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IMMUNOBIOLOGY
From the National Institute of Allergy and Infectious
Diseases, National Institutes of Health (NIH), Bethesda, MD; Science
Applications International Corp, Frederick, NC; Georgetown University,
Washington DC; and the Critical Care Medicine Department, Clinical
Center, NIH, Bethesda, MD.
The long-term immunologic effects of intermittent interleukin 2 (IL-2) therapy were evaluated in a cross-sectional study by comparing 3 groups: HIV-seronegative volunteers, HIV-infected (HIV+)
patients receiving highly active antiretroviral therapy (HAART), and
HIV+ patients receiving HAART and intermittent IL-2.
Whole-blood immunophenotyping was performed to study expression of the
IL-2 receptor chains on T lymphocytes and natural killer cells and to
further characterize CD4+/CD25+ T cells.
Increased CD25 expression, especially in CD4+ T cells but
also in CD8+ T cells, without increases in expression of
the Interleukin 2 (IL-2) or T-cell growth factor is
currently approved for the treatment of metastatic renal cell carcinoma
and melanoma. IL-2 has also been tested experimentally in HIV infection in phase I and II studies since the early years of the AIDS epidemic. In randomized controlled clinical trials, intermittent administration of IL-2 in HIV-infected (HIV+) patients has been shown to
lead to substantial and sustained expansion of the CD4+
T-cell pool.1,2 This expansion is enriched for naive
CD4+ T cells and is not associated with increases in HIV-1
viral load.3,4 Subcutaneous administration of IL-2 was
found to be equally effective and better tolerated than intravenous
administration, thus facilitating outpatient
management.5-7 In combination with highly active
antiretroviral therapy (HAART), intermittent administration of IL-2 can
lead to increases in CD4+ cell count even in cases in which
the baseline count is as low as 50 cells/µL.8-12 Phase
III studies with clinical end points (SILCCAT: Subcutaneous IL-2 in HIV
Infected Subjects with Low CD4 Counts under Active Antiretroviral
Therapy and ESPRIT: Evaluation of Subcutaneous Proleukin in a
Randomized International Trial) are under way to assess the clinical
benefit of the increases in CD4+ T cells induced by
IL-2.
IL-2 binds to a cellular receptor that is composed of 3 chains:
the Despite some disagreement on the exact percentage of human
peripheral blood T cells expressing CD25 On the basis of data from prospective controlled studies, it has been
reported that HIV+ patients treated with IL-2 have an
expansion of CD4+ T cells bearing the To better characterize the effect of IL-2 on expression of the IL-2
receptor by T cells and NK cells, we examined Study participants
Immunophenotyping
To study expression of CD25 on naive CD4+ cells, gating was
done in the CD4+/CD45RO Proliferation assays of CD4+/CD25+ and
CD4+/CD25 Cells (PBMCs, CD4+/CD25+, and
CD4+/CD25 In 6 experiments designed to test specifically for suppression,
5 × 104 CD4+/CD25 Statistical methods All 3-group comparisons were done by using the Kruskal-Wallis test. When significant differences (P = .05) were detected, 2-group comparisons were done with the Wilcoxon 2-sample test. The Student t test was used to compare normally distributed variables: the percentage of RA+/RO+ dull intermediate CD4 cells, the percentage of CD25 expression on the RA+/RO+ dull intermediate CD4 subset, and the percentage of Ki67+ T cells in the HAART and IL-2+HAART groups. The paired Student t test was used to compare the mean CD25 expression on naive and RA+/RO+ dull CD4 cells and the geometric means of the proliferative responses of CD25+ and CD25 CD4 cells. The associations between variables were
determined by using the Spearman rank correlation method. Adjustment of
P values for multiple testing was done with the
Bonferroni method.
Patient characteristics The characteristics of participants at study entry are shown in Table 1. Patients in the IL-2 group had received a minimum of 3 cycles of IL-2 in the past and were tested several months after the last IL-2 cycle (range, 3-54 months), with 3 of them studied immediately before initiation of an IL-2 cycle. The 3 groups did not differ significantly with respect to their total CD4+ count, percentage of naive and memory CD4+ cells, age, or viral load. Significant differences were observed for the following factors: CD4:CD8 ratio (HIV versus HAART or
IL-2+HAART group and IL-2+HAART versus HAART group,
P = .01), percentage of CD4+ T cells
(HIV versus HAART group and IL-2+HAART versus HAART
group, P = .005) and percentage and total CD8+
T cells (HAART and IL-2+HAART versus HIV group,
P < .001).
