Interleukin-7 deficiency in rheumatoid arthritis: consequences for therapy-induced lymphopenia.
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.
Ponchel
Frederique
F
Molecular Medicine Unit, University of Leeds, Leeds, UK. f.ponchel@leeds.ac.uk
Verburg
Robert J
RJ
Bingham
Sarah J
SJ
Brown
Andrew K
AK
Moore
John
J
Protheroe
Andrew
A
Short
Kath
K
Lawson
Catherine A
CA
Morgan
Ann W
AW
Quinn
Mark
M
Buch
Maya
M
Field
Sarah L
SL
Maltby
Sarah L
SL
Masurel
Aurelie
A
Douglas
Susan H
SH
Straszynski
Liz
L
Fearon
Ursula
U
Veale
Douglas J
DJ
Patel
Poulam
P
McGonagle
Dennis
D
Snowden
John
J
Markham
Alexander F
AF
Ma
David
D
van Laar
Jacob M
JM
Papadaki
Helen A
HA
Emery
Paul
P
Isaacs
John D
JD
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
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