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Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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or perforin, and these cells do not have a regulatory suppressive
effect on other T cells. In vivo IL-4-producing CD8+ T
cells can be stably detected over a year. When put into culture they
also have a stable cytokine production pattern but fail to produce
perforin even in the presence of IL-12. This special T cell type does
not occur in persons under the age of 40, but is present in 36% of the
persons >60 years of age. In this age group, IL-4-producing
CD8+ T cells are more frequent in persons who are still
capable of raising a humoral immune response following immunization
than in others who fail to produce protective Abs after vaccination.
Our results suggest that CD8+ T cells with a
CD62L++(bright) phenotype accumulate in a
subgroup of older adults. Due to their phenotype that enables them to
migrate into lymphoid tissues and to their capacity to produce IL-4,
these cells may counterbalance the overproduction of proinflammatory
cytokines in old age. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF-
and are primarily involved in
cell-mediated immune responses, whereas Th2 cells secrete IL-4 and IL-5
and play an important role in humoral and allergic responses (2, 3). A polarized cytokine production pattern is also a feature of
human CD4+ T cells (4, 5). In
contrast, CD8+ T cells have historically been
regarded as a homogeneous population of cytotoxic cells that produce
exclusively type 1 cytokines. Only during the last decade the existence
of type 2 cytokine-producing CD8+ T cells has
become evident (6, 7). Analogous to the common terminology
of Th1 and Th2 cells for the CD4+
compartment, T cytotoxic (Tc)3 1 and
Tc2 cells can be distinguished within CD8+ cells
in vitro (8, 9) and in vivo. The in vivo persistence of
Tc2 cells has mainly been reported under pathological conditions such
as HIV (10), tuberculosis (11), lepromatous
leprosy (12), asthma (13), periodontitis
(14) and Graves’ ophthalmopathy (15).
Recently the occurrence of IL-4-producing CD8+ T
cells has been reported to be a feature of healthy aging
(16). A substantial production of IL-4 by purified
CD8+ T cells was found in 15% of healthy elderly
persons who were selected according to the stringent criteria of the
SENIEUR protocol (17). A low IL-4 production by
CD8+ cells was found in 55% of the proband
participants. These data were in good agreement with recent preliminary
results from our laboratory that demonstrated IL-5 and IL-4 were
produced by purified CD8+ T cells from a subgroup
of elderly persons known to produce protective Abs following influenza
vaccination. In contrast, CD8+ T cells from
elderly persons who failed to raise a humoral immune response following
immunization and from young persons did not produce type 2 cytokines.
These results suggested that IL-4 production by
CD8+ T cells might be associated with the
maintenance of intact humoral immunity in old age.
Because little information on the characteristics of IL-4-producing
CD8+ T cells in the context of aging is still
available, the present study was undertaken. We demonstrate that
IL-4-producing CD8+ T cells, which accumulate
with age in a subgroup of healthy adults, have a
CD45RO+CD62L++(bright)
phenotype and do not produce IFN- and perforin. A high frequency of
this special cell type seems to be associated with intact humoral
immunity in elderly persons.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Seventy-four apparently well, healthy persons age 20–90 years were included in the study. Before bleeding, a health check was performed in each participant. All participants had given their informed written consent, and the study was approved by the local ethical committee. Peripheral blood was taken by venipuncture and preparation of PBMCs was performed by standard Ficoll-Paque gradient centrifugation (Amersham Biosiences, Uppsala, Sweden). For intracellular cytokine staining PBMCs were stored in liquid nitrogen until used. Some experiments were done with freshly isolated PBMCs or whole blood.
