|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
Prepublished online as a Blood First Edition Paper on October 31, 2002; DOI 10.1182/blood-2002-07-2297.
IMMUNOBIOLOGY
From the Pediatric Oncology Branch, Center for
Cancer Research, National Cancer Institute, National Institutes of
Health, Bethesda, MD; Animal Model and Retrovirus Vaccine Section,
Basic Research Laboratory, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, MD; Developmental
Therapeutics Program, Biological Therapy, Division of Cancer
Therapy & Diagnosis, National Cancer Institute; Toxicology and
Pharmacology Branch, Division of Cancer Therapy & Diagnostics, National
Cancer Institute, Bethesda, MD; Vaccine Research Program, National
Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD; and Biopharmaceutical Development Program, SAIC,
Frederick, MD.
Interleukin-7 (IL-7) is important for thymopoiesis in mice and
humans because IL-7 receptor Interleukin-7 (IL-7) is required for T and B
lymphopoiesis in mice.1,2 In humans, mutations in the IL-7
receptor In addition to effects on the thymus, IL-7 also has potent effects on
mature T cells by lowering the threshold for activation and increasing
survival via up-regulation of bcl-2 family members (reviewed by
Hofmeister et al6 and Fry and Mackall7). IL-7 is required for low-affinity antigen-induced T-cell proliferation, which occurs following T-cell depletion,8,9 and treatment of T-cell-replete mice with IL-7 leads to increased homeostatic expansion.10,11 Furthermore, there is an increased
availability of circulating IL-7 in humans with CD4
lymphopenia,12-14 thus providing a plausible mechanism for
the increased homeostatic expansion observed in T-cell-depleted hosts.
Recently, it has also been demonstrated that IL-7 can partially
substitute for IL-15 in the maintenance of memory T cells when
overexpressed as a transgene in mice.15 Thus, in addition
to thymopoietic effects, IL-7 plays a critical role in regulating
peripheral T-cell homeostasis following T-cell depletion through
effects on mature naive and memory T cells, occurring independent of
thymopoietic effects.16
Thus far, study of the effects of IL-7 therapy has been limited to
murine systems. In this report, we analyzed the immunologic changes
that occur with IL-7 therapy in nonhuman primates. We demonstrate that
IL-7 treatment alters peripheral T-cell homeostasis in nonhuman
primates, resulting in substantial but reversible elevations in
peripheral T-cell numbers through a dramatic increase in the number of
peripheral T cells undergoing cell cycling. Importantly, immunologic
effects of IL-7 were observed in simian immunodeficiency virus (SIV)
infection despite predicted elevations of endogenous IL-7. These
results provide further evidence for IL-7 as a central regulator of
peripheral T-cell homeostasis and suggest that IL-7 therapy will
potently immunomodulate both T-cell-depleted and T-cell-replete humans.
Animals
RhIL-7 production
Flow cytometry Within 24 hours of collection, EDTA (ethylenediaminetetraacetic acid)-anticoagulated peripheral blood samples were analyzed by flow cytometry. Antibody staining and whole blood lysis was performed using standard techniques. For surface immunoglobulin M (IgM) staining, antibody was added after red cell lysis and washing. Flow cytometric analysis was performed on a dual laser FACSCalibur (Becton Dickinson, San Jose, CA) using CellQuest software. Viable lymphocyte populations were gated based on forward scatter and side scatter characteristics and back-gating with CD45 and CD14. The antibodies used were CD3 fluorescein isothiocyanate (FITC)
and peridinin chlorophyll protein (PerCP) (clone SP34), CD45RA FITC
(clone 5H9), CD16 FITC (clone 3GB), CD14 FITC (clone M5E2), HLA-DR
R-phycoerythrin (R-PE) and Cy-Chrome (clone G46-6), CD25 R-PE (clone
M-A251), CD69 R-PE (clone FN50), CD95 R-PE (clone DX2), CD27 R-PE
(clone M-T271), CD11a R-PE and allophycocyanin (APC) (clone HI111),
CD28 Cy-Chrome and APC (clone CD28.2), CD56 R-PE (clone MY31), CD20
R-PE and APC (clone 2H7), CD4 PerCP (clone L200), CD45 PerCP (clone
TU116), CD10 Cy-Chrome (clone HI10a), CD8 APC (clone RPA-T8), and
isotype controls (all from BD PharMingen, San Diego, CA). In
addition, goat antimonkey IgM FITC (Kirkegard & Perry, Gaithersburg,
MD), CD8 R-PE and APC (clone 2ST8.5H7), and CD127 (IL-7R ) R-PE
(clone R34.34) (Immunotech, Marseille, France) were used.