Expression of the chains of the IL-2 receptor on CD4+ and CD8+ T cells and NK cells The results of the immunophenotypic analysis of expression of the 3 chains of the IL-2 receptor on T cells and NK cells are shown in Table 2. We found, as others did previously,21 that the percentage of CD4+ T cells expressing CD25 was higher than the percentage of CD8+ T cells or NK cells expressing CD25 in all 3 groups (Figure 1A and Table 2). The percentage of CD4+ T lymphocytes expressing CD25 was higher in the IL-2 group than in the other 2 groups. The same was observed for MFI of the CD25 population. No differences were observed in CD25 expression or MFI between the HAART group and the HIV volunteers. When  -chain
(CD122) expression was evaluated, the percentage of CD4+ T
cells expressing CD122 was found to be lower in the IL-2+HAART group
than in the HIV group. Finally, we observed significantly
lower expression of CD132 (MFI) on CD4+ T cells from the
IL-2+HAART group than on CD4+ T cells from the HAART group.
Transient increases in expression of and  chains were detected
during IL-2 cycles (Figure 1B).
CD25 expression and MFI were also elevated in CD8+ T cells
from the IL-2 group compared with the other 2 groups. The MFI for CD122
on CD8+ T cells was higher in both the HAART and IL-2+HAART
groups than in HIV Enhanced expression of CD25 on CD4+ T cells in patients treated with IL-2 is persistent and occurs predominantly in the naive subset of CD4+ T cells In HIV volunteers, 39% of CD4+ T cells
(range, 9%-61%) were naive and 10% of these cells expressed CD25. In
HIV+ patients treated with HAART, 24% of CD4+
T cells (range, 10%-57%) were naive and 13% of these expressed CD25
(P > .5 versus HIV controls). In
patients given IL-2, 30% of total CD4+ T cells (range,
3%-54%) were naive, and in contrast to findings in the other groups,
61% of naive CD4+ cells were CD25+
(P < .001 versus the HIV and HAART groups).
The absolute counts of naive CD4+/CD25+ cells
reflected the same differences (Figure
2A). No significant differences were
observed in the percentages of memory CD4+ T cells
expressing CD25 (56% in HIV volunteers, 52% in
HAART-treated patients, and 64% in IL-2+HAART-treated patients;
P > .11). As demonstrated by the shaded histograms in Figure 2B, the differences in CD25 expression on naive CD4+
cells of patients receiving IL-2 and participants in the other 2 groups
were striking.
To determine the contribution of the expansion of the naive
CD4+/CD25+ subset to the increases in the
overall size of the CD4+ pool in the HAART and IL-2+HAART
groups, we looked for correlations between the number of these cells
and the numbers of total naive and total CD4+ T cells. In
the HAART group, a strong correlation was found between the number of
naive CD4+/CD25+ cells and the total
CD4+ T-cell count (r = 0.75; P = .03) or the
total number of naive CD4+ T cells (r = 0.83;
P = .001; Figure 2C). Similarly, in the IL-2+HAART group,
a significant correlation was observed between the number of naive
CD4+/CD25+ T cells and the total
CD4+ T-cell counts (r = 0.61; P = .03) or
the absolute number of naive CD4+ T cells (r = 0.77;
P = .001). In HIV Cryopreserved cells obtained at various time points before and after
initiation of IL-2 therapy were tested to provide further documentation
of the emergence of naive CD4+/CD25+ cells
after administration of IL-2 and their persistence after an IL-2 cycle.