Influenza vaccination and Ab titers
Twenty-four volunteers (12 females and 12 males >60 years of
age) from the previously described cohort were vaccinated against
influenza with a commercially available trivalent split vaccine
(Vaxigrip; Aventis Pasteur, Lyon, France). Ab responses to the
vaccine hemagglutinin components were determined prior to as well as 4
wk after vaccination by standard hemagglutination inhibition assay as
described previously (18). According to our previous
definition criterion of "humoral nonresponders" (19),
five persons (two females, three males; mean age 81; age range 70–90
years) who did not have influenza-specific Abs before vaccination and
who failed to raise a protective humoral immune response to all three
influenza strains present in the vaccine were chosen as well as four
elderly persons (two females, two males; mean age 75; age range 70–80
years) who did not have influenza-specific Abs before vaccination, but
did have titers of 
1:40 to all three influenza strains 4 wk after
vaccination and thus corresponded to our previous definition of
"humoral responders." The number of CD8+
IL-4-producing cells was then compared in the two person groups. The
remaining persons vaccinated against influenza did not fulfill the
stringent criteria of humoral responders or nonresponders. This result
was either due to high prevaccination Ab titers or to a varying
response to the three influenza strains present in the vaccine. Results
were additionally compared in persons (n = 3)
with a 4-fold increase in titer to all three influenza strains
following vaccination, and with other persons (n = 7)
who did not fulfill this requirement.
Flow cytometry
Surface staining was performed by adding a panel of directly
conjugated titrated Abs (FITC, PerCP, PE, APC) against CD8, CD3,
CD45RO, CD62L, CD69, CD28, CD27, CD25 (all BD PharMingen, San Jose, CA)
to PBMCs or to 150 µl of whole blood. After an incubation period of
20 min at room temperature in the dark, PBMCs were washed and fixed
with 2% formaldehyde until analysis on a FACSCalibur (BD PharMingen).
When doing whole blood stainings, erythrocytes were lysed after the
staining step by adding 500 µl of FACS Lysing solution (BD
PharMingen). After washing, cells were fixed with 2% formaldehyde
until analysis on a FACSCalibur (BD PharMingen). Data were analyzed
with CellQuestPro software (BD PharMingen). CCR7 was stained by a
multistep procedure using purified mouse anti-CCR7 IgM Ab followed
by biotinylated rat anti-mouse IgM and streptavidin-APC conjugate
(all BD PharMingen). For measuring intracellular cytokines, PBMCs were
defrosted and suspended in RPMI 1640 (Life Technologies, Grand Island,
NY) supplemented with 10% FCS (Sigma-Aldrich, St. Louis, MO) at a
concentration of 2 x 106/ml. Cells were
stimulated with 10 ng/ml PMA and 0.5 µg/ml ionomycin (both
Sigma-Aldrich) in the presence of 1 µl/ml GolgiPlug (BD PharMingen)
for 4 h at 37°C. After this stimulation period, cells were
washed with FACS buffer (PBS containing 0.02% BSA) and stained with
titrated directly conjugated Abs recognizing CD3, CD8, CD45RO, CD28,
CD27, CD25 (all BD PharMingen) for 30 min at 4°C in the dark. After
washing, permeabilization of cells with Cytofix/Cytoperm (BD
PharMingen) solution was performed. Permeabilized cells were stained
for intracellular cytokines, for the activation marker CD69, or for
perforin by adding titrated Abs recognizing IL-4, IFN-, IL-2,
perforin, and CD69. Finally cells were washed and stored in 2%
formaldehyde until analysis. For properly setting the cut off, isotype
control and unstimulated control samples were used. CD62L is
proteolytically cleaved from the cell surface by metalloproteinases
even after mild stimulation (20, 21) and can therefore not
be stained together with intracellular cytokines without special
pretreatment. To overcome this problem, the hydroxamic acid derivative
GM6001 (Calbiochem, Darmstadt, Germany) was used for blocking
stimulation-induced shedding of CD62L from the cell surface. Cells were
prestained with fluorescence-conjugated Ab against CD62L for 15 min at
room temperature before stimulation as described (22).
After washing, GM6001 was added at a concentration of 100 µM to the
culture medium. This procedure completely prevented PMA-induced
shedding of CD62L from the cell surface.
Purification of T cells and IL-4 secretion assay
CD8+ T cells were purified by a positive
selection procedure using CD8+-labeled MicroBeads
and the MACS system (Miltenyi Biotec, Bergisch Gladbach, Germany).