T-cell receptor excision circle (TREC) analysis Frozen peripheral blood mononuclear cells (PBMCs) were rapidly thawed and washed in RPMI supplemented with 10% fetal bovine serum (FBS) (Invitrogen, Gaithersburg, MD). Cells were counted, washed, and labeled with either mouse antihuman CD4 or CD8 antibodies conjugated to magnetic beads (Miltenyi Biotec, Auburn, CA) according to the manufacturer's instructions. Cells were positively selected using an MS column. Three separate aliquots of the positively selected fraction were carefully counted and averaged. Cells were pelleted and stored at 80°C until analysis. Quantification of T-cell receptor excision
circles (TRECs) in sorted CD4+ and CD8+ T cells
was performed by quantitative polymerase chain reaction (PCR)
with an ABI7700 system (Perkin-Elmer, Norwalk, CT) using the conditions
exactly as previously described.21 Primer and probe
sequences were as follows: forward-CACATCCCTTTCAACCATGCT, reverse-GCCAGCTGCAGGGTTTAGG, and
probe-ACGCCTCTGGTTTTTGTAAAGGTGCTCACT. A standard curve was
plotted and TREC values for samples calculated by the ABI7700 software.
Samples were analyzed in duplicate.
Ki67 and BrdU Frozen PBMCs were thawed and washed in RPMI 1640 with FBS; 1 × 106 cells were washed and surface-labeled with antibodies as indicated. Cells were fixed, permeabilized, and labeled with anti-Ki67 FITC or isotype antibodies for 30 minutes on ice. For bromodeoxyuridine (BrdU) analysis, washed PBMCs were added to a 12-well plate at a concentration of 2 × 106/mL and pulsed with BrdU (BD Pharmingen) at a concentration of 10 µM. At 18 hours and 42 hours, cells were harvested and labeled with anti-BrdU FITC (BD Pharmingen) according to the manufacturer's instructions.Western blotting Analysis of protein levels in thawed PBMCs was performed using standard Western blotting techniques. The monoclonal antibodies used were as follows: anti-p27kip1 IgG1 (F-8), anti-p16Ink4a IgG2a (F-12) (Santa Cruz, Santa Cruz, CA), antihuman tubulin (0.1 µg/mL) (Ab-1) (Oncogene Research Products,
Cambridge, MA), and sheep antimouse horseradish peroxidase
(HRP)-conjugated IgG (Amersham Pharmacia Biotech, Piscataway, NJ)
In vitro IL-7R
Recombinant human IL-7 therapy induces substantial but reversible increases in circulating CD4+ and CD8+ counts, lymphadenopathy, and a preservation of the CD4/CD8 ratio IL-7 therapy dramatically increases T-cell numbers in normal10,22 and T-cell-depleted mice.11 To determine the immunologic effects of IL-7 therapy in nonhuman primates, we treated healthy juvenile cynomolgus monkeys with recombinant human IL-7 administered subcutaneously daily for 10 days using doses (50, 200, and 500 µg/kg/d) extrapolated from biologically active doses in mice. This short-term IL-7 therapy substantially increased the number of total lymphocytes and both CD4+ and CD8+ T cells in the peripheral blood. At 50 µg/kg/d and 200/µg/kg/d there were mixed responses, with 1 of 2 treated animals responding, whereas all 3 treated animals showed a substantial response at 500 µg/kg/d (Figure 1A-C). All responding animals had T-cell increases ranging from approximately 2-fold to 5-fold, with a median absolute increase in CD4 count of 5315 cells per microliter and CD8 count of 2849 cells per microliter (both P values less than .05, Wilcoxon signed-rank test), with preservation of the CD4/CD8 ratio (Figure 1D). Although changes in lymphocyte trafficking can alter peripheral blood lymphocyte numbers without altering total body lymphocyte counts,23-25 this was not the case with IL-7 therapy because clinically evident lymphadenopathy was observed in IL-7-treated primates on days 2, 6, and 11, coincident with increases in peripheral blood lymphocytes (PBLs). Both the effects on PBL numbers and lymphadenopathy were reversible, returning to near baseline by day 21. There were no changes in absolute B-cell or natural killer (NK) cell counts (data not shown). Thus, similar to murine models, a short course of IL-7 therapy substantially and reversibly increased total body T-cell numbers in nonhuman primates. However, unlike murine models, no increases in B-cell counts were observed, and the effects on CD4+ and CD8+ T cells were equivalent.10