After initiation of IL-2, a distinct CD25+ population
emerged in the CD45RO
On staining for CD45RA/CD45RO, a CD4+ population that
stained positive but had intermediate fluorescence intensity for both CD45RA and CD45RO isoforms was observed in all groups (Figure 4). This population was distinct from
RA+/RO
The mean absolute numbers of dull RA+/RO+ cells were 81/µL (95% CI, 48-114/µL) in the HAART group and 174 (95% CI, 125-223/µL) in the IL-2+HAART group (P = .01). In both groups, the total number (but not the percentage) of these cells correlated strongly with the total CD4+ count (r = 0.99; P = .002 in the HAART group and r = 0.74; P = .002 in the IL-2 group; Figure 4C), suggesting that expansion of these cells plays a role in the CD4+ increases observed with HAART or IL-2+HAART. When expression of CD25 in the dull RA+/RO+ CD4 subsets in these 2 groups was compared, a significant difference was observed (mean values, 75% in the IL-2+HAART group versus 35% in the HAART group; P < .001). Finally, in patients treated with IL-2+HAART, expression of CD25 was higher in the dull RA+/RO+ CD4 cells than in either the memory or naive CD4 subsets (both paired differences were significant; P = .002). This was in contrast to findings in the HAART group, in which progressive increases in CD25 expression from the naive to the dull RA+/RO+ to the memory CD4+ T-cell subsets were observed. CD25 up-regulation in patients treated with IL-2 is not accompanied by increased expression of other activation markers Staining with early (CD69) and late (CD95) activation markers was performed to investigate the possibility that increased CD25 expression reflected an overall state of immune activation similar to that occurring after antigenic stimulation. The percentage of either CD4+ or CD8+ T cells expressing CD69 was similar in all 3 groups (data not shown). CD95 expression on CD4+ T cells was similar in the 2 HIV+ groups but was higher than that in the HIV volunteers (56% in
the HIV group versus 83% in the HAART group and versus
80% in the IL-2+ HAART group; P = .02 for both
comparisons). A similar observation was made in the CD8+
T-cell pool (54% versus 87% and versus 83%;
P = .01).
To investigate the possibility that continuous increased levels of
CD4+ T-cell proliferation were sustaining the higher
CD4+ counts in patients treated with IL-2, intracellular
staining for the nuclear antigen Ki67 was performed in a subset of
HIV+ patients who had plasma HIV RNA levels below 50 copies/mL and for whom cryopreserved cells from the study-entry time
point were available (8 of 10 patients in the HAART group and 9 of 9 patients in the IL-2+HAART group). Ki67 is expressed during the late
G1, S, G2, and M phases of the cell cycle and
is considered a marker of recent proliferation. An increased percentage
of Ki67-positive staining cells has been reported in HIV+
patients before initiation of HAART.28 Surprisingly, we
found that patients given IL-2 had a lower fraction of T cells
(CD4+ or CD8+) that stained positive for Ki67
(Figure 5), a result suggesting that
after IL-2 therapy, continuous higher rates of proliferation do not
account for the sustained increases in CD4+ T-cell
counts. Although the differences were not statistically significant (P = .14 for the CD4+ and
P = .48 for the CD8+ T cells), the data
suggest that decreased turnover and increased survival may be
responsible for the increases in CD4+ T cells observed in
patients who have received IL-2.
Both CD4+/CD25+ and
CD4+/CD25 cells to the
mitogens PHA and PWM (P = .03) and to CMV antigen (P = .01). A trend toward higher responses to IL-2 was
also observed (P = .06). Additionally, in all experiments,
the background proliferation of CD4+/CD25
cells was higher than that of CD4+/CD25+ cells
(P < .01). In experiments designed to detect suppression (Figure 6B), no evidence of suppression was found in the response to
TCR stimulation with anti-CD3 or anti-CD3 with anti-CD28.
Interestingly, a blunting of the response to PHA that did not lead to
complete suppression was evident. This observation is under further
investigation.
This study clearly demonstrated the emergence of a unique population of CD4+/CD25+ T cells in HIV+ patients who had received intermittent IL-2 therapy. These cells are not anergic, do not proliferate continuously or express increased levels of the trimeric IL-2 receptor, and may represent a long-lived population of cells that are predominantly responsible for the increases in CD4+ T cells observed with IL-2 therapy. It is likely that these cells represent the product of IL-2-induced T-cell expansion in the absence of antigenic stimulation. It was previously reported that naive human T cells can proliferate in
vitro and retain their naive phenotype if stimulated in the absence of
antigen with a combination of IL-2, IL-6, and tumor necrosis factor In our study, we also found a population of dull double-positive
RA+/RO+ CD4+ T cells that
constituted approximately 10% of the total CD4+ pool in
HIV The current study highlights the fact that increased expression of the
Intracellular staining for the nuclear activation antigen Ki67 was used as an indirect measurement of recent proliferation and activation in a subset of study participants who had an HIV burden of less than 50 copies/mL. No evidence of increased Ki67 expression was detected in the IL-2 group, suggesting that persistent, increased T-cell proliferation in response to endogenously produced IL-2 cannot account for the sustained high CD4+ counts observed in that group. Given this finding, decreased turnover and prolonged survival of these cells is a more plausible explanation for this observation. Other data seem to support this hypothesis.42 Ongoing studies that allow longitudinal evaluation of cell survival in vivo with tracking of T lymphocytes labeled with bromodeoxyuridine or deuterium-glucose should shed additional light on these fundamental areas.43 A CD4+/CD25+ cell population has been
identified in studies in animals and humans as a subset of cells with
regulatory function that are anergic and
immunosuppressive.27,44 These cells have been studied
extensively in animal models and are considered to be of thymic origin.