CD8+ T cells were labeled with MultiSort
MicroBeads and positively selected in a MACS column. Subsequently the
selected cells were incubated with the MultiSort Release Reagent
(Miltenyi Biotec), which enzymatically removes the MicroBeads from the
cells. A purity of 96% could be obtained. The
CD8+ fraction obtained was used for further
enrichment or isolation of the cell populations described below. For
the enrichment of live IL-4-producing CD8+ cells,
a commercially available IL-4 Secretion Assay, Cell Enrichment and
Detection kit (Miltenyi Biotech) was used. Purified
CD8+ T cells were stimulated with 10 ng/ml PMA
and 0.5 µg/ml ionomycin for 4 h. Subsequently the assay was
performed according to the manufacturer’s instructions. A fraction
with a 6-fold enrichment of IL-4-producing CD8+
cells could be obtained. For the isolation of
CD8+CD25+ cells, the
purified CD8+ fraction was separated over a MACS
column for a second time using anti-CD25-labeled MicroBeads. The
purity of the positively selected cells was >96%, as determined by
FACS analysis.
Cell culture
CD8+ cell populations that had been enriched for IL-4-producing cells by the IL-4 secretion assay were seeded at a density of 5 x 105 cells/well in 24-well plates in medium supplemented with 20 ng/ml rIL-2 (Novartis, Basel, Switzerland) and plate-bound OKT3 (Orthoclone, Transplant, Vienna, Austria), 10 ng/ml rIL-4 (Chemicon, Temecula, CA) or 10 ng/ml rIL-12 (Chemicon). Cytokines and media were replaced every 2 days. After 1 wk of culture, the cells were restimulated with PMA and ionomycin for 4 h, and intracellular cytokine and perforin staining was performed as described previously.
Mixed lymphocyte reaction
For MLR cultures, PBMCs from two donors with a "type 2" IL-4
production pattern (Fig. 1
) were
incubated with irradiated (30 Gy) allogeneic PBMCs (both at 1 x
105/well) in a total volume of 200 µl of
RPMI/10% FCS. Increasing numbers of purified
CD8+CD25+ T cells obtained
from the donors whose PBMCs served as responder cells were added to the
cultures. After 1 wk, the cells were pulsed with 1 µCi
[3H]thymidine (ICN Pharmaceuticals, Costa Mesa,
CA) for the last 8 h of culture and then harvested onto glass
fiber filters (Wallac, Turku, Finland).
[3H]Thymidine incorporation was quantified on a
liquid scintillation counter. The results are expressed as cpm as mean
of triplicate determinations.
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For the comparison of the percentages of IL-4-producing CD8+ T cells between humoral responders and nonresponders to influenza vaccination, a Student’s t test for unpaired data was performed. A Pearson’s regression analysis was performed to analyze the relationship between the percentage of IL-4-producing CD8+ T cells after stimulation with PMA and ionomycin and the percentage of CD45RO+CD62L+CD8+ T cells within unstimulated PBMCs.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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T cells from young persons of up to 40 years of age had a
homogeneous IL-4 production pattern on stimulation with PMA and
ionomycin. These cells produced IL-4 within the
CD8-CD3+ population,
whereas CD8+CD3+ cells
hardly contained IL-4. This IL-4 production pattern (type 1 production
pattern; Fig. 1
a) was also found in 65% of the persons
between the ages of 41 and 60 years and in 33% of the 61–90-year-old
cohort (Fig. 1b). In contrast, IL-4 production by
CD8+ T cells was observed in older persons.
CD8+ as well as
CD8-CD3+ cells produced
IL-4 (type 2 production pattern; Fig. 1a) in 15% of the
persons between the ages of 41 and 60 years and in 36% of elderly
persons between 61 and 90 years of age (Fig. 1b). The
remaining persons (20% in the 41–60 years and 30% in the 61–90
years age group) produced very little IL-4 (<1.5% of the
CD3+ cells) in both CD8+
and CD8-CD3+ cells. This
IL-4 production pattern is referred to as type 3. IL-4-producing cells
reached an average percentage of 11 ± 3% (range 7–16% of all
CD8+ T cells in persons with a type 2 IL-4
production pattern). CD8+ T cells from persons
with a type 2 cytokine production pattern also produced IL-5, whereas
IL-5 production by CD8+ T cells was never
observed in persons with a type 1 or a type 3 cytokine production
pattern. There was no statistical difference in the production of
IFN- by CD8+ T cells among the groups. To
characterize CD8+ IL-4-producing T cells in more
detail the following experiments were performed.