Treatment with rhIL-7 increases both naive and nonnaive T cells and induces declines in peripheral blood TREC levels IL-7 therapy potently up-regulates thymopoiesis in murine models4,5,11 and in vitro in human fetal thymic organ culture systems.26 Thus, we anticipated that increases in the numbers of recent thymic emigrants would result in an increase in the absolute number of circulating T cells bearing a naive phenotype.Using multiparameter flow cytometric analysis of peripheral blood, we
monitored changes in T-cell subsets after IL-7 treatment. We defined
naive CD8+ T cells as
CD8+/CD45RAhi/CD27+/CD11alow/mod
and naive CD4+ T cells as
CD4+/CD45RAhi/CD27+. While IL-7
therapy increased the absolute number of naive CD4+ and
CD8+ T cells (Figure 2A),
IL-7 therapy also induced a transient change in CD11a expression on
CD8+ cells with the emergence of a dominant population of
CD11amod cells (Figure 2B) suggesting a partial conversion
of the naive subset to an activated/memory phenotype as has been
described in peripherally expanding T cells in settings of T-cell
depletion.27,28 Thus, although phenotypic
categorization led to the impression that naive cell number was
increased following short-term IL-7 therapy, changes in CD11a
expression suggested that IL-7 may have been inducing cycling
of the naive compartment, as has been described following IL-7
treatment of human cord blood naive T cells.29-31
To determine whether the increases in naive T cells reflected enhanced thymic output, we measured T-cell receptor excision circles (TRECs) in separated CD4+ and CD8+ T cells in IL-7-treated primates. Interestingly, IL-7 therapy induced a dramatic decline in the frequency (Figure 2C) and absolute number (Figure 2D) of circulating TREC+ T cells. Because TRECs are diluted by cell division, a marked increase in T-cell turnover would be expected to lead to dilution of the frequency of TREC+ T cells in the periphery. Thus, the decline in TRECs in both CD4+ and CD8+ T cells suggested that IL-7 therapy was inducing cycling of multiple T-cell subsets. Dramatic increase in the percentage of cycling peripheral T cells with IL-7 therapy To further investigate whether IL-7 therapy induced peripheral T-cell activation and/or turnover, we evaluated T-cell activation markers and T-cell cycling parameters before and after IL-7 treatment. We observed no evidence for up-regulation of classical activation markers such as CD69, HLA-DR, or CD25; however, Fas was up-regulated on both CD4+ and CD8+ T cells (data not shown). To assess whether IL-7 might induce T-cell cycling in the absence of classical activation, we evaluated Ki67 expression following IL-7 therapy. Ki67 is a nuclear antigen that is expressed in cells undergoing proliferation. At baseline the percentage of both CD4+ and CD8+ T cells expressing Ki67 was less than 2% (Figure 3A). By day 6 of IL-7 treatment, 30% to 60% of the circulating CD4+ and CD8+ T cells were Ki67+, a feature that persisted to day 11. By day 21 (11 days following cessation of therapy) the percentage of cells expressing Ki67 had declined to near baseline, providing evidence that the increase in proliferation induced by IL-7 is reversible. To confirm the observation of IL-7-induced cycling and to determine whether IL-7-induced effects can persist, at least transiently, in the absence of the cytokine, we cultured PBMCs from IL-7-treated animals in media without any specific T-cell stimulus and pulsed with BrdU for 18 hours. Because peripheral blood mononuclear cells do not produce IL-7, it would be expected that IL-7 was essentially absent from these cultures. In cultures containing PBMCs collected prior to IL-7 treatment, less than 0.1% of CD4+ and CD8+ T cells incorporated BrdU (Figure 3B). By day 6 of IL-7 therapy, the fraction of CD4+ and CD8+ T cells that incorporated BrdU following overnight culture increased to 1% to 3% and was persistently elevated at day 11, returning to near baseline by day 21. To determine whether increases in cell cycling were observed in both naive and memory cells, Ki67 expression was analyzed in CD95loCD28+ "naive" cells and CD95hiCD28 memory
cells.32 For both CD4+ T cells and
CD8+ T cells, substantial increases in Ki67 occurred with
rhIL-7 therapy in both naive and memory subsets as defined by these
parameters (data not shown). Thus, treatment with IL-7 leads to a
profound but transient increase in the number of cycling T cells,
an effect that persists, at least temporarily, following removal
from exposure to IL-7.
