PeproTech Inc.
Originally published online as doi:10.1189/jlb.1103592 on March 23, 2004

Published online before print March 23, 2004
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.1103592v1
76/2/291    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Plackett, T. P.
Right arrow Articles by Kovacs, E. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Plackett, T. P.
Right arrow Articles by Kovacs, E. J.
(Journal of Leukocyte Biology. 2004;76:291-299.)
© 2004 by Society for Leukocyte Biology

Aging and innate immune cells

Timothy P. Plackett*,{dagger},{ddagger}, Eric D. Boehmer*, Douglas E. Faunce{dagger},§,¶ and Elizabeth J. Kovacs*,{dagger},§,¶,1

* Departments of Cell Biology, Neurobiology, and Anatomy and
Surgery,
§ Immunology and Aging Program,
{dagger} Burn and Shock Trauma Institute, Loyola University Chicago, Maywood, Illinois; and
{ddagger} Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, Illinois

1Correspondence: Department of Cell Biology, Neurobiology, and Anatomy, Department of Surgery, Loyola University Chicago, Stritch School of Medicine, Building 110, Room 4237, 2160 South First Avenue, Maywood, IL 60513. E-mail: ekovacs{at}lumc.edu


arrow
ABSTRACT
 
The innate immune system serves an important role in preventing microbial invasion. However, it experiences significant changes with advancing age. Among the age-associated changes are: Aged macrophages and neutrophils have impaired respiratory burst and reactive nitrogen intermediates as a result of altered intracellular signaling, rendering them less able to destroy bacteria. Aged neutrophils are also less able to respond to rescue from apoptosis. Aged dendritic cells (DC) are less able to stimulate T and B cells. The altered T cell stimulation is a result of changes in human leukocyte antigen expression and cytokine production, and lower B cell stimulation is a result of changes in DC immune complex binding. Natural killer (NK) cells from the elderly are less capable of destroying tumor cells. NK T cells increase in number and have greater interleukin-4 production with age. Levels of various complement components are also altered with advancing age.

Key Words: immunosenescence • macrophage • dendritic cell • polymorphonuclear neutrophil


arrow
INTRODUCTION
 
Clinical data have demonstrated that the ability of the elderly to respond to infection is diminished in comparison with young adults. As a result, aged individuals make up a disproportionate number of infectious disease patients and are at greater risk of contracting more severe and longer lasting infections. In particular, they have higher rates of respiratory tract infections, which are more likely to be caused by atypical organisms [1 , 2 ]. Moreover, elderly individuals are more prone to developing invasive Staphyloccus aureus infections and tetanus [3 , 4 ] and have poor responses to influenza vaccination [5 , 6 ]. The aged population also has a higher incidence of infections and sepsis after a traumatic injury than young adults [7 ]. An age-associated decline in immunity is implicated as the primary cause of these problems. This review will examine the effects of aging on the innate immune system, in particular, examining neutrophils, dendritic cells (DC), macrophages, natural killer (NK) cells, NK T (NKT) cells, and complement.

For the purposes of this review, any study using a human population 60 years of age or greater is considered elderly, and groups between 18 and 59 years of age are considered young. The SENIEUR protocol, which designates young as 25–34 years old and aged as 65 and above, is not exclusively used as a result of its limitations [8 ]. The SENIEUR protocol has extensive exclusion criteria, limiting studies to only the most healthy individuals. As a consequence, as much as 85% of the aged population is not included by these studies [9 , 10 ]. These subjects are excluded based on the concern that any altered immune responses may be a result of underlying infection or pathology; however, it is equally possible that this group has an aging-related, altered immune system that predisposed them to developing infection or pathology. Given our inability to resolve these two possibilities, we have noted when information is based on studies using the strict SENIEUR protocol guidelines.

Concerning animal studies, no concise definition of aged has been developed. However, Miller and Nadon [11 ] have outlined multiple considerations relevant to such a definition; in light of these factors, rodents, aged 16 months and older, are considered aged for the purposes of this review. Aging studies that specifically used animals with cancer, autoimmune disorders, or other conditions are excluded from this discussion.


arrow
POLYMORPHONUCLEAR NEUTROPHILIC LEUKOCYTES (PMN)
 
PMN quickly respond to the site of infection and begin to phagocytose opsonized particles. Consequently, they are among the first cells to produce bacteriostatic and bacteriocidal products, as well as influence adaptive immunity. As the body’s first response to microbial invasion and injury, the chemotactic migration, adhesion, and phagocytic capabilities of PMN are critical to their proper functioning. In vivo, examination of skin abrasion exudate demonstrated equal migration of PMN into the site of injury in young and old, although there was a greater variation in migration amongst the elderly subjects meeting the SENIEUR protocol guidelines compared with the young [12 ]. When young and old volunteers were compared in an experimental gingivitis model, an equal number of PMN were detected in the junctional epithelium 7 days after injury [13 ]. In vitro research has yielded more conflicting results. Corberand et al. [14 ] reported chemotaxis to be significantly decreased in people over the age of 80 years, and there was no significant difference in 60- to 70-year-olds compared with young volunteers. The very opposite was true in a study by Niwa et al. [15 ], which found a correlation between 60- to 70-year-old volunteers with diminished PMN chemotaxis and respiratory burst and their mortality 7 years after the initial study. However, the study demonstrated no difference between people older than 80 years old and the young. They suggested that the lack of significant difference between the over-80-year-old population and the youth was a result of a selective pressure that left only those individuals with the "healthiest" PMN surviving into the oldest age group.

Once PMN have migrated to the site of injury or bacterial entry, they must adhere to the endothelium to diapedis out of the vasculature. Adhesion, however, is not impaired in the elderly. When stimulated by f-Met-Leu-Phe (fMLP), opsonized zymosan, phorbol myristate acetate (PMA), or calcium ionophore A23187, human PMN obtained from young and aged subjects adhere equally to plastic, gelatin, and bovine aortic endothelium [12 , 16 ].

Phagocytosis is also unimpaired in the elderly. Studies show that the amount of opsonized paraffin oil or yeast cells engulfed is equal in PMN from young and aged volunteers [15 , 17 ]. It is interesting that another study with yeast cells showed an increase in phagocytosis by the elderly in comparison to 20- to 29-year-olds; however, no difference between the elderly and 30- to 60-year-olds [14 ] was noted. These combined results indicated that there is no impairment in the ability of PMN from aged subjects to traffic to tissues and engulf microbes.

