Guang-Huan Tu and John Lin were full-time employees of Rinat-Pfizer when the study was performed. The other authors report no conflict of interest. Publication of the data, irrespective of outcome, was part of the contractual agreement between Rinat-Pfizer and the BPRC as an independent research center.

Author Contributions

J.D., N.v.D. and Y.K have designed the study and performed the in vivo study as well as the ex vivo experiments and analyses. JB has performed the histology. J.D., J.D.L., B.t.H., and Y.K. have written the paper. B.t.H. and J.D.L. have supervised the in vivo study. L.L., G.T. and J.C.L. designed and performed the in vitro assays of the therapeutic antibodies. I.N. and W.Z. screened, cloned and generated the therapeutic antibodies.

Supplementary material

11481_2015_9629_MOESM1_ESM.pdf (103 kb)
Supplemental figure 1 (PDF 103 kb)
11481_2015_9629_MOESM2_ESM.pdf (118 kb)
Supplemental figure 2 (PDF 118 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Jordon Dunham
    • 1
    • 2
    • 3
    • 4
  • Li-Fen Lee
    • 5
  • Nikki van Driel
    • 1
  • Jon D. Laman
    • 4
  • Irene Ni
    • 6
  • Wenwu Zhai
    • 6
  • Guang-Huan Tu
    • 5
  • John C. Lin
    • 5
  • Jan Bauer
    • 7
  • Bert A. ‘t Hart
    • 1
    • 2
    • 3
    • 4
  • Yolanda S. Kap
    • 1
    • 2
    Email author
  1. 1.Department of ImmunobiologyBiomedical Primate Research CentreRijswijkThe Netherlands
  2. 2.MS Centre ErasmusRotterdamThe Netherlands
  3. 3.Department of Immunology, Erasmus MCUniversity Medical CenterRotterdamThe Netherlands
  4. 4.Department of NeuroscienceUniversity Groningen, University Medical CenterGroningenThe Netherlands
  5. 5.Department of Experimental MedicineRinat, Pfizer IncSouth San FranciscoUSA
  6. 6.Department of Protein EngineeringRinat, Pfizer IncSouth San FranciscoUSA
  7. 7.Center for Brain ResearchMedical University of ViennaViennaAustria

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