Barata et al recently reported that IL-7-induced cycling of T-cell acute lymphoblastic leukemia (ALL) cells was associated with a down-regulation of p27kip1 and that forced expression of p27 kip1 in this system prevented IL-7-induced cell cycle progression.33 To assess the status of p27kip1 in PBMCs from normal primates following IL-7 therapy, we performed Western blotting of lysates from PBMCs following IL-7 therapy. Treatment with IL-7 led to a decrease in p27kip1 protein levels by day 6 and day 11 as well as a decrease in p16Ink4a (Figure 3C), findings that further confirm cycling of PBMCs following IL-7 treatment. Together these results provide compelling evidence that IL-7-induced cycling of mature T cells is a primary effect of IL-7 therapy. Although these studies could not directly assess whether IL-7-induced cycling required concomitant signaling through the T-cell receptor (TCR), evidence from murine models has shown that homeostatic-induced proliferation, which is mediated by IL-7, requires signaling through the TCR and that low-affinity ligands, which normally are not capable of inducing T-cell cycling, result in TCR-induced proliferation in the presence of IL-7.34,35 Thus, it appears most likely that most cycling cells following IL-7 therapy are those that encounter low-affinity antigen, which, when coupled with IL-7 signaling, results in T-cell proliferation without full-scale activation. Immunologic effects of IL-7 therapy are preserved in SIV-infected macaques Increased levels of IL-7 are observed in humans with T-cell depletion due to HIV infection or due to treatment with chemotherapy for cancer.12-14 The results presented thus far in normal T-cell-replete primates provide evidence that IL-7 therapy induces profound changes in peripheral T-cell homeostasis, but it was important to determine whether similar immunologic effects of IL-7 therapy would occur in situations where endogenous levels of IL-7 are expected to be elevated. Thus, we treated rhesus macaques with moderate CD4 depletion due to infection with simian immunodeficiency virus with rhIL-7 (100 µg/kg/d for 9 days). Plasma levels of more than 1000 pg/mL were achieved (mean at day 3, 1159 ± 60 pg/mL), markedly increased from undetectable levels present at baseline in these animals and substantially higher than endogenous levels observed in humans with T-cell depletion (Figure 4A). Interestingly, these levels are still 1 log less than standard concentrations used in vitro (10 ng/mL). As with normal cynomolgus monkeys, responding SIV-infected primates showed significant increases in the absolute numbers of CD4+ (Figure 4B) and CD8+ T cells (Figure 4C) (mean CD4 increase, 449 cells/mm3; mean CD8 increase, 501 cells/mm3, both P values less than .05, Wilcoxon signed-rank test). Furthermore, in these SIV-infected animals that received continuing antiretroviral therapy during IL-7 treatment, no change in viral load was observed (data not shown).
Marked but transient declines in IL-7 receptor expression on circulating T cells following rhIL-7 treatment Further evidence of biologic effects of IL-7 treatment in moderately T-cell-depleted SIV-infected primates is the marked decline in IL-7R expression observed on both
CD3+CD8+ and CD3+CD8
T cells coincident with IL-7 therapy (Figure 4D-E).
To determine whether these observations reflected true decreases in
receptor level or simply blocking of antibody binding by saturating
levels of IL-7, PBMCs form normal cynomolgus monkeys were incubated
with IL-7 for 24 hours. Marked decreases in IL-7R
In summary, pharmacologic dosing of IL-7 induces obvious measurable biologic responses that include dramatic rises in peripheral T-cell numbers in T-cell-replete and T-cell-depleted hosts. Further, these modest doses, which were well tolerated, result in circulating levels greatly exceeding those observed in T-cell-depleted humans.12-14 Together, these results provide evidence that physiologic elevations in circulating IL-7 that occur following T-cell depletion will not preclude responses to pharmacologic dosing of this agent and indicate that IL-7 therapy will likely augment peripheral T-cell numbers in humans following T-cell depletion. Importantly, when administered as a short course, the peripheral effects of IL-7 predominate due to a dramatic increase in peripheral T-cell cycling, which is physiologically similar to the increased homeostatic expansion known to occur in T-cell-depleted hosts. In both normal cynomolgus and SIV-infected rhesus macaques (M.M., T.F., C.L.M., G.F., manuscript in preparation), increases in cycling were observed in both naive and nonnaive T cells, indicating that the effects of pharmacologic dosing will not be confined to the naive subset. With regard to IL-7's capacity for immune reconstitution, the peripheral effects preclude a clear enumeration of thymopoiesis in this model system. Indeed, the dilution of TREC levels in cycling cells has been cited as a possible limitation of this assay for measuring thymopoiesis, especially in states of robust peripheral cell cycling.36 This suggests that alternative approaches for measuring thymic functions such as evaluation of repertoire diversification may be necessary to accurately assess thymopoietic effects in this setting. Importantly, it should also be noted that enhanced homeostatic expansion can result in substantial improvements in host immunocompetence-independent thymopoietic effects.37 Therefore, these findings provide further evidence to suggest that IL-7 is a promising immunorestorative agent. They also raise the intriguing possibility that IL-7 may be a useful adjunct in the context of immunotherapies such as tumor vaccines wherein enhanced T-cell cycling may increase the magnitude and/or the breadth of the response to therapeutic or protective vaccination. Indeed, preliminary studies suggest that IL-7 administration increases the number of effector and memory T-cell populations to immunodominant and subdominant epitopes when administered concomitantly with a T-cell-based vaccine (T.F., C.L.M., manuscript in preparation).
We thank Dr Fariba Navid for her indispensable help with the Western blotting. We also acknowledge John Merrill, Patricia J. Tosca, and the other staff at Battelle Memorial Institute.
Submitted July 31, 2002; accepted October 20, 2002.
Prepublished online as Blood First Edition Paper, October 31, 2002; DOI 10.1182/blood-2002-07-2297.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: T. Fry, Bldg 10, Rm 13N240, MSC 1928, 10 Center Dr, Bethesda, MD 20892-1928; e-mail: tf60y{at}nih.gov.
1.
von Freeden-Jeffry U, Vieira P, Lucian LA, McNeil T, Burdach SE, Murray R.
Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine.
J Exp Med.
1995;181:1519-1526
2.
Peschon JJ, Morrissey PJ, Grabstein KH, et al.
Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice.
J Exp Med.
1994;180:1955-1960 3. Puel A, Ziegler SF, Buckley RH, Leonard WJ. Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet. 1998;20:394-397[CrossRef][Medline] [Order article via Infotrieve]. 4. Abdul-Hai A, Or R, Slavin S, et al. Stimulation of immune reconstitution by interleukin-7 after syngeneic bone marrow transplantation in mice. Exp Hematol. 1996;24:1416-1422[Medline] [Order article via Infotrieve].
5.
Bolotin E, Smogorzewska M, Smith S, Widmer M, Weinberg K.
Enhancement of thymopoiesis after bone marrow transplant by in vivo interleukin-7.
Blood.
1996;88:1887-1894 6. Hofmeister R, Khaled AR, Benbernou N, Rajnavolgyi E, Muegge K, Durum SK. Interleukin-7: physiological roles and mechanisms of action. Cytokine Growth Factor Rev. 1999;10:41-60[CrossRef][Medline] [Order article via Infotrieve].
7.
Fry TJ, Mackall CL.
Interleukin-7: from bench to clinic.
Blood.
2002;99:3892-3904 8. Schluns KS, Kieper WC, Jameson SC, Lefrancois L. Interleukin-7 mediates the homeostasis of naive and memory CD8 T cells in vivo. Nat Immunol. 2000;1:426-432[CrossRef][Medline] [Order article via Infotrieve].
9.
Tan JT, Dudl E, LeRoy E, et al.
IL-7 is critical for homeostatic proliferation and survival of naive T cells.
Proc Natl Acad Sci U S A.
2001;98:8732-8737 10. Komschlies KL, Gregorio TA, Gruys ME, Back TC, Faltynek CR, Wiltrout RH. Administration of recombinant human IL-7 to mice alters the composition of B-lineage cells and T cell subsets, enhances T cell function, and induces regression of established metastases. J Immunol. 1994;152:5776-5784[Abstract].
11.
Mackall CL, Fry TJ, Bare C, Morgan P, Galbraith A, Gress RE.
IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation.
Blood.
2001;97:1491-1497 12. Bolotin E, Annett G, Parkman R, Weinberg K. Serum levels of IL-7 in bone marrow transplant recipients: relationship to clinical characteristics and lymphocyte count. Bone Marrow Transplant. 1999;23:783-788[CrossRef][Medline] [Order article via Infotrieve].
13.
Fry TJ, Connick E, Falloon J, et al.
A potential role for interleukin-7 in T-cell homeostasis.
Blood.
2001;97:2983-2990 14. Napolitano LA, Grant RM, Deeks SG, et al. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat Med. 2001;7:73-79[CrossRef][Medline] [Order article via Infotrieve].
15.
Kieper WC, Tan JT, Bondi-Boyd B, et al.
Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells.
J Exp Med.
2002;195:1533-1539 16. Fry TJ, Mackall CL. Interleukin-7: master regulator of peripheral T-cell homeostasis? Trends Immunol. 2001;22:564-571[CrossRef][Medline] [Order article via Infotrieve].
17.
Pal R, Venzon D, Letvin NL, et al.
ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A*01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency.
J Virol.
2002;76:292-302 18. Romano JW, Williams KG, Shurtliff RN, Ginocchio C, Kaplan M. NASBA technology: isothermal RNA amplification in qualitative and quantitative diagnostics. Immunol Invest. 1997;26:15-28[Medline] [Order article via Infotrieve].
19.
Benson J, Chougnet C, Robert-Guroff M, et al.
Recombinant vaccine-induced protection against the highly pathogenic simian immunodeficiency virus SIV(mac251): dependence on route of challenge exposure.
J Virol.
1998;72:4170-4182 20. Hel Z, Johnson J, Tryniszewska E, et al. A novel chimeric Rev, Tat, and Nef (Retanef) antigen as a component of an SIV/HIV vaccine. Vaccine. 2002;20:3171-3186[CrossRef][Medline] [Order article via Infotrieve]. 21. Douek DC, Vescio RA, Betts MR, et al. Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet. 2000;355:1875-1881[CrossRef][Medline] [Order article via Infotrieve].
22.
Geiselhart LA, Humphries CA, Gregorio TA, Mou S, Subleski J, Komschlies KL.
IL-7 administration alters the CD4:CD8 ratio, increases T cell numbers, and increases T cell function in the absence of activation.
J Immunol.
2001;166:3019-3027 23. Mosier DE. HIV results in the frame. CD4+ cell turnover. Nature. 1995;375:193-194[Medline] [Order article via Infotrieve]discussion 198. 24. Dimitrov DS, Martin MA. HIV results in the frame. CD4+ cell turnover. Nature. 1995;375:194-195[Medline] [Order article via Infotrieve]discussion 198. 25. Sprent J, Tough D. HIV results in the frame. CD4+ cell turnover. Nature. 1995;375:194[Medline] [Order article via Infotrieve]discussion, 198.