In contrast to phagocytosis, the microbiocidal capacity of PMN is significantly decreased with advancing age. The ability of stimulated and unstimulated PMN to kill Candida albicans is attenuated by 10–50% in the elderly [14 , 18 ], and Eschericihia coli killing is 44% lower than that of young subjects [19 ]. Contributing to this depressed killing ability is a significant decrease in the production of reactive oxygen species (ROS) by PMN. Following stimulation with fMLP, interferon-{gamma} (IFN-{gamma}), granulocyte/monocyte-colony stimulating factor (GM-CSF), or lipopolysaccharide (LPS) [18 19 20 21 22 ], the production of superoxide was greatest by PMN from young rather than aged humans and rodents. Likewise, nitroblue tetrazolium dye-reduction tests have yielded higher rates of oxidative dye reduction by a mixture of young, mature, human neutrophilic granulocytes and macrophages [14 ].

Impaired intracellular signaling has been implicated as a leading cause for the altered oxygen-free radial production in the aged. Intracellular Ca2+ is decreased in stimulated PMN from elderly volunteers, suggesting that there is an impairment in Ca2+ flux during cell signaling [18 , 23 ]. Also, actin, which may play a role in cell-surface receptor movement and expression, has been suggested to contribute to the altered free-radical production. Using actin-stabilizing and -disrupting agents, Piazzolla et al. [20 ] demonstrated that the release of O2– by PMN from elderly volunteers is more sensitive to these agents, yielding significantly lower superoxide release. Additionally, actin polymerization is significantly diminished after stimulation of PMN from aged subjects with fMLP or PMA, relative to young [24 , 25 ]. These age-associated differences in actin correlate with altered cell-surface markers. In particular, there is lower surface expression of the activation-inducer molecule CD69 and chemotactic peptide receptor for N-formyl-Nle-Leu-Phe,Tyr-Lys hexapeptide on aged PMN after stimulation, and no differences are noted in CD11b or complement receptor b [25 , 26 ]. These results, taken in their totality, suggest that the diminished production of ROS may be caused partially by impaired intracellular signaling, resulting from an inability of actin to adequately transport the appropriate cell-surface receptors to the cell membranes of PMN from the aged.

Given the short life-span of a PMN, alterations in apoptotic cell death may also predispose the elderly to an increased risk of infection. In the absence of stimulation, the amount of apoptotic cell death of human PMN is unaltered by aging [27 28 29 ], and there is no difference in the expression of CD95, APO1/Fas, an apoptotic ligand [30 ]. In contrast, there are significant variations in apoptosis following cell stimulation. Under normal conditions, in the young, inflammatory mediators are able to prevent apoptosis [31 32 33 34 ]. This response to inflammation helps guarantee the continued involvement of PMN in preventing the spread of microbes, while other cell populations traffic to the site of injury or insult. However, unlike with the young, interleukin (IL)-2, LPS, GM-CSF, or G-CSF do not rescue PMN from the elderly [28 , 29 ]. This is paralleled by alterations in the Janus tyrosine kinase (Jak)2-signal transducer and activator of transcription (STAT)5 signaling pathway in PMN from the elderly. Ultimately, this results in aged PMN producing increased Bax and decreased Mcl-1, creating a proapoptotic environment [35 ].

The failure of inflammatory mediators to prevent apoptosis in the elderly may also reflect an inability of the cells to prevent reactive oxygen-induced damage. Tortorella et al. [27 ] demonstrated that high levels of superoxide dismutase were better able to inhibit apoptosis in PMN from young volunteers than from aged; however, the addition of catalase raised the apoptosis inhibition of the aged subjects to a similar level as the young. As inflammatory mediators not only prevent apoptosis but also stimulate the production of ROS in the young [36 , 37 ], these results suggest that in an inflammatory environment, the PMN from the aged are less able to neutralize free radicals that escape from phagolysosomes and will be substantially damaged. As a result of this damage, these cells are shifted toward a proapoptotic environment and instead undergo programmed cell death.


arrow
DC
 
Between a few hours to several days after PMN migration, antigen-presenting cells (APCs) enter the site of infection and inflammation. DC are the most potent, professional APC of the immune system [38 ]. With their ability to interact with B and T cells and their widespread localization, they are a vital component of the innate immune system.

The follicular DC (FDC) is critical to the formation of plasma cells in the germinal centers of secondary lymphoid organs and the subsequent generation of antibodies [39 ]. Szakal and co-workers [40 , 41 ] reported that decreases in the cell-surface receptors for complement, CD21, and Fc{gamma} in aged mice impaired the initial trapping of immune complexes by FDC. This is further complicated by a decrease in the number of iccosomes, antigen:antibody complexes that bud off FDC and are taken up by B cells [40 ]. The combined effect is less-stable binding and decreased stimulation of B cells. Deficient antibody production can be partially restored in vitro by using FDC that have a higher percentage of immune complexes and complement bound [40 , 41 ]. In addition, FDC of aged mice often remained trapped in the subcapsular sinus of lymph nodes and are unable to reach the follicle and its B cells, resulting in decreased germinal center formation [40 , 42 ]. These changes in FDC are partially responsible for the significant modification of humoral immunity in the elderly [43 ].

Non-FDC, hereafter referred to simply as DC, are capable of activating CD4+ T cells via their major histocompatibility complex class II (MHC-II) [44 ]. DC from young and aged humans induce similar amounts of T cell proliferation and have similar levels of human leukocyte antigen (HLA) expression [45 , 46 ]. However, lower HLA-DR expression has also been reported [47 ]. In the former studies, DC were obtained by stimulating monocytes with GM-CSF, and the latter study analyzed peripheral blood DC. Differences in these protocols may account for the opposing results and suggest that there is a need for careful interpretation of ex vivo experiments. These different results also suggest that although circulating DC from the elderly are less prepared to bind antigens, the deficiency can be corrected in the appropriate environment. Animal models have also encountered conflicting information. T cell proliferation was attenuated when cultured with DC from aged DBA or A mice, and there was no difference with BALB/c, CBA, or C3H/He mouse DC [48 ]. Reasons for these differences remain to be explored. Aside from T cell proliferation, aged, murine DC are also less able to stimulate peripheral blood mononuclear cell (PBMC) production of IFN-{gamma}, further contributing to the changes in T cell functionality with advancing age [49 ].