Once they encounter their cognate antigen, they become anergic (do not
proliferate in response to TCR-mediated signals) and acquire an
immunosuppressive function that is not antigen specific.45
Their ability to suppress the cytotoxic T lymphocytes of
CD8+ T cells has also been reported.46 These
immunoregulatory CD4+/CD25+ cells have been
observed in humans and identified as terminally differentiated memory
cells that do not proliferate in response to anti-CD3, anti-CD3 with
anti-CD28, or mitogens such as PHA and concanavalin A; are prone to
apoptosis; and express CD25 with high fluorescence
intensity.47,48 Despite some similarities (such as the
high MFI for CD25 and the expression of homing molecules such as 62L),
there are important phenotypic differences between these cells and the
CD4+/CD25+ cells in our IL-2-treated group. In
animal models, the immunoregulatory cells have been described as CD45RB
low, indicating a memory phenotype. Similarly, studies in humans found
that these cells were present exclusively in the CD45RO+
fraction of CD4+ T cells.49 In the current
study, the expanded CD4+/CD25+ cells in
patients given IL-2 included a high proportion of naive or dull
intermediate RA+/RO+ cells. In addition, no
evidence of anergy or suppression of TCR responses was detected in the
proliferative responses of the CD25+ and CD25 In summary, in HIV+ patients receiving intermittent IL-2 therapy, a sustained increase in CD4+ T-cell counts was observed with a preferential expansion of CD4+ T cells with a naive phenotype. A high proportion of these cells expressed CD25 but not the other chains of the IL-2 receptor. Preliminary data suggest that prolonged survival of this population may represent the main mechanism of the sustained increases in CD4+ count observed after administration of IL-2. Additional studies focusing on the origin, functional characteristics, and properties of these cell subsets will further clarify their role in T-cell homeostasis. The results of ongoing phase III trials of intermittent IL-2 therapy in HIV infection that are assessing clinical end points will be critical in clarifying the clinical implications of our observations.
We thank all the participating patients and the staff of the National Institute of Allergy and Infectious Diseases/Critical Care Medicine Department Clinic for their commitment and enthusiasm, Dr Anthony Fauci for his continued encouragement and support, and Mary Rust for assistance in the preparation of the manuscript.
Submitted September 6, 2001; accepted May 8, 2002.
Funded in whole or in part with federal funds under National Cancer Institute contract NO1-CO-56000. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the US Government.
The US Government has been granted a use patent for intermittent interleukin-2 therapy including Drs. H. Clifford Lane and Joseph A. Kovacs as inventors.
Partly presented in abstract form at the American Association of Immunologists meeting, Experimental Biology 2001, Orlando, Florida, March 31-April 4, 2001. Abstract B-816.
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: H. Clifford Lane, Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10, Room 11S-231, 10 Center Drive, MSC 1876, Bethesda, MD 20892; e-mail: clane{at}niaid.nih.gov.
1.
Kovacs JA, Vogel S, Albert JM, et al.
Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus.
N Engl J Med.
1996;335:1350-1356
2.
Kovacs JA, Baseler M, Dewar RJ, et al.
Increases in CD4 T lymphocytes with intermittent courses of interleukin- 2 in patients with human immunodeficiency virus infection. A preliminary study.
N Engl J Med.