IL-4-producing CD8+ T cells do not produce IFN-
Cytokine double-stained experiments were performed to find out
whether IL-4-producing
CD8+CD3+ T cells also
produced other cytokines (Fig. 2). Most
IL-4-producing CD8+ cells coexpressed IL-2 at
high intensity, but a smaller subpopulation of
IL-4+ cells did not produce IL-2. IFN- was
never detectable in IL-4-producing CD8+ cells.
IL-10 was not produced by CD8+ T cells under the
described conditions.
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To find out whether the occurrence of IL-4-producing
CD8+ T cells was a consistent feature in a
subgroup of older adults, we analyzed the IL-4 production of persons
with a type 2 cytokine production pattern twice at a year’s interval.
Intracellular IL-4 production did not change, suggesting that the
IL-4-producing CD8+ T cell population was stable
in vivo (Fig. 3a). To analyze
the stability of IL-4-producing CD8+ cells in
vitro, we enriched
CD8+IL-4+ cells from PBMCs
(5 ± 2% to 28 ± 3% enrichment) and cultured the obtained
population for 1 wk in the presence of different stimuli. Cells were
stimulated with IL-4, IL-12, or with plate-bound OKT3 in combination
with IL-2. After 1 wk in culture, the cells were restimulated with PMA
and ionomycin and the production of IL-4 and IFN- was analyzed.
Under all culture conditions tested, a polarized IL-4 production
pattern by CD8+ cells was maintained (Fig. 3b). The percentage of IL-4-producing cells was similar
after culture with IL-4 or the combination of OKT3 and IL-2 (26%), but
was slightly decreased in the presence of IL-12. No perforin was
produced under any of the culture conditions tested (not shown).
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IL-4-producing CD4+ memory T cells have been
described to express CD62L (22). This led us to
hypothesize that IL-4-producing CD8+ cells might
have a similar phenotype. We therefore analyzed the production of IL-4,
IFN-, and IL-2 in
CD8+CD45RO+ as well as in
CD62L+CD45RO+CD8+
cells (Fig. 4, a and
b). IL-4 was only produced by
CD8+CD45RO+ cells, whereas
IFN- was produced by
CD8+CD45RO+ as well as
CD45RO- cells. IL-2 was produced primarily
by CD45RO+ cells. Fig. 4b depicts the
cytokine production of CD62L cells in the
CD8+CD45RO+ gate. The
results demonstrate that IL-4 was produced exclusively by
CD62L++(bright) cells. In contrast IFN- was
produced mostly by CD62L- cells. Only a few
IFN--producing cells expressed CD62L at low intensity
(CD62L+(dim)). IL-2 was produced by
CD62L++, CD62L+, and
CD62L- cells. We also analyzed the relationship
between the percentage of unstimulated
CD45RO+CD62L+ cells and of
PMA/ionomycin-stimulated IL-4-producing cells within the
CD8+ gate. A Pearson’s regression analysis
showed a direct correlation between the expression of CD62L on
unstimulated CD45RO+CD8+
and the production of IL-4 by stimulated CD8+ T
cells (Fig. 4c). CD62L mediates the rolling and attachment
of lymphocytes on high endothelial venules, but for firm arrest and
extravasation at these sites the chemokine receptor CCR7 is needed
(23, 24). We therefore studied the expression of CCR7 on
CD8+CD45RO+CD62L++
T cells. Fig. 4d shows that the whole
CD62L++ population within the
CD8+CD45RO+ gate, which
contains almost 100% of the IL-4-producing
CD8+ cells expressed CCR7.
CD8+CD45RO+CD62L++
had not been recently activated, as they did not express the early
activation marker CD69.
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For further phenotypic characterization of the
CD8+CD3+ IL-4-producing
population, the expression of CD28, CD27, and CD25 was analyzed.
IL-4-producing CD8+ cells were
CD28+ and had a variable expression of CD27, as
about two-thirds of the population was CD27+,
whereas one-third was not (Fig. 5).
IL-4-producing CD8+ cells were also
CD25+. CD8+ IL-4-producing
cells expressed CD25 following PMA stimulation, and unstimulated
CD8+CD45RO+CD62L++
cells also contained a CD25+ population that
corresponded in size to the CD8+ IL-4-producing
cell. Isolated CD8+CD25+
cells also characteristically had a high production of IL-4 and IL-2,
but hardly contained IFN- following stimulation with PMA and
ionomycin (data not shown). To find out whether the IL-4-producing
CD8+ T cell population had cytolytic capacity, we
analyzed the expression of perforin after stimulation with PMA.