Within the peripheral blood of the elderly, there is nearly 50% less CD11c+B220+ plasmacytoid DC [50 ]. However, it is unknown if there are differences in the CD11c+B220–CD8+ lymphoid or CD11c+B220–CD8– myeloid DC subsets with advancing age. This decrease in DC exists despite an increase in the proliferation of peripheral DC from the elderly after in vivo GM-CSF incubation when compared with the young [45 ]. The proliferation studies, however, use the SENIEUR protocol and did not account for age-related differences in circulating GM-CSF, whose levels are lower in aged animals; therefore, stimulating PBMC from young and aged subjects with equivalent concentrations of GM-CSF does not accurately reflect the natural microenviroment [51 , 52 ]. The lower circulating GM-CSF of the elderly may result in less DC proliferation. Additionally, it has been noted that in vitro and in vivo models of DC function have resulted in divergent results [53 ]. Consequently, although there is a decrease in absolute number of DC, further research is needed to determine if DC retained their proliferative capacity with advancing age and what effects lower circulating GM-CSF levels may have on DC function.


arrow
MACROPHAGES
 
Macrophages play important roles in the immune response, capable of not only phagocytosis and destruction of foreign cells and debris but also acting as APCs. Like DC, they stand at the crossroads between adaptive and innate immunity.

Macrophages are able to directly destroy microbes through the products of the respiratory burst and reactive nitrogen-intermediate pathways. Both of these processes are induced by IFN-{gamma} from T cells and NK cells or by components of bacterial cell walls [54 , 55 ]. The binding of IFN-{gamma} or bacterial products to their appropriate receptors results in phosphorylation of mitogen-activated protein kinase (MAPK) and the subsequent release of free radicals. Studies using rats have demonstrated a 75% decrease in the ability of macrophages from aged animals to produce superoxide anion following incubation with IFN-{gamma} or opsonized zymosan [56 ]. The impaired superoxide production by macrophages from the aged was further investigated by Ding et al. [57 ], who demonstrated that caseinate-elicited peritoneal macrophages from aged mice had undetectable phosphorylation of MAPK following incubation of the cells with IFN-{gamma}. Functionally, this abrogation in MAPK activation was correlated with 50% less hydrogen peroxide production following stimulation of macrophages from aged mice with PMA or opsonized zymosan. Others [58 59 60 ] have also reported a similar decrease in oxygen free-radial production by macrophages from aged mice. As a consequence of reduced respiratory burst in the elderly, the intercellular killing of bacteria is hindered and thus may cause the elderly to have infections of longer duration [61 62 63 ].

The production of reactive nitrogen intermediates is the other key mechanism by which macrophages exert their microbicidal properties; however, studies into the production of nitrogen compounds in the aged offer conflicting results. Several reports demonstrated that inducible nitric oxide synthase (iNOS) mRNA is decreased in aged mice [64 , 65 ]. Additionally, in the absence of iNOS, aged mice [64 65 66 ] significantly decreased the production of NO2– and other intermediates. Conversely, enhanced iNOS mRNA and nitrite production by macrophages of the aged have also been reported. Chen et al. [67 ] demonstrated an increase in nitrite production in resident and thioglycollate-elicited peritoneal macrophages of aged mice after LPS stimulation, as well as increased iNOS mRNA in thioglycollate-elicited peritoneal macrophages. Others [68 ] have also reported similar increases. The conflicting reports are likely a result of differences in experimental protocols. Recently, it was demonstrated that thioglycollate-elicited macrophages stimulated with LPS and IFN-{gamma} display different age-specific nitrite production patterns based on the dose of IFN-{gamma} with which the cells were cultured [69 ]. At low doses of IFN-{gamma}, the production of nitrite was higher in young mice than in old mice. However, at a higher dose, the macrophage from older mice had a greater production of nitrite than the young mice. Therefore, interpretation and application of the results require a consideration of the microenvironment in which the cells function.

Macrophages from the aged can also contribute to the dysregulation seen in other immune cell populations (Fig. 1 ). The production of PGE2 by macrophages is enhanced in aged mice, which correlates with an increase in COX-2 mRNA and enzyme levels [70 ]. PGE2 is able to alter DC function by blocking the production of IL-12, increasing production of IL-10, and decreasing MHC-II expression in mice [71 72 73 ]. It also exerts effects on T cells. The arachidonic acid metabolite is capable of decreasing IL-2 production and subsequently lowering T cell-proliferative responses [74 , 75 ], two well-documented changes seen with advancing age [76 77 78 ]. Up-regulation of T helper cell type 2 (Th2) cytokines, which are known to be elevated in elderly human patients and in animal models of aging [76 , 79 , 80 ], is also a result of mouse splenocyte stimulation with PGE2 [74 ].



View larger version (23K):
[in this window]
[in a new window]
  		Figure 1. Changes in macrophage signaling, enzymatic processes, and output with advancing age. Arrows ({uparrow} and {downarrow}) indicate increased or decreased levels in the elderly compared with young. TNF-{alpha}, Tumor necrosis factor {alpha}; JNK, c-jun NH2-terminal kinase; TLR4, Toll-like receptor 4; COX, cyclooxygenase; PGE2, prostaglandin E2.

Macrophage-derived cytokines also affect the immune response. Several recent reports have suggested that there is a decrease in the production of proinflammatory cytokines by macrophages from aged humans and mice. Renshaw et al. [81 ] showed that LPS stimulation of splenic and thioglycollate-elicited peritoneal macrophages resulted in less IL-6 and TNF-{alpha} secretion by macrophages from aged mice compared with young mice. Furthermore, the study suggested that lower proinflammatory cytokine differences may be a result of lower TLR4 mRNA in macrophages of aged mice, rendering the macrophages less responsive to LPS. Lower IL-6 and TNF-{alpha} production by LPS-stimulated macrophages is also associated with decreased, activated p38 and JNK MAPKs [82 ]. Beharka et al. [83 ] demonstrated a decrease in the production of IL-6 by human PBMC cultured with autologous plasma. Most literature, however, suggests that circulating levels of proinflammatory cytokines are elevated in the aged [84 85 86 87 ]. Macrophages have been assumed to be the primary producer of these cytokines. Several studies have demonstrated that in fact, underlying inflammatory disease and poor nutrition may actually be responsible for this circulating, proinflammatory state, rather than the natural aging process [88 89 90 91 ]. Also, although macrophages have been assumed to be a primary producer of the proinflammatory cytokines in the elderly, other cell populations may contribute to cytokine production as well. In light of the more recent findings, further research is needed to determine which cell population is responsible for potential heightened inflammatory states.

