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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Pediatric Oncology Branch, Biostatistics and
Data Management Section, and HIV and AIDS Malignancy Branch of the
National Cancer Institute; and National Institute of Allergy and
Infectious Diseases; all of the National Institutes of Health,
Bethesda, MD; University of Colorado Health Sciences Center, Denver CO;
Case Western Reserve University School of Medicine and University
Hospitals of Cleveland, Cleveland, OH; Center for Biostatistics in AIDS
Research, Harvard School of Public Health, Boston, MA; and Rush Medical
College, Chicago IL.
Interleukin (IL)-7 is known to up-regulate thymopoietic pathways of
T-cell regeneration. Recent work also has shown it to potently enhance
thymic-independent peripheral expansion and to restore immunocompetence
in athymic T-cell-depleted hosts. We hypothesized that endogenous IL-7
could contribute to the restoration of T-cell homeostasis following
T-cell depletion. To analyze this, we evaluated circulating IL-7 levels
and lymphocyte subsets in multiple clinical cohorts with T-cell
depletion of varying etiologies. In pediatric (n = 41) and adult
(n = 51) human immunodeficiency virus-infected CD4-depleted
patients, there were strong inverse correlations between IL-7 levels
and CD4 counts (r = The size of the peripheral T-cell compartment
remains tightly regulated throughout life, implying that homeostatic
mechanisms function to carefully maintain peripheral T-cell
numbers.1,2 The nature of such homeostatic mechanisms
remains poorly understood. Because considerable reductions in thymic
output are known to occur during the normal human
lifespan,3-6 primary regulation of T-cell number is
thought to occur peripherally.7-10 Currently held
paradigms for peripheral mechanisms that contribute to T-cell homeostasis emphasize the critical role for major histocompatibility complex engagement in T-cell survival,11-14 and that
antigen-driven peripheral expansion contributes significantly to
modulating the size of the peripheral T-cell compartment, especially
following T-cell depletion.15,16 Regulation of such events
has been postulated to occur in the context of a vaguely defined entity
termed the "lymphoid niche."8,17 While the exact
anatomic location and unique microenvironmental factors that exist
within lymphoid niches are unknown, it is thought to be a site where
adequate availability of antigen, major histocompatibility complex, and
growth factors exist to allow competing T-cell populations to vie for
survival and expansion signals. Growth factors that contribute to the
regulation of the peripheral T-cell compartment within the putative
lymphoid niche have not yet been defined.
Evidence compiled from clinical and experimental models of T-cell
depletion provide some clues as to the factors that contribute to
T-cell homeostasis. First, it has been observed that compensatory homeostatic responses to T-cell depletion are "blind" to CD4 and CD8 subsets18-20 because, in murine models, isolated
depletion of CD4 or CD8 T-cell populations leads to subsequent
expansion of the reciprocal subset.18 In the human
immunodeficiency virus (HIV) infection, following bone marrow
transplantation and following T-cell-depleting chemotherapy, declines
in CD4 T cells are accompanied by concomitant rises in CD8 T cells,
sometimes to supranormal levels.19,20 Second, large
numbers of activated cells accumulate during periods of T-cell
depletion.21-23 Because activated cells are susceptible to
programmed cell death under normal circumstances, it is plausible that
growth factors permissive to the survival of such cells may be active
in this setting.
We have hypothesized that interleukin (IL)-7 may contribute to
regulation of peripheral T-cell homeostasis for the following reasons.
First, because IL-7 is produced predominantly by stromal tissues24,25 as well as by dendritic cells within the
lymph node,26,27 high levels might exist within the
lymphoid tissues and lymphocyte depletion would not diminish
availability, as would occur with lymphocyte-produced growth factors.