1995;332:567-575 3. Emery S, Capra WB, Cooper DA, et al. Pooled analysis of 3 randomized, controlled trials of interleukin-2 therapy in adult human immunodeficiency virus type 1 disease. J Infect Dis. 2000;182:428-434[CrossRef][Medline] [Order article via Infotrieve]. 4. Davey RT Jr, Chaitt DG, Albert JM, et al. A randomized trial of high- versus low-dose subcutaneous interleukin-2 outpatient therapy for early human immunodeficiency virus type 1 infection. J Infect Dis. 1999;179:849-858[CrossRef][Medline] [Order article via Infotrieve]. 5. Levy Y, Capitant C, Houhou S, et al. Comparison of subcutaneous and intravenous interleukin-2 in asymptomatic HIV-1 infection: a randomised controlled trial. ANRS 048 study group. Lancet. 1999;353:1923-1929[CrossRef][Medline] [Order article via Infotrieve]. 6. Carr A, Emery S, Lloyd A, et al. Outpatient continuous intravenous interleukin-2 or subcutaneous, polyethylene glycol-modified interleukin-2 in human immunodeficiency virus-infected patients: a randomized, controlled, multicenter study. Australian IL-2 Study Group. J Infect Dis. 1998;178:992-999[Medline] [Order article via Infotrieve]. 7. Davey RT Jr, Chaitt DG, Piscitelli SC, et al. Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons. J Infect Dis. 1997;175:781-789[Medline] [Order article via Infotrieve]. 8. Tubiana R, Carcelain G, De Sa M, et al. ILSTIM (ANRS 082). Interleukin 2 (IL2) accelerates CD4 cells reconstitution in patients with CD4 < 200/MM3 despite effective HAART. Presented at: First International AIDS Society Conference on HIV Pathogenesis and Treatment; July 7-11, 2001; Buenos Aires, Argentina. Abstract 102.
9.
Davey RT Jr, Murphy RL, Graziano FM, et al.
Immunologic and virologic effects of subcutaneous interleukin 2 in combination with antiretroviral therapy: a randomized controlled trial.
JAMA.
2000;284:183-189 10. Arno A, Ruiz L, Juan M, et al. Efficacy of low-dose subcutaneous interleukin-2 to treat advanced human immunodeficiency virus type 1 in persons with </= 250/µL CD4 T cells and undetectable plasma virus load. J Infect Dis. 1999;180:56-60[CrossRef][Medline] [Order article via Infotrieve]. 11. Abrams DI, Bebchuk JD, Denning ET, Markowitz NP, Beirn T. AIDS CPfCRo. IL-2 therapy produces no change in HIV RNA after one year. Presented at: 40th Conference on Antimicrobial Agents and Chemotherapy; September 17-20, 2000; Toronto, Ontario, Canada. Abstract L-11. 12. Mitsuyasu RT. A randomized, controlled phase II study of HAART with intermittent IL-2 by continuous IV or subcutaneous routes in HIV-infected patients with CD4 counts 50-350 cells/mm3: ACTG 328 results at 60 weeks. Presented at: Fifth International Conference on Drug Therapy in HIV Infection; October 22-26, 2000; Glasgow, United Kingdom.
13.
Bani L, David D, Moreau JL, et al.
Expression of the IL-2 receptor
14.
Giri JG, Ahdieh M, Eisenman J, et al.
Utilization of the
15.
Leonard WJ, Noguchi M, Russell SM.
Sharing of a common 16. Nelson BH, Willerford DM. Biology of the interleukin-2 receptor. Adv Immunol. 1998;70:1-81[Medline] [Order article via Infotrieve].
17.
Roessler E, Grant A, Ju G, Tsudo M, Sugamura K, Waldmann TA.
Cooperative interactions between the interleukin 2 receptor
18.
Kono T, Minami Y, Taniguchi T.
The interleukin-2 receptor complex and signal transduction: role of the 19. Zola H, Mantzioris BX, Webster J, Kette FE. Circulating human T and B lymphocytes express the p55 interleukin-2 receptor molecule (TAC, CD25). Immunol Cell Biol. 1989;67:233-237.
20.
Sereti I, Gea-Banacloche J, Kan MY, Hallahan CW, Lane HC.
Interleukin 2 leads to dose-dependent expression of the
21.
David D, Bani L, Moreau JL, et al.
Further analysis of interleukin-2 receptor subunit expression on the different human peripheral blood mononuclear cell subsets.
Blood.