Wound healing is dependent on macrophage function, as macrophages are able to keep the wound bed free from infection and promote angiogenesis [92 ]. With its dual roles, macrophage migration to the site of injury can be critical in the post-injury immune response. After injury, chemokines, including monocyte chemoattractant protein-1 (MCP-1), are produced to promote the migration of monocytes and macrophages into the wound bed. Following excisional wounding, macrophages begin to infiltrate into the wound bed within 24 h [93 ]. The infiltration is significantly greater in aged mice and correlates with increased MCP-1 in wound homogenates 12 h after injury, relative to young mice. However, burn injury is associated with decreased MCP-1 by aged, injured mice, relative to young, injured mice, 24 h after injury. However there was equal macrophage accumulation in the region immediately adjacent to the necrotic, burn-injured tissue in young and aged, injured mice [94 ]. The differences between the results of these two studies may reflect variations in the experiment models. Burn injury is associated with significant increases in proinflammatory cytokines in aged mice [85 ], which may alter macrophage migration. Studies of excisional wound healing in humans demonstrate a delay in monocyte and macrophage infiltration with age [95 ]. The slow infiltration is associated with a decrease in intercellular adhesion molecule-1 and vascular adhesion molecule-1 expression, suggesting an impairment in the ability of the cells to bind to the endothelium to leave the circulation [95 ].

Once at the site of injury, macrophages can promote angiogenesis and wound healing through the production of vascular endothelial growth factor (VEGF). This angiogenic mediator is present at lower levels in excisional wounds from aged mice, which correlates with 37% less VEGF production by stimulated peritoneal macrophages from aged mice [96 ]. The diminished VEGF production and angiogenesis may delay wound closure, allowing more time for bacteria to circumvent the natural skin barrier and develop into a full infection. With only isolated studies exploring the role of macrophages in wound healing of the elderly, further research is needed before definitive conclusions can be reached.


arrow
NK CELLS
 
Although PMN, DC, and macrophages are capable of seeking out and eliminating extracellular pathogens, NK cells are critical to removal of intracellular pathogens. In addition to their importance in viral infections, they also possess vital tumoricidal activities.

There is an increase in the relative percentage of NK cells with advancing age when comparing SENIEUR protocol-qualified elderly and young individuals [97 98 99 ]. The rise in percentage of NK cells in the elderly is related to a decrease in the number of T cells and an increase in the absolute number of NK cells [30 , 97 , 100 101 102 ]. Aside from an increase in number, NK cells obtained from the aged are more likely to have a mature phenotype, having a higher percentage and absolute number of CD56dim cells and a smaller CD56bright population [100 , 103 ]. Additionally, NK cells from the aged may be less prepared to carryout their prescribed function, as there is a significant increase in the number of agranular cells in humans [97 ] and a decrease in the adherence to tumor cells in mice [104 ].

Conflicting reports exist as to the cytolytic ability of NK cells in the elderly. Independent studies demonstrated that NK cells in the elderly have normal [105 ] or enhanced activity [106 ] compared with young individuals when the elderly population is selected based on strict adherence to the SENIEUR protocol. However, when elderly patients were selected for good health but did not fully meet the SENIEUR protocol, the NK cell activity against tumor cells was significantly decreased compared with young adults. Other human studies, which more loosely followed the suggestion of the SENIEUR protocol, also demonstrated an age-specific decrease in NK cell cytotoxicity toward tumor cells [98 , 107 , 108 ], and similar results in animal models used LPS or concanavalin A as cell stimulants [109 110 111 112 ]. These reports indicate that although fully functional NK cells may be desirable for optimal health, the majority of the elderly population will experience some deficit in NK cell activity. This also highlights the need for careful interpretation and application of SENIEUR protocol-based information.

Alterations in intracellular signaling are key contributors to the tumoricidal deficiency [102 ]. In particular, there is a delay in phosphatidlyinositol biphosphate hydrolysis, coupled with a failure of inositol triphosphate to increase above basal levels [102 ]. However, these results were specific to spontaneous cytolytic activity directed toward tumor cells, as antibody-dependent, cell-mediated cytotoxicity (ADCC), assayed by anti-CD16 antibody stimulation of the Fc receptor, was intact in the aged subjects. Likewise, the production of insositol phosphate activity was comparable with the young during ADCC. Others have also reported an intact ADCC [113 , 114 ]. The impaired, spontaneous cytolytic activity allows for continued growth and expansion of neoplastic cells and is likely a contributor to the increased incidence of cancer among the elderly [115 , 116 ].

In addition to decreased toxicity, the NK cells from the elderly are unable to properly proliferate following IL-2 stimulation. In human- and murine-derived NK cells, the proliferative response to IL-2 is decreased by 40–60% among the elderly [100 , 104 ]. The decreased, proliferative response is paralleled by an age-specific decrease in Ca2+ mobilization [100 ]. The diminished Ca2+ prevented the up-regulation of CD69 on elderly human NK cells, an early activator of NK cell proliferation and cytotoxicity. The combined effect of diminished proliferation responses and cytotoxic activity of NK cells is that the elderly are more prone to developing longer lasting infections and a decreased ability to rid the body of tumor cells [117 , 118 ].


arrow
NKT CELLS
 
NKT cells are a minor cell population found in most lymphoid organs. They are characterized as CD1d-restricted cells [119 ] and have been implicated as a significant contributor to post-injury responses [120 ], microbial clearance [121 ], autoimmune disease [122 ], and other immune responses [123 , 124 ].

Absolute numbers and relative percentages of NKT cells increase in number with advancing age. The increase in NKT cells appears to be a global rise, as increases of 150–400% have been reported in circulating, splenic, hepatic, mesenteric lymph node, and peripheral lymph node counts in humans and rodents [125 126 127 128 ]. Cytokine production by NKT cells has also varied with aging. Dubey et al. [129 ] showed an increase in production of IL-4 mRNA and protein by CD4+ NKT cells from aged B.10 mice and a concurrent decrease in IFN-{gamma} mRNA and protein after stimulation of the cells with {alpha}CD3 and IL-2; however, the aged group included mice as young as 12 months old [129 ]. In contrast, Poynter et al. [128 ] found that {alpha}CD3 stimulation of NKT cells leads to lower IL-4 and IL-2 mRNA in aged C57BL/6 mice. Although both studies concluded that there is a decrease in Th1 cytokine mRNA, the discrepancy in IL-4 remains to be resolved.