Second, the capacity of IL-7 to enhance the survival of mature T
cells28-30 could allow the accumulation of activated
cells, which is known to occur in T-cell-depleted
hosts.16,23 Third, IL-7 expands both peripheral CD4 and
CD8 T cells in T-cell-replete hosts,31 and we have
observed that administration of IL-7 enhances the peripheral expansion of mature T cells after T-cell depletion in thymic-deficient
hosts.49 Finally, IL-7 exerts profound effects on
thymopoiesis,32-34 suggesting a potential role in the
thymic rebound observed following T-cell depletion.4,35,36
Patient groups
Longitudinal analysis was performed on 18 HIV-infected pediatric
patients treated on the ritonavir study. Briefly, patients received
ritonavir monotherapy (dose escalation from 250 to 400 mg/m2 twice daily) for 12 weeks followed by combination
therapy with ritonavir, didanosine (90 mg/m2 twice daily),
and zidovudine (90 mg/m2 twice daily) for 96 weeks. Details
of this trial have been reported elsewhere.38
Adult HIV-infected patients included 31 adult patients naive to
protease inhibitors, with CD4 lymphocyte counts between 100 and 300 cells/µL, at initial screening enrolled on ACTG (AIDS Clinical Trials
Group) protocol 315 after informed consent. Baseline plasma samples
were collected after a 5-week "washout" period off all
antiretroviral agents. A second adult cohort comprised 20 additional
patients with CD4 lymphocyte counts below 100 cells/µL enrolled on
clinical trials at the NCI. Patients enrolled on ACTG 315 were also
followed longitudinally for 48 weeks on highly active antiretroviral
therapy (HAART). Patients received ritonavir (600 mg/d begun day 0, 1200 mg/d begun day 7), lamivudine (300 mg/d begun day 10), and
zidovudine (900 mg/d begun day 10). Details of the protocol have been
reported previously.39
Following informed consent, patients were enrolled on one of 3 approved
protocols within the Pediatric Oncology Branch of the NCI (86-C-169,
89-C-41, and 93-C-0125) for newly diagnosed sarcoma or non-Hodgkin's
lymphoma. Lymphocyte depletion and immune reconstitution in these
patients has been reported previously.4,40,41 Ages ranged
from 5 to 23 years. Patients received 4 to 18 cycles of intensive
multiagent chemotherapy with or without high-dose chemotherapy and stem
cell rescue as described previously and, where appropriate, surgical
resection and/or radiation therapy was administered. Lymphocyte subset
analysis was performed at the time of maximal hematologic recovery from
successive cycles of multiagent chemotherapy and following completion
of therapy if the patient remained free of recurrent neoplastic disease.
Patients suspected of idiopathic CD4 lymphopenia were referred to the
National Institutes of Health for evaluation. Serum samples were
collected at initial screening after informed consent and enrollment on
approved protocol. The case definition for this entity is lack of HIV
infection, with CD4 count below 300 cells/µL in the absence of other
coexisting disease that might be associated with CD4
lymphopenia.42 All patients referred for evaluation were
included in the initial analysis of this group, including those
subsequently found to not meet the case definition because CD4
lymphocyte count was above 300 cells/µL.
Normal IL-7 levels
After obtaining informed consent, normal pediatric ranges for
circulating IL-7 were determined from plasma obtained from
HIV-noninfected children born to HIV-infected mothers. Data and
specimens were kindly provided by the Women and Infants Transmission
Study (WITS). Eleven patients were analyzed longitudinally at 6 months,
12 months, 18 months, 24 months, 36 months, and 48 months. Nineteen
additional samples from HIV-negative children collected at presurgical
screening at Children's National Medical Center (CNMC, Washington, DC)
following informed consent were also analyzed (age range 2 months to
5.5 years). There was no correlation between IL-7 level and age in either group (r = Enzyme-linked immunosorbent assay All samples were frozen at the time they were obtained and were previously unthawed. Prior to analysis, samples were thawed on ice and analyzed using a high-sensitivity colorimetric enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN) according to the manufacturer's recommendations. A separate standard curve was prepared on each plate using serial dilutions. Samples exceeding the highest value on the standard curve were reanalyzed using serial dilutions. Plates were read with a Bio-Tek Instruments EL-340 Biokinetics reader (Winooski, VT) and analyzed using Delta Soft 3.0 software (Biometallics, Princeton, NJ). All samples were run in duplicate. At least 2 samples on each plate had been analyzed previously to determine interassay variability. Intraassay and interassay variability was less than 15%.Immunologic and virologic assessments Enumeration of lymphocyte subsets was performed using standard flow cytometric methods at central flow cytometry facilities according to National Committee for Clinical Laboratory Standards guidelines. B cells expressed CD19 or CD20. Naive CD4 lymphocytes were CD45RA+/CD45RO and, where indicated, were
also CD62L+. Memory CD4 subsets were
CD45RA/CD45RO+. HIV-1 RNA levels in the
pediatric cohort were determined using standard polymerase chain
reaction methods (Roche Amplicor Assay, Branchburg, NJ; lower
limits of detection 200 copies/mL). For the ACTG group, plasma HIV-1
RNA levels were measured by nucleic acid sequence-based amplification
(Organon Teknika, Durham, NC; lower limit of sensitivity adjusted to
100 copies/mL).
