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

Ponchel F, Verburg RJ, Bingham SJ, Brown AK, Moore J, Protheroe A, Short K, Lawson CA, Morgan AW, Quinn M, Buch M, Field SL, Maltby SL, Masurel A, Douglas SH, Straszynski L, Fearon U, Veale DJ, Patel P, McGonagle D, Snowden J, Markham AF, Ma D, van Laar JM, Papadaki HA, Emery P, Isaacs JD - Arthritis Res. Ther. (2004)

Bottom Line: Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells.In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Medicine Unit, University of Leeds, Leeds, UK. f.ponchel@leeds.ac.uk

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.

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Circulating IL-7 levels are directly correlated with the TREC content of CD4+ T-cells in rheumatoid arthritis (RA) patients in clinical remission. (a) The T-cell receptor excision circle (TREC) content of total CD4+ T-cells, measured in patients in clinical remission (n = 36, all triangles [Table 1]), is heterogeneous, ranging from values observed in healthy control individuals to values in active RA patients. Using the age relationship to TREC content in healthy control individuals (black circles and thin line, correlation coefficient R = -0.816, P < 0.00001; previously reported [24]), two groups of patients can be differentiated: group 1 exhibits TREC content similar to or greater than that in age-matched healthy control individuals; and group 2 exhibits lower TREC content. We used the median value for TREC content to separate patients into two groups. We refer to these two groups as group 1 (G1; above median value, indicated by black triangles) and group 2 (G2; below median value, indicated by open triangles). The age relationship to TREC content is recovered only in group 1 (thick line; correlation coefficient R = -0.738, P = 0.001; for group 2 R = 0.341, P = 0.174). (b) Circulating IL-7 levels are directly correlated with TREC content of CD4+ T-cells in 36 patients in clinical remission (R = 0.777, P < 0.00001). In addition, patients satisfying the American College of Rheumatology (ACR) criteria for remission are indicated by open diamonds and patients not satisfying the ACR criteria by closed diamonds (Table 3). These two groups are undistinguishable.
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Figure 5: Circulating IL-7 levels are directly correlated with the TREC content of CD4+ T-cells in rheumatoid arthritis (RA) patients in clinical remission. (a) The T-cell receptor excision circle (TREC) content of total CD4+ T-cells, measured in patients in clinical remission (n = 36, all triangles [Table 1]), is heterogeneous, ranging from values observed in healthy control individuals to values in active RA patients. Using the age relationship to TREC content in healthy control individuals (black circles and thin line, correlation coefficient R = -0.816, P < 0.00001; previously reported [24]), two groups of patients can be differentiated: group 1 exhibits TREC content similar to or greater than that in age-matched healthy control individuals; and group 2 exhibits lower TREC content. We used the median value for TREC content to separate patients into two groups. We refer to these two groups as group 1 (G1; above median value, indicated by black triangles) and group 2 (G2; below median value, indicated by open triangles). The age relationship to TREC content is recovered only in group 1 (thick line; correlation coefficient R = -0.738, P = 0.001; for group 2 R = 0.341, P = 0.174). (b) Circulating IL-7 levels are directly correlated with TREC content of CD4+ T-cells in 36 patients in clinical remission (R = 0.777, P < 0.00001). In addition, patients satisfying the American College of Rheumatology (ACR) criteria for remission are indicated by open diamonds and patients not satisfying the ACR criteria by closed diamonds (Table 3). These two groups are undistinguishable.

Mentions: We measured TREC in total CD4+ T-cells in these patients in clinical remission in relation to age. The results were also heterogeneous (Fig. 5a; all triangles). Comparing these values with our previous results in healthy control individuals (small circles [24]), there appeared to be two distinct patient groups. One of these groups had a CD4+ T-cell TREC content similar to or higher than that in age-matched healthy control individuals, and the other group exhibited lower TREC content. We used the median TREC content to distinguish two groups. Open and closed triangles relate to group 1 (above the median TREC value) and group 2 (below the median TREC value), respectively. The relationship between TREC content and age was present in group 1 (thick line; R = -0.738, P = 0.001) but not in group 2. No clinical parameter was able to predict TREC content (disease duration, remission duration, previous or current therapy, rheumatoid factor).