Expression of Fas ligand following cell stimulation displays an age-related effect as well. Younger mice express lower levels of Fas ligand after injection of {alpha}-GalCer into the mice [130 ]. Studies with young Fas-deficient and wild-type mice have demonstrated that injection of {alpha}-GalCer results in an increase in NKT cell apoptosis and that the cell death is Fas-dependent [131 ]. However, whether the increased Fas ligand in aged mice exerts an effect on NKT apoptosis is unknown.


arrow
COMPLEMENT
 
Most studies examining the relationship of age and complement focused on the role of C1q in Alzheimer’s disease [132 133 134 ]; however, a limited number of studies compare the levels of complement proteins and their functionality in the young and aged. When considering the classical complement pathway, serum levels of C4 were increased in aged volunteers [135 136 137 ] or unchanged between the young and old [138 ]. These differences in C4 protein may reflect the use of the SENIEUR protocol by Bellavia et al. [138 ]. In an isolated study, there was an increase in the plasma levels of C4-binding protein (C4BP) with age [139 ]. However, interpretation of this datum is limited, as the study does not state which age groups were compared. The role that the age-associated increase in C4BP has on immunity is also uncertain, as the increase is attributed to a rise in C4BPß. The C4BPß subunit interacts with the coagulation cascade, whereas C4BP{alpha} specifically binds to C4b and inhibits complement activation [140 ]. Using a rat model, Lavery and Goyns [141 ] described a decrease in the expression of the C4BP{alpha} in the livers of aged animals; however, it is unknown whether this observation is organ- or species-specific.

Description of age-related changes in the alternative complement pathway has also yielded conflicting results. Serum C3 levels were reported to be increased [135 , 137 ] in the elderly or equivalent in young and aged [136 , 138 ]. Additionally, Factor B levels in elderly humans are either decreased [135 ] or not significantly different from the young [136 ].

As with the components unique to the classic and alternative complement pathways, research into the common pathway components is also extremely limited and fraught with contradictions. Cannon et al. [142 ] found equivalent rises of C3a anaphylatoxin in plasma obtained from young and old humans after exercise-induced tissue damage, whereas Kyrkanides et al. [143 ] showed an increase in C3a1 mRNA in aged mice after a cortical stab injury. The ultimate significance of either of these results remains to be demonstrated.

Functional studies of complement activity indicate normal functioning or a decrease in activity with advancing age. Hazlett et al. [144 ] reported a 50% decrease in alternative pathway-induced hemolysis by aged Swiss ICR mice. The impaired, alternative pathway was also associated with a decrease in the number of PMN undergoing phagocytosis of Pseudomonas aeruginosa. However, there was no difference in the total amount of bacteria remaining after the incubation. Using the SENIEUR protocol, Bellavia et al. [138 ] found no difference in the ability of the alternative or classical pathway to induce hemolysis in aged versus young individuals. Given the limited number of studies examining complement functionality, further research is needed before definitive conclusions can be drawn.


arrow
CONCLUSION
 
This review has provided an in-depth examination of the current knowledge concerning aging and its effects on innate immunity. Contrary to prior beliefs, the innate immune system is not free from the effects of aging. Although the age-associated decrease in T and B cell populations allows for an increase in the percentage of innate cell, like their adaptive cell counterparts, the innate cells do not function normally (Table 1 ). The production of ROS and nitrogen species is significantly impaired in neutrophils and macrophages from the aged, possibly affecting bacterial destruction, and NK cells are less able to destroy tumor cells. There is a significant increase in the number of NKT cells in the aged, but further research is needed to determine the functional significance. Likewise, complement research remains a vastly understudied area of aging research. Finally, the innate immune system also contributes to altered acquired immunity with aging, via interactions between DC and macrophages with T and B cells. Thus, the effect of aging on innate immunity is not merely an increase in relative percentage of innate immune cells, but it is a dynamic system reflecting vast changes in all of its many components.


View this table:
[in this window]
[in a new window]
  		Table 1. Significant Changes with Advancing Age


arrow
ACKNOWLEDGEMENTS
 
We thank Dr. Pamela Witte, Director of the Immunology and Aging Program (Loyola University, Maywood, IL), for her critical review of the manuscript and thoughtful discussion. NIH R01 AG18859 supported this work.

Received November 25, 2003; accepted February 16, 2004.