1998;91:165-172 22. Vanham G, Kestens L, Vingerhoets J, et al. The interleukin-2 receptor subunit expression and function on peripheral blood lymphocytes from HIV-infected and control persons. Clin Immunol Immunopathol. 1994;71:60-68[CrossRef][Medline] [Order article via Infotrieve]. 23. Shahabuddin S. Expression of IL-2 receptor subunit p55 (CD25) on normal human lymphocytes. Clin Immunol Immunopathol. 1993;69:175-179[CrossRef][Medline] [Order article via Infotrieve].
24.
Johnson N, Parkin JM.
Dysregulation of the interleukin-2 receptor 25. De Paoli P, Zanussi S, Simonelli C, et al. Effects of subcutaneous interleukin-2 therapy on CD4 subsets and in vitro cytokine production in HIV+ subjects. J Clin Invest. 1997;100:2737-2743[Medline] [Order article via Infotrieve].
26.
Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA.
CD4+CD25high regulatory cells in human peripheral blood.
J Immunol.
2001;167:1245-1253 27. Shevach EM, Thornton A, Suri-Payer E. T lymphocyte-mediated control of autoimmunity. Novartis Found Symp. 1998;215:200-211[Medline] [Order article via Infotrieve].
28.
Hazenberg MD, Stuart JW, Otto SA, et al.
T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART).
Blood.
2000;95:249-255
29.
Thornton AM, Shevach EM.
CD4+CD25+ immunoregulatory T cells suppress polyclonal T cell activation in vitro by inhibiting interleukin 2 production.
J Exp Med.
1998;188:287-296
30.
Hamann D, Baars PA, Hooibrink B, van Lier RW.
Heterogeneity of the human CD4+ T-cell population: two distinct CD4+ T-cell subsets characterized by coexpression of CD45RA and CD45RO isoforms.
Blood.
1996;88:3513-3521 31. Shevach EM. Certified professionals: CD4+CD25+ suppressor T cells. J Exp Med. 2001;193:F41-F46[CrossRef][Medline] [Order article via Infotrieve].
32.
Unutmaz D, Baldoni F, Abrignani S.
Human naive T cells activated by cytokines differentiate into a split phenotype with functional features intermediate between naive and memory T cells.
Int Immunol.
1995;7:1417-1424
33.
Unutmaz D, Pileri P, Abrignani S.
Antigen-independent activation of naive and memory resting T cells by a cytokine combination.
J Exp Med.
1994;180:1159-1164
34.
Kanegane H, Miyawaki T, Kato K, et al.
A novel subpopulation of CD45RA+ CD4+ T cells expressing IL-2 receptor 35. Kovacs JA, Vogel S, Metcalf JA, et al. Interleukin-2 induced immune effects in human immunodeficiency virus-infected patients receiving intermittent interleukin-2 immunotherapy. Eur J Immunol. 2001;31:1351-1360[CrossRef][Medline] [Order article via Infotrieve]. 36. Hengge UR, Borchard C, Esser S, Schroder M, Mirmohammadsadegh A, Goos M. Lymphocytes proliferate in blood and lymph nodes following interleukin-2 therapy in addition to highly active antiretroviral therapy. AIDS. 2002;16:151-160[CrossRef][Medline] [Order article via Infotrieve]. 37. Sereti I, Herpin B, Metcalf JA, et al. CD4 T cell expansions are associated with increased apoptosis rates of T lymphocytes during IL-2 cycles in HIV infected patients. AIDS. 2001;15:1765-1775[CrossRef][Medline] [Order article via Infotrieve].
38.
Lempicki RA, Kovacs JA, Baseler MW, et al.
Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients.
Proc Natl Acad Sci U S A.
2000;97:13778-13783
39.
Murali-Krishna K, Ahmed R.
Cutting edge: naive T cells masquerading as memory cells.
J Immunol.
2000;165:1733-1737
40.
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 41. Picker LJ, Treer JR, Ferguson-Darnell B, Collins PA, Buck D, Terstappen LW. Control of lymphocyte recirculation in man. I. Differential regulation of the peripheral lymph node homing receptor L-selection on T cells during the virgin to memory cell transition. J Immunol. 1993;150:1105-1121[Abstract]. 42. Sereti I, Martinez-Wilson H, Metcalf J, Kovacs J, Lane HC. Intermittent IL-2 administration in HIV infected patients leads to a decrease in CD4+ T cell turnover rates. Presented at: First International AIDS Society Conference on HIV Pathogenesis and Treatment; July 7-11, 2001; Buenos Aires, Argentina. Abstract 103.