Statistical analysis Association between IL-7 levels and other parameters was calculated using Spearman rank correlation. In the pediatric patients, multiple linear regression analysis was performed at each time point using IL-7 as the dependent variable, and absolute CD4 count,2 absolute CD8 count,2 absolute B-cell count,2 CD4:CD8 ratio,2 age, and CDC classification were considered as possible independent variables to include in the model. At each time point, we report the model that contained no more than 3 independent variables, resulted in the largest adjusted R2, and contained relatively few influential observations (as determined by Cook's D statistic43). The global correlation coefficient across all time points was derived using an adaptation of a method for combining dependent statistical tests using repeated measurements.44
If IL-7 plays a role in the homeostatic regulation of T-cell
number, T-cell depletion would be predicted to be associated with
increased levels of IL-7. To test this, serum IL-7 levels were measured
in HIV-infected pediatric patients (n = 41, median age 6.7 years)
with varying degrees of CD4 T-cell depletion. We observed a strong
inverse correlation between IL-7 and absolute CD4 count (Figure
1) (r =
If elevated levels of IL-7 in patients with T-cell lymphopenia reflect
a homeostatic response, recovery of CD4 counts should lead to a decline
in IL-7 levels. To test this, IL-7 levels were analyzed longitudinally
in a subset of the pediatric HIV-infected cohort enrolled on a protease
inhibitor-based HAART. As seen in Figure
2, patients with a good immunologic
response to HAART showed temporally related declines in serum IL-7
levels, while patients with persistently low CD4 counts despite
antiretroviral therapy maintained elevated serum IL-7 levels throughout
the trial. Sequential multiple linear regression analyses were also
performed on this cohort. Among the multiple independent variables
considered (CD4 count, CD8 count, CD4:CD8 ratio, B-cell count, absolute
lymphocyte count, age, and CDC classification), the most important
variables in defining circulating IL-7 level were CD4 count, CD8 count, and CD4:CD8 ratio (Table 2). As a measure
of the overall correlation between serum IL-7 levels and lymphocyte
counts during the entire period of the study, global correlation
coefficients were calculated for each parameter using data from all
available time points. The strongest inverse correlation was between
IL-7 and CD4 cells (global correlation coefficient
Given the evidence that a substantial amount of IL-7 is produced within
the thymus,45 one potential source for the increased IL-7
observed in the HIV-infected pediatric cohort is thymic stroma. If the
thymus was the principal site of production for the increased IL-7 seen
in HIV-infected children with CD4 T-cell depletion, one would predict
lower IL-7 levels in CD4-depleted HIV-infected adults as a result of
reduced thymic mass in relation to total body mass.46 To
address this, we measured IL-7 levels in a cohort of HIV-infected adult
patients, including 20 adults with severe (< 100 cells/µL) and 31 patients with less severe CD4 depletion (100-300 cells/µL at initial
screening). IL-7 levels in this cohort were significantly higher
(median 15.8 pg/mL, mean 22.3 ± 14.6 pg/mL) than in normal adult
volunteers (n = 17, median 2.7 pg/mL, mean 3.1 ± 2.5 pg/mL,
P < .0001, Wilcoxon rank sum test) and were elevated to
the same degree as the HIV-infected pediatric cohort (median 14.1 pg/mL, mean 17.2 ± 13.3 pg/mL, P = .15, Wilcoxon rank
sum test). As observed in the HIV-infected pediatric cohort, there was
a strong inverse correlation between IL-7 and CD4 cells (r = Longitudinal data and extensive immunophenotyping for patients enrolled
on a HAART clinical trial (ACTG 315, n = 31) allowed analysis of
relationships between circulating IL-7 levels and lymphocyte subsets
over time in this population with moderate CD4 cell depletion (median
CD4 count at baseline, 213 cells/µL). When this population was
analyzed independent of the more severely depleted HIV-infected adults
for whom longitudinal data were not available, IL-7 levels were
not correlated with the only moderately depleted CD4 counts (Table
3). However, a strong inverse correlation was observed with the profoundly depleted
CD4+RA+62L+ subset. Because
recovery of this subset occurred during HAART, this inverse
relationship progressively diminished and was lost by 24 weeks.
Therefore, in HIV infection, an inverse correlation existed between CD4
counts and circulating IL-7 levels in the setting of profound CD4 cell
depletion (CD4 count < 100 cells/µL), whereas this relationship is
not observed in populations with moderate CD4 cell depletion or in
healthy, non-CD4 cell-depleted individuals. Furthermore, these data
suggest that isolated depletion of the
CD4+45RA+62L+ subset is sufficient
to maintain elevated circulating IL-7 levels but, again, the
relationship is lost upon partial recovery of this subset and
normalization of circulating IL-7 levels.