arrow
REFERENCES
 
    1
  1. Gotfried, M. H. (2001) Epidemiology of clinically diagnosed community-acquired pneumonia in the primary care setting: results from the 1999–2000 respiratory surveillance program Am. J. Med. 111,25S-29S
    2. 2
  2. Ruiz, M., Santiago, E., Marcos, M. A., Martinez, J. A., Arancibia, F., Mensa, J., Torres, A. (1999) Etiology of community-acquired pneumonia: impact of age, comorbidity, and severity Am. J. Respir. Crit. Care Med. 160,397-405[Abstract/Free Full Text]
    3. 3
  3. Laupland, K. B., Church, D. L., Mucenski, M., Sutherland, L. R., Davies, H. D. (2003) Population-based study on the epidemiology of and the risk factors for invasive Staphylococcus aureus infections J. Infect. Dis. 187,1452-1459[CrossRef][Medline]
    4. 4
  4. Pascual, F. B., McFinley, E. L., Zanardi, L. R., Cortese, M. M., Murphy, T. V. (2003) Tetanus surveillance–United States, 1998–2000 MMWR Surveill. Summ. 52,1-8[Medline]
    5. 5
  5. Bridges, C. B., Harper, S. A., Fukuda, K., Uyeki, T. M., Cox, N. J., Singleton, J. A., . Advisory Committee on Immunization Practices (2003) Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Recomm. Rep. 52,1-34[Medline]
    6. 6
  6. Potter, J. M., O’Donnell, B., Carman, W. F., Roberts, M. A., Stott, D. J. (1999) Serological response to influenza vaccination and nutritional and functional status of patients in geriatric medical long-term care Age Ageing 28,141-145[Abstract/Free Full Text]
    7. 7
  7. Linn, B. S. (1980) Age differences in the severity and outcomes of burns J. Am. Geriatr. Soc. 28,118-123[Medline]
    8. 8
  8. Ligthart, G. J., Corberand, J. X., Fournier, C., Galanaud, P., Hijmans, W., Kennes, B., Muller-Hermelink, H. K., Steinmann, G. G. (1984) Admission criteria for immunogerontological studies in man: the SENIEUR protocol Mech. Ageing Dev. 28,47-55[CrossRef][Medline]
    9. 9
  9. Ligthart, G. J., Corberand, J. X., Geertzen, H. G., Meinders, A. E., Knook, D. L., Hijmans, W. (1990) Necessity of the assessment of health status in human immunogerontological studies: evaluation of the SENIEUR protocol Mech. Ageing Dev. 55,89-105[CrossRef][Medline]
    10. 10
  10. Traill, K. N., Schonitzer, D., Jurgens, G., Bock, G., Pfeilschifter, R., Hilchenbach, M., Holasek, A., Forster, O., Wick, G. (1985) Age-related changes in lymphocyte subset proportions, surface differentiation antigen density and plasma membrane fluidity: application of the Eurage SENIEUR protocol admission criteria Mech. Ageing Dev. 33,39-66[CrossRef][Medline]
    11. 11
  11. Miller, R. A., Nadon, N. L. (2000) Principles of animal use for gerontological research J. Gerontol. A Biol. Sci. Med. Sci. 55,B117-B123[Abstract/Free Full Text]
    12. 12
  12. Biasi, D., Carletto, A., Dell’Agnola, C., Caramaschi, P., Montesanti, F., Zavateri, G., Zeminian, S., Bellavite, P., Bambara, L. M. (1996) Neutrophil migration, oxidative metabolism, and adhesion in elderly and young subjects Inflammation 20,673-681[CrossRef][Medline]
    13. 13
  13. Fransson, C., Mooney, J., Kinane, D. F., Berglundh, T. (1999) Differences in the inflammatory response in young and old human subjects during the course of experimental gingivitis J. Clin. Periodontol. 26,453-460[CrossRef][Medline]
    14. 14
  14. Corberand, J., Ngyen, F., Laharrague, P., Fontanilles, A. M., Gleyzes, B., Gyrard, E., Senegas, C. (1981) Polymorphonuclear functions and aging in humans J. Am. Geriatr. Soc. 29,391-397[Medline]
    15. 15
  15. Niwa, Y., Kasama, T., Miyachi, Y., Kanoh, T. (1989) Neutrophil chemotaxis, phagocytosis and parameters of reactive oxygen species in human aging: cross-sectional and longitudinal studies Life Sci. 44,1655-1664[CrossRef][Medline]
    16. 16
  16. Damtew, B., Spagnuolo, P. J., Goldsmith, G. G., Marino, J. A. (1990) Neutrophil adhesion in the elderly: inhibitory effects of plasma from elderly patients Clin. Immunol. Immunopathol. 54,247-255[CrossRef][Medline]
    17. 17
  17. Fulop, T., Foris, G., Leovey, A. (1984) Age-related changes in cAMP and cGMP levels during phagocytosis in human polymorphonuclear leukocytes Mech. Ageing Dev. 27,233-237[CrossRef][Medline]
    18. 18
  18. Seres, I., Csongor, J., Mohacsi, A., Leovey, A., Fulop, T. (1993) Age-dependent alterations of human recombinant GM-CSF effects on human granulocytes Mech. Ageing Dev. 71,143-154[CrossRef][Medline]
    19. 19
  19. Fu, Y-K., Arkins, S., Li, Y. M., Dantzer, R., Kelley, K. W. (1994) Reduction in superoxide anion secretion and bactericidal activity of neutrophils from aged rats: reversal by combination of {gamma} interferon and growth hormone Infect. Immun. 62,1-8[Abstract/Free Full Text]
    20. 20
  20. Piazzolla, G., Tortorella, C., Serrone, M., Jirillo, E., Antonaci, S. (1998) Modulation of cytoskeleton assembly capacity and oxidative response in aged neutrophils Immunopharmacol. Immunotoxicol. 20,251-266[Medline]
    21. 21
  21. Tortorella, C., Ottolenghi, A., Pugliese, P., Jirillo, E., Antonaci, S. (1993) Relationship between respiratory burst and adhesiveness capacity in elderly polymorphonuclear cells Mech. Ageing Dev. 69,53-63[CrossRef][Medline]
    22. 22
  22. Tortorella, C., Polignano, A., Piazzolla, G., Serrone, M., Jirillo, E., Antonaci, S. (1996) Lipopolysaccharide-, granulocyte-monocyte colony stimulating factor- and pentoxifylline-mediated effects on formyl-methionyl-leucine-phenylalanine-stimuated neutrophil respiratory burst in the elderly Microbios 85,189-198[Medline]
    23. 23
  23. Fulop, T., Varga, Z., Jacob, M. P., Robert, L. (1997) Effect of lithium on superoxide production and intracellular free calcium mobilization in elastin peptide ({kappa}-elastin) and FMLP stimulated human PMNs. Effect of age Life Sci. 60,325-332[Medline]
    24. 24
  24. Rao, K. M. K. (1986) Age-related decline in ligand-induced actin polymerization in human leukocytes and platelets J. Gerontol. 41,561-566
    25. 25