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

Ponchel F, Verburg RJ, Bingham SJ, Brown AK, Moore J, Protheroe A, Short K, Lawson CA, Morgan AW, Quinn M, Buch M, Field SL, Maltby SL, Masurel A, Douglas SH, Straszynski L, Fearon U, Veale DJ, Patel P, McGonagle D, Snowden J, Markham AF, Ma D, van Laar JM, Papadaki HA, Emery P, Isaacs JD - Arthritis Res. Ther. (2004)

Circulating IL-7 levels are directly correlated with the TREC content of CD4+ T-cells in rheumatoid arthritis (RA) patients in clinical remission. (a) The T-cell receptor excision circle (TREC) content of total CD4+ T-cells, measured in patients in clinical remission (n = 36, all triangles [Table 1]), is heterogeneous, ranging from values observed in healthy control individuals to values in active RA patients. Using the age relationship to TREC content in healthy control individuals (black circles and thin line, correlation coefficient R = -0.816, P < 0.00001; previously reported [24]), two groups of patients can be differentiated: group 1 exhibits TREC content similar to or greater than that in age-matched healthy control individuals; and group 2 exhibits lower TREC content. We used the median value for TREC content to separate patients into two groups. We refer to these two groups as group 1 (G1; above median value, indicated by black triangles) and group 2 (G2; below median value, indicated by open triangles). The age relationship to TREC content is recovered only in group 1 (thick line; correlation coefficient R = -0.738, P = 0.001; for group 2 R = 0.341, P = 0.174). (b) Circulating IL-7 levels are directly correlated with TREC content of CD4+ T-cells in 36 patients in clinical remission (R = 0.777, P < 0.00001). In addition, patients satisfying the American College of Rheumatology (ACR) criteria for remission are indicated by open diamonds and patients not satisfying the ACR criteria by closed diamonds (Table 3). These two groups are undistinguishable.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1064881&req=5

Figure 5: Circulating IL-7 levels are directly correlated with the TREC content of CD4+ T-cells in rheumatoid arthritis (RA) patients in clinical remission. (a) The T-cell receptor excision circle (TREC) content of total CD4+ T-cells, measured in patients in clinical remission (n = 36, all triangles [Table 1]), is heterogeneous, ranging from values observed in healthy control individuals to values in active RA patients. Using the age relationship to TREC content in healthy control individuals (black circles and thin line, correlation coefficient R = -0.816, P < 0.00001; previously reported [24]), two groups of patients can be differentiated: group 1 exhibits TREC content similar to or greater than that in age-matched healthy control individuals; and group 2 exhibits lower TREC content. We used the median value for TREC content to separate patients into two groups. We refer to these two groups as group 1 (G1; above median value, indicated by black triangles) and group 2 (G2; below median value, indicated by open triangles). The age relationship to TREC content is recovered only in group 1 (thick line; correlation coefficient R = -0.738, P = 0.001; for group 2 R = 0.341, P = 0.174). (b) Circulating IL-7 levels are directly correlated with TREC content of CD4+ T-cells in 36 patients in clinical remission (R = 0.777, P < 0.00001). In addition, patients satisfying the American College of Rheumatology (ACR) criteria for remission are indicated by open diamonds and patients not satisfying the ACR criteria by closed diamonds (Table 3). These two groups are undistinguishable.
Mentions: We measured TREC in total CD4+ T-cells in these patients in clinical remission in relation to age. The results were also heterogeneous (Fig. 5a; all triangles). Comparing these values with our previous results in healthy control individuals (small circles [24]), there appeared to be two distinct patient groups. One of these groups had a CD4+ T-cell TREC content similar to or higher than that in age-matched healthy control individuals, and the other group exhibited lower TREC content. We used the median TREC content to distinguish two groups. Open and closed triangles relate to group 1 (above the median TREC value) and group 2 (below the median TREC value), respectively. The relationship between TREC content and age was present in group 1 (thick line; R = -0.738, P = 0.001) but not in group 2. No clinical parameter was able to predict TREC content (disease duration, remission duration, previous or current therapy, rheumatoid factor).

Bottom Line: Poor reconstitution could result either from reduced de novo T-cell production through the thymus or from poor peripheral expansion of residual T-cells.In the present study we demonstrated reduced levels of circulating IL-7 in a cross-section of RA patients.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Molecular Medicine Unit, University of Leeds, Leeds, UK. f.ponchel@leeds.ac.uk

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.

Show MeSH
Related in: MedlinePlus