title: Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia.
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 naive 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.
authors.affiliation: Molecular Medicine Unit, University of Leeds, Leeds, UK. f.ponchel@leeds.ac.uk
authors.forename: Frederique
authors.initials: F
authors.lastname: Ponchel
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Verburg
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Bingham
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Brown
authors.forename: John
authors.initials: J
authors.lastname: Moore
authors.forename: Andrew
authors.initials: A
authors.lastname: Protheroe
authors.forename: Kath
authors.initials: K
authors.lastname: Short
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Lawson
authors.forename: Ann W
authors.initials: AW
authors.lastname: Morgan
authors.forename: Mark
authors.initials: M
authors.lastname: Quinn
authors.forename: Maya
authors.initials: M
authors.lastname: Buch
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Field
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Maltby
authors.forename: Aurelie
authors.initials: A
authors.lastname: Masurel
authors.forename: Susan H
authors.initials: SH
authors.lastname: Douglas
authors.forename: Liz
authors.initials: L
authors.lastname: Straszynski
authors.forename: Ursula
authors.initials: U
authors.lastname: Fearon
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Veale
authors.forename: Poulam
authors.initials: P
authors.lastname: Patel
authors.forename: Dennis
authors.initials: D
authors.lastname: McGonagle
authors.forename: John
authors.initials: J
authors.lastname: Snowden
authors.forename: Alexander F
authors.initials: AF
authors.lastname: Markham
authors.forename: David
authors.initials: D
authors.lastname: Ma
authors.forename: Jacob M
authors.initials: JM
authors.lastname: van Laar
authors.forename: Helen A
authors.initials: HA
authors.lastname: Papadaki
authors.forename: Paul
authors.initials: P
authors.lastname: Emery
authors.forename: John D
authors.initials: JD
authors.lastname: Isaacs
mesh_terms: D000074323:Alemtuzumab; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm / Q000009:adverse effects / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000188:drug therapy; D001327:Autoimmune Diseases / Q000097:blood* / Q000188:drug therapy; D001800:Blood Specimen Collection / Q000295:instrumentation; D001853:Bone Marrow / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology*; D002478:Cells, Cultured / Q000378:metabolism; D015331:Cohort Studies; D003131:Combined Modality Therapy; D016207:Cytokines / Q000097:blood; D015329:Gene Rearrangement, T-Lymphocyte; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D015851:Interleukin-7 / Q000096:biosynthesis / Q000097:blood / Q000172:deficiency*; D008212:Lymphocyte Depletion; D008231:Lymphopenia / Q000139:chemically induced*; D038041:Lymphopoiesis; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy; D053683:Oncostatin M; D036102:Peripheral Blood Stem Cell Transplantation; D017154:Stromal Cells / Q000378:metabolism; D013950:Thymus Gland / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D016207:Cytokines; D015850:Interleukin-6; D015851:Interleukin-7; C508351:OSM protein, human; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D053683:Oncostatin M; D000074323:Alemtuzumab