Although the relationship between CD4 cells or CD4 cell subsets and
IL-7 levels in HIV is striking, the increases in serum IL-7 levels
observed in patients with advanced HIV infection could be a
disease-specific phenomenon related to direct or indirect effects of
the virus rather than reflecting a causal relationship between CD4 cell
depletion and IL-7 levels. Therefore, we also analyzed a cohort of
patients with cancer treated with T-cell-depleting chemotherapeutic
regimens to determine whether these findings could be extended to other
states associated with T-cell deficiency. Prior to chemotherapy
(n = 30, median CD4 count 639 cells/µL), there was no correlation
between IL-7 levels and CD4 count, similar to non-T-cell-depleted,
HIV-uninfected children. However, as seen in Figure
3, depletion of CD4 cells with
chemotherapy (treated with 3-10 cycles, median 76 cells/µL) resulted
in a rise in serum IL-7 levels and a strong inverse correlation between
IL-7 levels and CD4 counts (n = 17, r =
Finally, we analyzed serum IL-7 levels in a cohort of patients
evaluated for idiopathic CD4 lymphopenia. When the entire cohort was
analyzed (n = 50), including patients who did not meet the case
definition at initial evaluation (median CD4 count 235 cells/µL, range 12-887 cells/µL), weak inverse correlations existed between serum IL-7 levels and CD4 counts (r =
T-cell depletion is associated with increases in circulating IL-7 levels, suggesting that IL-7 may be involved in homeostatic regulation of T-cell numbers. These results confirm and expand on the study by Bolotin et al,47 which demonstrated increased IL-7 levels in pediatric patients undergoing bone marrow transplantation wherein the highest IL-7 levels were observed in patients with the most severe lymphocyte depletion. Additional mechanistic data from murine models indicate that IL-7 increases T-cell numbers, often to supranormal levels, both in T-cell-replete hosts31 and following bone marrow transplantation.48 IL-7 enhances both thymic-dependent pathways and thymic-independent peripheral expansion following T-cell depletion.49 Further, IL-7 therapy restores immune responses in both thymus-bearing48 and thymus-deficient hosts50 following T-cell depletion. Lastly, emerging data suggest that IL-7 can also enhance extrathymic pathways of T-cell differentiation (Kenneth Weinberg, written communication, 2000). Thus, the effects of IL-7 on multiple pathways of T-cell regeneration suggest a model wherein increased availability of IL-7 following CD4 depletion would be highly effective in restoring host immune competence. The mechanism underlying the increases in circulating IL-7 levels
observed in states of T-cell depletion are not clear and will require
additional studies using animal systems. At least 2 scenarios are
possible. In the first, decreased T-cell numbers result in diminished
IL-7 receptor availability, leading to increased levels of free IL-7
with no change in overall IL-7 production, as has been suggested for
thrombopoietin.51,52 Such a model requires no interaction
between the IL-7-producing cells and peripheral T cells but could
result in elevated levels of this cytokine in the microenvironment of
the lymphoid tissues. Evidence against this model comes from analysis
of the results presented here. If increased circulating IL-7 resulted
solely from diminished target cell binding, this should occur in all
clinical settings associated with CD4 depletion, including idiopathic
CD4 lymphopenia, unless there is an increase in IL-7 receptor
expression in this entity. Furthermore, while CD8 cells also express
IL-7 receptor,53,54 preliminary results suggest that the
level may be less than that seen on resting CD4 cells, which would
provide a possible explanation for why expansions of this subset
following cancer chemotherapy are not sufficient to lower circulating
IL-7 levels in the absence of CD4 cell recovery. Finally, in patients
recovering from CD4 depletion, there appears to be a delay before IL-7
levels return to normal, whereas regulation by binding to IL-7 receptor
would be expected to occur rapidly. In the second model, changes in T-cell counts would lead to increased production of IL-7, as occurs with erythropoietin.55 This model invokes interaction
between T-cell populations and IL-7-producing cells via a soluble
mediator or through direct contact within the lymphoid
microenvironment. The nature of such an interaction has not been
defined but could involve local production of a factor such as