IL-4-producing CD8+ cells did not express
perforin. In contrast, IFN--producing CD8+ T
cells were frequently CD28- and
CD27- but never CD25+, and
a high percentage of IFN--producing CD8+ T
cells produced perforin.
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The expression of CD25 on IL-4-producing
CD8+ cells raises the question whether these
cells might have regulatory effects as described for
CD4+CD25+ cells (25, 26). CD8+CD25+ cells
were therefore separated by MACS technology and tested for a possible
suppressive effect on the proliferation of autologous PBMCs on
allogeneic stimulation in an MLR experiment. Increasing numbers of
CD8+CD25+ T cells had no
inhibitory effect on the proliferation of PBMCs in an MLR (Fig. 6) suggesting that
CD8+CD25+ T cells were not
suppressor cells.
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We also analyzed whether the occurrence of IL-4-producing
CD8+ cells was related to an effective humoral
immune response following immunization. Because influenza vaccination
is frequently performed in elderly persons and does not lead to Ab
production in 30–50% of this cohort (27, 28), we used
this type of immunization as a model situation. The percentage of
IL-4-producing CD8+ cells was compared in persons
who did or did not produce influenza-specific Abs following
vaccination. The strategy of defining subgroups of elderly persons
according to their humoral immune response has been used previously by
our group (19). The percentage of IL-4-producing
CD8+ cells was significantly higher in persons
who did produce protective Ab titers following vaccination than in
persons who failed to produce protective Ab titers (Fig. 7), suggesting that IL-4 production by
CD8+ cells was a feature associated with intact
humoral immunity in old age. Identical results were obtained when
results were compared in persons with a 4-fold increase in titer to all
three influenza strains following vaccination and others who failed to
fulfill this requirement (difference between groups p
< 0.05).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Old age is characteristically associated with an overproduction of type
1 cytokines (37, 38), and high serum neopterin
concentrations suggest an increased whole body load of IFN-
(39, 40). High IFN- does not only trigger chronic
inflammatory processes that seem to support the development of
age-related diseases such as Alzheimer’s disease (41) and
atherosclerosis (42), but may also be responsible for the
insufficient efficacy of vaccines to induce Ab production in elderly
persons (19, 43, 44). In this context, our finding that
elderly persons who produced protective Ab titers following influenza
vaccination had increased numbers of IL-4-producing
CD8+ T cells than did those elderly persons who
could not raise a sufficient humoral immune response seems of special
interest (Fig. 7). It suggests that IL-4-producing
CD8+ T cells do indeed have a beneficial effect
because they may stimulate humoral immunity and thus counteract one of
the detrimental effects of increased IFN- production in old
age.
IL-4-producing CD8+ T cells that occur in healthy
older adults are strictly polarized, cannot be triggered to produce
IFN-, and do not produce perforin. This suggests that this
CD8+ T cell subpopulation is unable to kill. It
may still play a regulatory role. Despite expressing CD25,
CD8+ IL-4-producing T cells are not regulatory
suppressor cells. In contrast to
CD4+CD25+ regulatory cells
that do not produce IL-2 (45), the
CD8+ IL-4-producing cell type described in this
study expresses IL-2 at high intensity (Fig. 2). In addition its
capacity to suppress other cells was tested in an MLR. Regulatory
CD4+CD25+ suppressor T
cells inhibit the activation and proliferation of other T cells on
TCR-mediated or allogeneic stimulation (25, 26). In
contrast no inhibitory effect of purified
CD8+CD25+ was observed
(Fig. 6).
It is presently not clear why CD8+ IL-4-producing
T cells express CD25. Repeated antigenic reactivation may be a possible
explanation. The association of certain T cell differentiation stages
with different viral infections has recently been demonstrated
(46). The accumulation of
CD8+CD28- T cells has for
instance been suggested to concur with CMV infection (46, 47). Whether the increase in
CD8+CD28-
IFN--producing T cells characteristically observed in healthy
elderly persons (48, 49) is also a symptom of underlying
latent CMV infection is still a matter of debate (50, 51).
