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

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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.

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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

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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.

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Authors and Affiliations

  1. Department of Immunobiology, Biomedical Primate Research Centre, P.O. Box 3306, 2280, GH, Rijswijk, The Netherlands

    Jordon Dunham, Nikki van Driel, Bert A. ‘t Hart & Yolanda S. Kap

  2. MS Centre Erasmus, Rotterdam, The Netherlands

    Jordon Dunham, Bert A. ‘t Hart & Yolanda S. Kap

  3. Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    Jordon Dunham & Bert A. ‘t Hart

  4. Department of Neuroscience, University Groningen, University Medical Center, Groningen, The Netherlands

    Jordon Dunham, Jon D. Laman & Bert A. ‘t Hart

  5. Department of Experimental Medicine, Rinat, Pfizer Inc, South San Francisco, CA, USA

    Li-Fen Lee, Guang-Huan Tu & John C. Lin

  6. Department of Protein Engineering, Rinat, Pfizer Inc, South San Francisco, CA, USA

    Irene Ni & Wenwu Zhai

  7. Center for Brain Research, Medical University of Vienna, Vienna, Austria

    Jan Bauer

Authors
  1. Jordon Dunham
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  2. Li-Fen Lee
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  3. Nikki van Driel
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  4. Jon D. Laman
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  5. Irene Ni
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  7. Guang-Huan Tu
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  8. John C. Lin
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  9. Jan Bauer
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  10. Bert A. ‘t Hart
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  11. Yolanda S. Kap
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Corresponding author

Correspondence to Yolanda S. Kap.

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Dunham, J., Lee, LF., van Driel, N. et al. Blockade of CD127 Exerts a Dichotomous Clinical Effect in Marmoset Experimental Autoimmune Encephalomyelitis. J Neuroimmune Pharmacol 11, 73–83 (2016). https://doi.org/10.1007/s11481-015-9629-6

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  • DOI: https://doi.org/10.1007/s11481-015-9629-6

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