43.
Kovacs JA, Lempicki RA, Sidorov IA, et al.
Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV.
J Exp Med.
2001;194:1731-1741
44.
Takahashi T, Kuniyasu Y, Toda M, et al.
Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state.
Int Immunol.
1998;10:1969-1980
45.
Thornton AM, Shevach EM.
Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific.
J Immunol.
2000;164:183-190
46.
Piccirillo CA, Shevach EM.
Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells.
J Immunol.
2001;167:1137-1140 47. Taams LS, Smith J, Rustin MH, Salmon M, Poulter LW, Akbar AN. Human anergic/suppressive CD4+CD25+ T cells: a highly differentiated and apoptosis-prone population. Eur J Immunol. 2001;31:1122-1131[CrossRef][Medline] [Order article via Infotrieve]. 48. Stephens LA, Mottet C, Mason D, Powrie F. Human CD4+CD25+ thymocytes and peripheral T cells have immune suppressive activity in vitro. Eur J Immunol. 2001;31:1247-1254[CrossRef][Medline] [Order article via Infotrieve].
49.
Jonuleit H, Schmitt E, Stassen M, Tuettenberg A, Knop J, Enk AH.
Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood.
J Exp Med.
2001;193:1285-1294
© 2002 by The American Society of Hematology.
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  D. I. Zonios, J. Falloon, J. E. Bennett, P. A. Shaw, D. Chaitt, M. W. Baseler, J. W. Adelsberger, J. A. Metcalf, M. A. Polis, S. J. Kovacs, et al. Idiopathic CD4+ lymphocytopenia: natural history and prognostic factors Blood, July 15, 2008; 112(2): 287 - 294. [Abstract] [Full Text] [PDF]
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 F. Gesbert, J.-L. Moreau, and J. Theze IL-2 Responsiveness of CD4 and CD8 lymphocytes: further investigations with human IL-2R{beta} transgenic mice Int. Immunol., August 1, 2005; 17(8): 1093 - 1102. [Abstract] [Full Text] [PDF]
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M. Kleinewietfeld, F. Puentes, G. Borsellino, L. Battistini, O. Rotzschke, and K. Falk CCR6 expression defines regulatory effector/memory-like cells within the CD25+CD4+ T-cell subset Blood, April 1, 2005; 105(7): 2877 - 2886. [Abstract] [Full Text] [PDF]
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L. Weiss, V. Donkova-Petrini, L. Caccavelli, M. Balbo, C. Carbonneil, and Y. Levy Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients Blood, November 15, 2004; 104(10): 3249 - 3256. [Abstract] [Full Text] [PDF]
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I. Sereti, K. B. Anthony, H. Martinez-Wilson, R. Lempicki, J. Adelsberger, J. A. Metcalf, C. W. Hallahan, D. Follmann, R. T. Davey, J. A. Kovacs, et al. IL-2-induced CD4+ T-cell expansion in HIV-infected patients is associated with long-term decreases in T-cell proliferation Blood, August 1, 2004; 104(3): 775 - 780. [Abstract] [Full Text] [PDF]
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E. Assier, V. Jullien, J. Lefort, J.-L. Moreau, J. P. Di Santo, B. B. Vargaftig, J. R. Lapa e Silva, and J. Theze NK Cells and Polymorphonuclear Neutrophils Are Both Critical for IL-2-Induced Pulmonary Vascular Leak Syndrome J. Immunol., June 15, 2004; 172(12): 7661 - 7668. [Abstract] [Full Text] [PDF]
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B. H. Nelson IL-2, Regulatory T Cells, and Tolerance J. Immunol., April 1, 2004; 172(7): 3983 - 3988. [Abstract] [Full Text] [PDF]
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A. Audige, E. Schlaepfer, A. Bonanomi, H. Joller, M. C. Knuchel, M. Weber, D. Nadal, and R. F. Speck HIV-1 Does Not Provoke Alteration of Cytokine Gene Expression in Lymphoid Tissue after Acute Infection Ex Vivo J. Immunol., February 15, 2004; 172(4): 2687 - 2696. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
chain (CD25), 
likely reflecting differences in the monoclonal antibodies used, staining techniques, or populations under study