transforming growth factor- Interestingly, in both HIV-infected groups, the inverse relationship is not linear with the slope, increasing substantially at CD4 counts below 200 cells/µL. In attempting to understand this, it is important to note that all examinations employed in this report are derived from the peripheral blood. As shown previously, peripheral blood lymphocyte counts correlate only roughly with tissue lymphocyte counts because lymphocyte numbers in nodal tissues are relatively well preserved despite relatively early depletion in the peripheral blood.59,60 Similarly, circulating IL-7 levels might only rise after increases have already occurred in the lymphoid tissue to a degree sufficient to allow "spillover" into the circulation. Therefore, the inflection point of this curve, while of interest, may not accurately reflect the absolute point at which an increased level of IL-7 is available to cells within the lymphoid tissue itself. From these observations, a number of potential therapeutic implications emerge. Because replication of HIV is enhanced in activated CD4 cells61 and IL-7 can enhance the replication of HIV in in vitro systems,62 neutralizing of IL-7 in patients with increased circulating levels could potentially diminish viral replication. Additionally, lymphodepletion has been associated with the development of lymphoproliferative disorders and autoimmunity. In animal models, IL-7 can contribute to both scenarios,63-66 potentially implicating chronic elevation of circulating IL-7 in such events. Finally, following control of viral replication with antiretroviral agents, and in the setting of chemotherapy-induced T-cell depletion, pharmacologic doses of IL-7 would be predicted to enhance immune reconstitution. In summary, CD4 T-cell deletion in humans leads to elevated circulating levels of IL-7. In HIV and following cancer chemotherapy, significant inverse correlations exist between CD4+ and CD4+CD45RA+ T cells in patients with profound depletion of these subsets. Restoration of these subsets leads to normalization of circulating IL-7 levels and loss of the inverse relationship. Some patients with idiopathic CD4 lymphopenia have an aberrant relationship between IL-7 and CD4 count, suggesting a disruption of this system in a subset of these patients. We postulate that elevation of IL-7 within the lymphoid microenvironment in patients with CD4 depletion contributes to the increased peripheral expansion, accumulation of activated cells, and thymic rebound observed CD4-depleted hosts.
We thank Drs Claire Chougnet and Gene Shearer for providing the presurgical pediatric samples and Kathleen M. Wyvill for sample coordination and data analysis for the HIV-infected adults from the NCI. We also thank all members of the AIDS Clinical Trials Group and acknowledge WITS for providing samples for determination of IL-7 levels in HIV-uninfected children. WITS consists of 6 clinical centers (multiple sites located in Boston and Worcester, MA; Columbia-Presbyterian Medical Center, New York, NY; University of Illinois at Chicago; University of Puerto Rico; State University of New York at Brooklyn; and Baylor College of Medicine, Waco, TX), one coordinating center (Clinical Trials and Surveys Corporation), and is jointly funded by the National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, and National Institute on Drug Abuse. Finally, we thank Drs Ron Gress and Ron Germain for their careful review of the manuscript.
Submitted October 24, 2000; accepted January 22, 2001.
AIDS Clinical Trials Group studies were funded by the National Institutes of Health (AI-25879, AI-32770, AI-25915, AI-44748, AI-38855, AI-38858, R-0080, RR-00051, CA-46934).
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.
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L. Pedroza-Martins, W. J. Boscardin, D. J. Anisman-Posner, D. Schols, Y. J. Bryson, and C. H. Uittenbogaart Impact of Cytokines on Replication in the Thymus of Primary Human Immunodeficiency Virus Type 1 Isolates from Infants J. Virol., June 14, 2002; 76(14): 6929 - 6943. [Abstract] [Full Text] [PDF]
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T. J. Fry and C. L. Mackall Interleukin-7: from bench to clinic Blood, May 13, 2002; 99(11): 3892 - 3904. [Full Text] [PDF]
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C. M. Steffens, E. Z. Managlia, A. Landay, and L. Al-Harthi Interleukin-7-treated naive T cells can be productively infected by T-cell-adapted and primary isolates of human immunodeficiency virus 1 Blood, May 1, 2002; 99(9): 3310 - 3318. [Abstract] [Full Text] [PDF]
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A. Llano, J. Barretina, A. Gutierrez, J. Blanco, C. Cabrera, B. Clotet, and J. A. Este Interleukin-7 in Plasma Correlates with CD4 T-Cell Depletion and May Be Associated with Emergence of Syncytium-Inducing Variants in Human Immunodeficiency Virus Type 1-Positive Individuals J. Virol., November 1, 2001; 75(21): 10319 - 10325. [Abstract] [Full Text] [PDF]
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A. R.M. Almeida, J. A.M. Borghans, and A. A. Freitas T Cell Homeostasis: Thymus Regeneration and Peripheral T Cell Restoration in Mice with a Reduced Fraction of Competent Precursors J. Exp. Med., August 27, 2001; 194(5): 591 - 600. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
0.77, P < .0001, and
r = 
(data not shown).
and solid line indicate IL-7; 
and broken line,
CD4.
by T cells that can down-regulate
stromal IL-7 secretion.