It seems, however, tempting to speculate that the accumulation of
IL-4-producing
CD8+CD45RO+CD62L++
T cells in a subgroup of persons >40 years of age is the result of
latent or past infections with so far unidentified pathogens. This
would explain why an only relatively small percentage of persons from a
certain age onward is affected. A recent report demonstrates that
immunization of mice with heat killed but not live Listeria
monocytogenes primed CD8+ T cell populations
with a CD62L++ phenotype that were substantial in
size, but did not provide full protection from subsequent L.
monocytogenes infection (36). This also suggests that
vaccinations with inactivated or attenuated microorganisms might have
induced the accumulation of memory CD8+ cells in
older adults. Experiments to determine the specificity and exact
activation requirements as well as a clonotypic analysis of
CD8+ IL-4-producing cells are presently underway
in our laboratory.
The concept that infections or even vaccinations may affect the aging
of the immune system differently in different persons is not only
tempting from an academic point of view, but could also have practical
consequences. If CMV, for instance, drives the accumulation of
CD28- IFN--producing T cells, this infection
should be prevented by vaccination in early childhood. Knowledge that
certain inactivated bacteria trigger the accumulation of IL-4-producing
T cells could on the other hand be of great interest for the design of
new adjuvants. Presently the highly unsatisfactory results of
vaccinations such as that against pneumococcal pneumonia in the elderly
(52) could thus be improved.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Beatrix Grubeck-Loebenstein, Institute for Biomedical Aging Research, Austrian Academy of Sciences, Rennweg 10, A-6020 Innsbruck, Austria. E-mail address: Beatrix.Grubeck{at}oeaw.ac.at
3 Abbreviation used in this paper: Tc, T cytotoxic.
Received for publication August 9, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and interleukin-4 secretion by purified human CD4+ and CD8+ T cells. J. Biomed. Sci. 7:317.[Medline]
plus IFN induce the production of Alzheimer 
-amyloid peptides and decrease the secretion of APPs. FASEB J. 13:63.This article has been cited by other articles:
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  H. J. Baek, L. Zhang, L. B. Jarvis, and J. S. H. Gaston Increased IL-4+ CD8+ T cells in peripheral blood and autoreactive CD8+ T cell lines of patients with inflammatory arthritis Rheumatology, June 1, 2008; 47(6): 795 - 803. [Abstract] [Full Text] [PDF]
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 J. Ho, C. C. Kurtz, M. Naganuma, P. B. Ernst, F. Cominelli, and J. Rivera-Nieves A CD8+/CD103high T Cell Subset Regulates TNF-Mediated Chronic Murine Ileitis J. Immunol., February 15, 2008; 180(4): 2573 - 2580. [Abstract] [Full Text] [PDF]
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B. H. Lemster, J. J. Michel, D. T. Montag, J. J. Paat, S. A. Studenski, A. B. Newman, and A. N. Vallejo Induction of CD56 and TCR-Independent Activation of T Cells with Aging J. Immunol., February 1, 2008; 180(3): 1979 - 1990. [Abstract] [Full Text] [PDF]
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D. Herndler-Brandstetter, S. Schwaiger, E. Veel, C. Fehrer, D. P. Cioca, G. Almanzar, M. Keller, G. Pfister, W. Parson, R. Wurzner, et al. CD25-Expressing CD8+ T Cells Are Potent Memory Cells in Old Age J. Immunol., August 1, 2005; 175(3): 1566 - 1574. [Abstract] [Full Text] [PDF]
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 G. Almanzar, S. Schwaiger, B. Jenewein, M. Keller, D. Herndler-Brandstetter, R. Wurzner, D. Schonitzer, and B. Grubeck-Loebenstein Long-Term Cytomegalovirus Infection Leads to Significant Changes in the Composition of the CD8+ T-Cell Repertoire, Which May Be the Basis for an Imbalance in the Cytokine Production Profile in Elderly Persons J. Virol., March 15, 2005; 79(6): 3675 - 3683. [Abstract] [Full Text] [PDF]
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 M. Leslie All Pain, No Gain Sci. Aging Knowl. Environ., July 7, 2004; 2004(27): ns4 - ns4. [Abstract] [Full Text] [PDF]
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