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Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia

Ponchel, F., Verburg, R.J., Bingham, S.J., Brown, A.K., Moore, J., Protheroe, A., Short, K., Lawson, C.A., Morgan, A.W., Quinn, M., Buch, M., Field, S.L., Maltby, S.L., Masurel, A., Douglas, S.H., Straszynski, L., Fearon, U., Veale, D.J., Patel, P., McGonagle, D., Snowden, J., Markham, A.F., Ma, D., van Laar, J.M., Papadaki, H.A., Emery, P. and Isaacs, J.D. (2004) Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia. Arthritis Research and Therapy, 7 (1). R80-R92. ISSN 1478-6362

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Abstract

We previously demonstrated prolonged, profound CD4+ T-lymphopenia in rheumatoid arthritis (RA) patients following lymphocyte-depleting therapy. Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells. Interleukin-7 (IL-7) is known to stimulate the thymus to produce new T-cells and to allow circulating mature T-cells to expand, thereby playing a critical role in T-cell homeostasis. In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients. IL-7 production by bone marrow stromal cell cultures was also compromised in RA. To investigate whether such an IL-7 deficiency could account for the prolonged lymphopenia observed in RA following therapeutic lymphodepletion, we compared RA patients and patients with solid cancers treated with high-dose chemotherapy and autologous progenitor cell rescue. Chemotherapy rendered all patients similarly lymphopenic, but this was sustained in RA patients at 12 months, as compared with the reconstitution that occurred in cancer patients by 3–4 months. Both cohorts produced naïve T-cells containing T-cell receptor excision circles. The main distinguishing feature between the groups was a failure to expand peripheral T-cells in RA, particularly memory cells during the first 3 months after treatment. Most importantly, there was no increase in serum IL-7 levels in RA, as compared with a fourfold rise in non-RA control individuals at the time of lymphopenia. Our data therefore suggest that RA patients are relatively IL-7 deficient and that this deficiency is likely to be an important contributing factor to poor early T-cell reconstitution in RA following therapeutic lymphodepletion. Furthermore, in RA patients with stable, well controlled disease, IL-7 levels were positively correlated with the T-cell receptor excision circle content of CD4+ T-cells, demonstrating a direct effect of IL-7 on thymic activity in this cohort.

Item Type: Article
Copyright, Publisher and Additional Information: © 2004 Ponchel et al., licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is cited.
Keywords: immune reconstitution, interleukin-7, T-cell differentiation, therapeutic lymphodepletion
Institution: The University of Leeds
Academic Units: The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Musculoskeletal Disease (Leeds)
The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Genetics (Leeds)
Depositing User: Repository Officer
Date Deposited: 13 Mar 2006
Last Modified: 05 Jun 2014 08:24
Published Version: http://arthritis-research.com/content/7/1/R80
Status: Published
Refereed: Yes
Identification Number: 10.1186/ar1452
URI: http://eprints.whiterose.ac.uk/id/eprint/1056

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