  25. Rao, K. M. K., Currie, M. S., Padmanabhan, J., Cohen, H. J. (1992) Age-related alteration in actin cytoskeleton and receptor expression in human leukocytes J. Gerontol. 47,B37-B44
    26. 26
  26. Noble, J. M., Ford, G. A., Thomas, T. H. (1999) Effect of aging on CD11b and CD69 surface expression by vesicular insertion in human polymorphonuclear leukocytes Clin. Sci. 97,323-329[Medline]
    27. 27
  27. Tortorella, C., Piazzolla, G., Spaccavento, F., Jirillo, E., Antonaci, S. (1999) Age-related effects of oxidative metabolism and cyclic AMP signaling on neutrophil apoptosis Mech. Ageing Dev. 110,195-205[CrossRef][Medline]
    28. 28
  28. Tortorella, C., Piazzolla, G., Spaccavento, F., Pece, S., Jirillo, E., Antonaci, S. (1998) Spontaneous and Fas-induced apoptotic cell death in aged neutrophils J. Clin. Immunol. 18,321-329[CrossRef][Medline]
    29. 29
  29. Fulop, T., Fouquet, C., Allaire, P., Perrin, N., Lacombe, G., Stankova, J., Rola-Pleszczynski, M., Gagne, D., Wagner, J. R., Khalil, A., Dupuis, G. (1997) Changes in apoptosis of human polymorphonuclear granulocytes with aging Mech. Ageing Dev. 96,15-34[CrossRef][Medline]
    30. 30
  30. Di Lorenzo, G., Balistreri, C. R., Candore, G., Cigna, D., Colombo, A., Romano, G. C., Colucci, A. T., Gervasi, F., Listi, F., Potestio, M., Caruso, C. (1999) Granulocyte and natural killer activity in the elderly Mech. Ageing Dev. 108,25-38[CrossRef][Medline]
    31. 31
  31. Colotta, F., Re, F., Polentarutti, N., Sozzani, S., Mantovani, A. (1992) Modulation of granulocyte survival and programmed cell death by cytokines and bacterial products Blood 80,2012-2020[Abstract/Free Full Text]
    32. 32
  32. Brach, M. A., de Vos, S., Gruss, H. J., Herrmann, F. (1992) Prolongation of survival of human neutrophils by granulocyte-macrophage colony-stimulating factor is caused by inhibition of programmed cell death Blood 80,2920-2924[Abstract/Free Full Text]
    33. 33
  33. Pericle, F., Liu, J. H., Diaz, J. I., Blanchard, D. K., Wei, S., Forni, G., Djeu, J. Y. (1994) Interleukin-2 prevention of apoptosis in human neutrophils Eur. J. Immunol. 24,440-444[Medline]
    34. 34
  34. Lee, A., Whyte, M. K. B., Haslett, C. (1993) Inhibition of apoptosis and prolongation of neutrophil functional longevity by inflammatory mediators J. Leukoc. Biol 54,283-288[Abstract]
    35. 35
  35. Fulop, T., Larbi, A., Linteau, A., Desgeorges, S., Douziech, N. (2002) The role of Mcl-1 and Bax expression alteration in the decreased rescue of human neutrophils from apoptosis by GM-CSF with aging Ann. N. Y. Acad. Sci. 973,305-308[Medline]
    36. 36
  36. Power, C., Wang, J. H., Sookhai, S., Wu, Q. D., Redmond, H. P. (2001) Proinflammatory effects of bacterial lipoprotein on human neutrophil activation status, function, and cytotoxic potential in vitro Shock 15,461-466[Medline]
    37. 37
  37. Mansfield, P. J., Minkovska-Galcheva, V., Carey, S. S., Shayman, J. A., Boxer, L. A. (2002) Regulation of polymorphonuclear leukocyte degranulation and oxide production by ceramide through inhibition of phospholipase D Blood 99,1434-1441[Abstract/Free Full Text]
    38. 38
  38. Li, J., Schuler-Thurner, B., Schuler, G., Huber, C., Seliger, B. (2001) Bipartite regulation of different components of the MHC class I antigen-processing machinery during dendritic cell maturation Int. Immunol. 13,1515-1523[Abstract/Free Full Text]
    39. 39
  39. Zhang, X., Li, L., Jung, J., Xiang, S., Hollmann, C., Choi, Y. S. (2001) The distinct roles of T cell-derived cytokines and a novel follicular dendritic cell-signaling molecule 8D6 in germinal center-B cell differentiation J. Immunol. 167,49-56[Abstract/Free Full Text]
    40. 40
  40. Szakal, A. K., Taylor, J. K., Smith, J. P., Kosco, M. H., Burton, G. F., Tew, J. J. (1990) Kinetics of germinal center development in lymph nodes of young and aging immune mice Anat. Rec. 227,475-485[CrossRef][Medline]
    41. 41
  41. Aydar, Y., Balogh, P., Tew, J. G., Szakal, A. K. (2002) Age-related depression of FDC accessory functions and CD21 ligand-mediated repair of co-stimulation Eur. J. Immunol. 32,2817-2826[CrossRef][Medline]
    42. 42
  42. Holmes, K. L., Schnizlein, C. T., Perkins, E. H., Tew, J. G. (1984) The effect of age on antigen retention in lymphoid follicles and in collagenous tissue of mice Mech. Ageing Dev. 25,243-255[CrossRef][Medline]
    43. 43
  43. Szakal, A. K., Aydar, Y., Balogh, P., Tew, J. G. (2002) Molecular interactions of FDCs with B cells in aging Semin. Immunol. 14,267-274[CrossRef][Medline]
    44. 44
  44. Granucci, F., Feau, S., Zanoni, I., Pavelka, N., Vizzardelli, C., Raimondi, G., Ricciardi-Castagnoli, P. (2003) The immune response is initiated by dendritic cells via interaction with microorganisms and interleukin-2 production J. Infect. Dis. 187,S346-S350
    45. 45
  45. Steger, M. M., Maczek, C., Grubeck-Loebenstein, B. (1996) Morphologically and functionally intact dendritic cells can be derived from the peripheral blood of aged individuals Clin. Exp. Immunol. 105,544-550[CrossRef][Medline]
    46. 46
  46. Lung, T. L., Saurwein-Teissl, M., Parson, W., Schonitzer, D., Grubeck-Loebenstein, B. (2000) Unimpaired dendritic cells can be derived from monocytes in old age and can mobilize residual function in senescent T cells Vaccine 18,1606-1612[CrossRef][Medline]
    47. 47
  47. Pietschmann, P., Hahn, P., Kudlacek, S., Thomas, R., Peterlik, M. (2000) Surface markers and transendothelial migration of dendritic cells from elderly subjects Exp. Gerontol. 35,213-214[CrossRef][Medline]
    48. 48
  48. Komatsubara, S., Cinader, B., Muramatsu, S. (1986) Polymorphism of age-related changes in stimulatory capacity of murine dendritic cells Mech. Ageing Dev. 37,163-173[CrossRef][Medline]
    49. 49
  49. Looney, R. J., Falsey, A. R., Walsh, E., Campbell, D. (2002) Effects of aging on cytokine production in response to respiratory syncytial virus infection J. Infect. Dis. 185,682-685[CrossRef][Medline]