26.
Okamoto Y, Douek DC, McFarland RD, Koup RA.
Effects of exogenous interleukin-7 on human thymus function.
Blood.
2002;99:2851-2858
27.
Murali-Krishna K, Ahmed R.
Cutting edge: naive T cells masquerading as memory cells.
J Immunol.
2000;165:1733-1737
28.
Goldrath AW, Bogatzki LY, Bevan MJ.
Naive T cells transiently acquire a memory-like phenotype during homeostasis-driven proliferation.
J Exp Med.
2000;192:557-564 29. Webb LM, Foxwell BM, Feldmann M. Putative role for interleukin-7 in the maintenance of the recirculating naive CD4+ T-cell pool. Immunology. 1999;98:400-405[CrossRef][Medline] [Order article via Infotrieve].
30.
Soares MV, Borthwick NJ, Maini MK, Janossy G, Salmon M, Akbar AN.
IL-7-dependent extrathymic expansion of CD45RA+ T cells enables preservation of a naive repertoire.
J Immunol.
1998;161:5909-5917 31. Fukui T, Katamura K, Abe N, et al. IL-7 induces proliferation, variable cytokine-producing ability and IL-2 responsiveness in naive CD4+ T-cells from human cord blood. Immunol Lett. 1997;59:21-28[CrossRef][Medline] [Order article via Infotrieve].
32.
Pitcher CJ, Hagen SI, Walker JM, et al.
Development and homeostasis of T cell memory in rhesus macaque.
J Immunol.
2002;168:29-43
33.
Barata JT, Cardoso AA, Nadler LM, Boussiotis VA.
Interleukin-7 promotes survival and cell cycle progression of T-cell acute lymphoblastic leukemia cells by down-regulating the cyclin-dependent kinase inhibitor p27(kip1).
Blood.
2001;98:1524-1531 34. Goldrath AW, Bevan MJ. Low-affinity ligands for the TCR drive proliferation of mature CD8+ T cells in lymphopenic hosts. Immunity. 1999;11:183-190[CrossRef][Medline] [Order article via Infotrieve]. 35. Ernst B, Lee DS, Chang JM, Sprent J, Surh CD. The peptide ligands mediating positive selection in the thymus control T cell survival and homeostatic proliferation in the periphery. Immunity. 1999;11:173-181[CrossRef][Medline] [Order article via Infotrieve]. 36. Hazenberg MD, Verschuren MC, Hamann D, Miedema F, van Dongen JJ. T cell receptor excision circles as markers for recent thymic emigrants: basic aspects, technical approach, and guidelines for interpretation. J Mol Med. 2001;79:631-640[CrossRef][Medline] [Order article via Infotrieve].
37.
Fry TJ, Christensen BL, Komschlies KL, Gress RE, Mackall CL.
Interleukin-7 restores immunity in athymic T-cell-depleted hosts.
Blood.
2001;97:1525-1533 38. National Reserch Council. Guide for the Care and Use of Laboratory Animals. Washington, DC: National Academy Press; 1996.
© 2003 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  S. Beq, S. Rozlan, D. Gautier, R. Parker, V. Mersseman, C. Schilte, B. Assouline, I. Rance, P. Lavedan, M. Morre, et al. Injection of glycosylated recombinant simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques Blood, July 23, 2009; 114(4): 816 - 825. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Ray-Coquard, C. Cropet, M. Van Glabbeke, C. Sebban, A. Le Cesne, I. Judson, O. Tredan, J. Verweij, P. Biron, I. Labidi, et al. Lymphopenia as a Prognostic Factor for Overall Survival in Advanced Carcinomas, Sarcomas, and Lymphomas Cancer Res., July 1, 2009; 69(13): 5383 - 5391. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Sereti, R. M. Dunham, J. Spritzler, E. Aga, M. A. Proschan, K. Medvik, C. A. Battaglia, A. L. Landay, S. Pahwa, M. A. Fischl, et al. IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection Blood, June 18, 2009; 113(25): 6304 - 6314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. I. Azevedo, M. V. D. Soares, J. T. Barata, R. Tendeiro, A. Serra-Caetano, R. M. M. Victorino, and A. E. Sousa IL-7 sustains CD31 expression in human naive CD4+ T cells and preferentially expands the CD31+ subset in a PI3K-dependent manner Blood, March 26, 2009; 113(13): 2999 - 3007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Faller, J. Kakal, R. Kumar, and P. MacPherson IL-7 and the HIV Tat protein act synergistically to down-regulate CD127 expression on CD8 T cells Int. Immunol., March 1, 2009; 21(3): 203 - 216. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Eberly, M. Kader, W. Hassan, K. A. Rogers, J. Zhou, Y. M. Mueller, M. J. Mattapallil, M. Piatak Jr., J. D. Lifson, P. D. Katsikis, et al. Increased IL-15 Production Is Associated with Higher Susceptibility of Memory CD4 T Cells to Simian Immunodeficiency Virus during Acute Infection J. Immunol., February 1, 2009; 182(3): 1439 - 1448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Sportes, F. T. Hakim, S. A. Memon, H. Zhang, K. S. Chua, M. R. Brown, T. A. Fleisher, M. C. Krumlauf, R. R. Babb, C. K. Chow, et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets J. Exp. Med., July 7, 2008; 205(7): 1701 - 1714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Boyman, C. Ramsey, D. M. Kim, J. Sprent, and C. D. Surh IL-7/Anti-IL-7 mAb Complexes Restore T Cell Development and Induce Homeostatic T Cell Expansion without Lymphopenia J. Immunol., June 1, 2008; 180(11): 7265 - 7275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Dunham, B. Cervasi, J. M. Brenchley, H. Albrecht, A. Weintrob, B. Sumpter, J. Engram, S. Gordon, N. R. Klatt, I. Frank, et al. CD127 and CD25 Expression Defines CD4+ T Cell Subsets That Are Differentially Depleted during HIV Infection J. Immunol., April 15, 2008; 180(8): 5582 - 5592. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. M. Mueller, D. H. Do, S. R. Altork, C. M. Artlett, E. J. Gracely, C. D. Katsetos, A. Legido, F. Villinger, J. D. Altman, C. R. Brown, et al. IL-15 Treatment during Acute Simian Immunodeficiency Virus (SIV) Infection Increases Viral Set Point and Accelerates Disease Progression despite the Induction of Stronger SIV-Specific CD8+ T Cell Responses J. Immunol., January 1, 2008; 180(1): 350 - 360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Vranjkovic, A. M. Crawley, K. Gee, A. Kumar, and J. B. Angel IL-7 decreases IL-7 receptor {alpha} (CD127) expression and induces the shedding of CD127 by human CD8+ T cells Int. Immunol., December 1, 2007; 19(12): 1329 - 1339. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fluur, A. De Milito, T. J. Fry, N. Vivar, L. Eidsmo, A. Atlas, C. Federici, P. Matarrese, M. Logozzi, E. Rajnavolgyi, et al. Potential Role for IL-7 in Fas-Mediated T Cell Apoptosis During HIV Infection J. Immunol., April 15, 2007; 178(8): 5340 - 5350. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hryniewicz, D. A. Price, M. Moniuszko, A. Boasso, Y. Edghill-Spano, S. M. West, D. Venzon, M. Vaccari, W.-P. Tsai, E. Tryniszewska, et al. Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques J. Immunol., March 15, 2007; 178(6): 3492 - 3504. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. S. Albuquerque, C. S. Cortesao, R. B. Foxall, R. S. Soares, R. M. M. Victorino, and A. E. Sousa Rate of Increase in Circulating IL-7 and Loss of IL-7R{alpha} Expression Differ in HIV-1 and HIV-2 Infections: Two Lymphopenic Diseases with Similar Hyperimmune Activation but Distinct Outcomes J. Immunol., March 1, 2007; 178(5): 3252 - 3259. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Vassena, M. Proschan, A. S. Fauci, and P. Lusso Interleukin 7 reduces the levels of spontaneous apoptosis in CD4+ and CD8+ T cells from HIV-1-infected individuals PNAS, February 13, 2007; 104(7): 2355 - 2360. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Swainson, S. Kinet, C. Mongellaz, M. Sourisseau, T. Henriques, and N. Taylor IL-7-induced proliferation of recent thymic emigrants requires activation of the PI3K pathway Blood, February 1, 2007; 109(3): 1034 - 1042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Klonowski, K. J. Williams, A. L. Marzo, and L. Lefrancois Cutting Edge: IL-7-Independent Regulation of IL-7 Receptor {alpha} Expression and Memory CD8 T Cell Development J. Immunol., October 1, 2006; 177(7): 4247 - 4251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zhang, J. Drenkow, C. S. R. Lankford, D. M. Frucht, R. L. Rabin, T. R. Gingeras, C. Venkateshan, F. Schwartzkopff, K. A. Clouse, and A. I. Dayton HIV regulation of the IL-7R: a viral mechanism for enhancing HIV-1 replication in human macrophages in vitro J. Leukoc. Biol., June 1, 2006; 79(6): 1328 - 1338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Beq, M.-T. Nugeyre, R. H. T. Fang, D. Gautier, R. Legrand, N. Schmitt, J. Estaquier, F. Barre-Sinoussi, B. Hurtrel, R. Cheynier, et al. IL-7 Induces Immunological Improvement in SIV-Infected Rhesus Macaques under Antiviral Therapy J. Immunol., January 15, 2006; 176(2): 914 - 922. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Muthukumar, D. Zhou, M. Paiardini, A. P. Barry, K. S. Cole, H. M. McClure, S. I. Staprans, G. Silvestri, and D. L. Sodora Timely triggering of homeostatic mechanisms involved in the regulation of T-cell levels in SIVsm-infected sooty mangabeys Blood, December 1, 2005; 106(12): 3839 - 3845. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E.L.S. Verhoeyen, L. Swainson, F.-L. Cosset, and N. Taylor IL-7 Differentially Regulates Cell Cycle Entry and Exit of Naive and Memory CD4+ T Lymphocytes: Effects on HIV-Mediated Infection. Blood (ASH Annual Meeting Abstracts), November 16, 2005; 106(11): 2388 - 2388. [Abstract]
|
|
|
|
|
|
A. Audige, E. Schlaepfer, H. Joller, and R. F. Speck Uncoupled Anti-HIV and Immune-Enhancing Effects when Combining IFN-{alpha} and IL-7 J. Immunol., September 15, 2005; 175(6): 3724 - 3736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. J. Fry and C. L. Mackall The Many Faces of IL-7: From Lymphopoiesis to Peripheral T Cell Maintenance J. Immunol., June 1, 2005; 174(11): 6571 - 6576. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Paiardini, B. Cervasi, H. Albrecht, A. Muthukumar, R. Dunham, S. Gordon, H. Radziewicz, G. Piedimonte, M. Magnani, M. Montroni, et al. Loss of CD127 Expression Defines an Expansion of Effector CD8+ T Cells in HIV-Infected Individuals J. Immunol., March 1, 2005; 174(5): 2900 - 2909. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Higgins, J. A. Metcalf, R. A. Stevens, M. Baseler, M. C. Nason, H. C. Lane, and I. Sereti Effects of Lymphocyte Isolation and Timing of Processing on Detection of CD127 Expression on T Cells in Human Immunodeficiency Virus-Infected Patients Clin. Vaccine Immunol., January 1, 2005; 12(1): 228 - 230. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Powell Jr, M. E. Dudley, P. F. Robbins, and S. A. Rosenberg Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy Blood, January 1, 2005; 105(1): 241 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Conklyn, C. Andresen, P. Changelian, and E. Kudlacz The JAK3 inhibitor CP-690550 selectively reduces NK and CD8+ cell numbers in cynomolgus monkey blood following chronic oral dosing J. Leukoc. Biol., December 1, 2004; 76(6): 1248 - 1255. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Picker, S. I. Hagen, R. Lum, E. F. Reed-Inderbitzin, L. M. Daly, A. W. Sylwester, J. M. Walker, D. C. Siess, M. Piatak Jr., C. Wang, et al. Insufficient Production and Tissue Delivery of CD4+ Memory T Cells in Rapidly Progressive Simian Immunodeficiency Virus Infection J. Exp. Med., November 15, 2004; 200(10): 1299 - 1314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Moniuszko, T. Fry, W.-P. Tsai, M. Morre, B. Assouline, P. Cortez, M. G. Lewis, S. Cairns, C. Mackall, and G. Franchini Recombinant Interleukin-7 Induces Proliferation of Naive Macaque CD4+ and CD8+ T Cells In Vivo J. Virol., September 15, 2004; 78(18): 9740 - 9749. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Macallan, D. Wallace, Y. Zhang, C. de Lara, A. T. Worth, H. Ghattas, G. E. Griffin, P. C.L. Beverley, and D. F. Tough Rapid Turnover of Effector-Memory CD4+ T Cells in Healthy Humans J. Exp. Med., July 19, 2004; 200(2): 255 - 260. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Lenz, S. K. Kurz, E. Lemmens, S. P. Schoenberger, J. Sprent, M. B. A. Oldstone, and D. Homann IL-7 regulates basal homeostatic proliferation of antiviral CD4+T cell memory PNAS, June 22, 2004; 101(25): 9357 - 9362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Muthukumar, A. Wozniakowski, M.-C. Gauduin, M. Paiardini, H. M. McClure, R. P. Johnson, G. Silvestri, and D. L. Sodora Elevated interleukin-7 levels not sufficient to maintain T-cell homeostasis during simian immunodeficiency virus-induced disease progression Blood, February 1, 2004; 103(3): 973 - 979. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. C. Broers, S. J. Posthumus-van Sluijs, H. Spits, B. van der Holt, B. Lowenberg, E. Braakman, and J. J. Cornelissen Interleukin-7 improves T-cell recovery after experimental T-cell-depleted bone marrow transplantation in T-cell-deficient mice by strong expansion of recent thymic emigrants Blood, August 15, 2003; 102(4): 1534 - 1540. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Dainiak, J. K. Waselenko, J. O. Armitage, T. J. MacVittie, and A. M. Farese The Hematologist and Radiation Casualties Hematology, January 1, 2003; 2003(1): 473 - 496. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2003 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