    50. 50
  50. Shodell, M., Siegal, F. P. (2002) Circulating, interferon-producting plasmacytoid dentritic cells decline during human ageing Scand. J. Immunol. 56,518-521[CrossRef][Medline]
    51. 51
  51. Gon, Y., Hashimoto, S., Hayashi, S., Koura, T., Matsumoto, K., Horie, T. (1996) Lower serum concentrations of cytokines in elderly patients with pneumonia and the impaired production of cytokines by peripheral blood monocytes in the elderly Clin. Exp. Immunol. 106,120-126[CrossRef][Medline]
    52. 52
  52. Cai, N. S., Li, D. D., Cheung, H. T., Richardson, A. (1990) The expression of granulocyte/macrophage colony-stimulating factor in activated mouse lymphocytes declines with age Cell. Immunol. 130,311-319[CrossRef][Medline]
    53. 53
  53. Grewe, M. (2001) Chronological ageing and photoageing of dendritic cells Clin. Exp. Dermatol. 26,608-612[CrossRef][Medline]
    54. 54
  54. Bogdan, C., Nathan, C. (1993) Modulation of macrophage function by transforming growth factor ß, interleukin-4, and interleukin-10 Ann. N. Y. Acad. Sci. 685,713-739[Medline]
    55. 55
  55. Crawford, R. M., Leiby, D. A., Green, S. J., Nacy, C. A., Fortier, A. H., Meltzer, M. S. (1994) Macrophage activation: a riddle of immunological resistance Immunol. Ser. 60,29-46[Medline]
    56. 56
  56. Davila, D. R., Edwards, C. K., III, Arkins, S., Simon, J., Kelley, K. W. (1990) Interferon-{gamma}-induced priming for secretion of superoxide anion and tumor-necrosis factor-{alpha} declines in macrophages from aged rats FASEB J. 4,2906-2911[Abstract]
    57. 57
  57. Ding, A., Hwang, S., Schwab, R. (1994) Effect of aging on murine macrophages. Dimished response to IFN-{gamma} for enhanced oxidative metabolism J. Immunol. 153,2146-2152[Abstract]
    58. 58
  58. Hayakawa, H., Sato, A., Yagi, T., Uchiyama, H., Ide, K., Nakano, M. (1995) Superoxide generation by alveolar macrophages from aged rats: improvement by in vitro treatment with IFN-{gamma} Mech. Ageing Dev. 80,199-211[CrossRef][Medline]
    59. 59
  59. Lavie, L., Weinreb, O., Gershon, D. (1992) Age-related alterations in superoxide anion generation in mouse peritoneal macrophages studied by repeated stimulation and heat shock treatment J. Cell. Physiol. 152,382-388[CrossRef][Medline]
    60. 60
  60. Alvarez, E., Machado, A., Sobrino, F., Santa Maria, C. (1996) Nitric oxide and superoxide anion production decreases with age in resident and activated rat peritoneal macrophages Cell. Immunol. 169,152-155[CrossRef][Medline]
    61. 61
  61. Shepherd, V. L. (1986) The role of the respiratory burst of phagocytes in host defense Semin. Respir. Infect. 1,99-106[Medline]
    62. 62
  62. Johnston, R. B., Jr, Kitagawa, S., Edwards, C. K., III, Channon, J. Y., Suzuki, H., Pabst, M. J. (1988) The respiratory burst in activated macrophages: studies of its molecular basis and evidence for downregulation in chronic infection Adv. Exp. Med. Biol. 239,63-72[Medline]
    63. 63
  63. Kumar, P., Pai, K., Pandey, H., Sundar, S. (2002) NADH-oxidase, NADPH-oxidase and myeloperoxidase activity of visceral leishmaniasis patients J. Med. Microbiol. 51,832-836[Abstract/Free Full Text]
    64. 64
  64. Khare, V., Sodhi, A., Singh, S. M. (1996–1997) Effects of aging on the tumoricidal functions of muring peritoneal macrophages Nat. Immun. 15,285-296
    65. 65
  65. Lu, Q., Ceddia, M. A., Price, E. A., Ye, S-M., Woods, J. A. (1999) Chronic exercise increases macrophage-mediated tumor cytolysis in young and aged mice Am. J. Physiol. 276,R482-R489
    66. 66
  66. Kissen, E., Tomasi, M., McCartney-Francis, N., Gibbs, C. L., Smith, P. D. (1997) Age-related decline in murine macrophage production of nitric oxide J. Infect. Dis. 175,1004-1007[Medline]
    67. 67
  67. Chen, L-I., Pace, J. L., Russell, S. W., Morrison, D. C. (1996) Altered regulation of inducible nitric oxide synthase expression in macrophages from senescent mice Infect. Immun. 64,4288-4298[Abstract]
    68. 68
  68. Beharka, A. A., Wu, D., Serafini, M., Meydani, S. N. (2002) Mechanism of vitamin E inhibition of cyclooxygenase activity in macrophages from old mice: role of peroxynitrite Free Radic. Biol. Med. 32,503-511[CrossRef][Medline]
    69. 69
  69. Rollo, E. E., Denhardt, D. T. (1996) Differential effects of osteopontin on the cytotoxic activity of macrophages from young and old mice Immunology 88,642-647[CrossRef][Medline]
    70. 70
  70. Wu, D., Hayek, M. G., Meydani, S. (2001) Vitamin E and macrophage cyclooxygenase regulation in the aged J. Nutr. 131,382S-388S[Abstract/Free Full Text]
    71. 71
  71. Harizi, H., Juzan, M., Pitard, V., Moreau, J-F., Gualde, N. (2002) Cycloxygenase-2-issued prostaglandin E2 enhances the production of endogenous IL-10, which down-regulates dendritic cell function J. Immunol. 168,2255-2263[Abstract/Free Full Text]
    72. 72
  72. Harizi, H., Grosset, C., Gualde, N. (2003) Prostaglandin E2 modulates dendritic cell function via EP2 and EP4 receptor subtypes J. Leukoc. Biol 73,756-763[Abstract/Free Full Text]
    73. 73
  73. Rieser, C., Papesh, C., Herold, M., Bock, G., Ramoner, R., Klocker, H., Bartsch, G., Thurnher, M. (1998) Differential deactivation of human dendritic cells by endotoxin desensitization: role of tumor necrosis factor-{alpha} and prostaglandin E2 Blood 91,3112-3117[Abstract/Free Full Text]
    74. 74
  74. Hilkens, C. M. U., Snijders, A., Snijdewint, F. G. M., Wierenga, E. A., Kapsenberg, M. L. (1996) Modulation of T-cell cytokine secretion by accessory cell-derived products Eur. Respir. J. Suppl. 22,90s-94s[Medline]
    75. 75
  75. Woods, J. J., Grbic, J. T., Rodrick, M. L., Jordan, A., Mannick, J. A. (1987) Suppression of interleukin-2 production in an animal model of thermal injury is related to prostaglandin synthesis Arch. Surg. 122,179-184[Abstract/Free Full Text]
    76. 76
  76. Plackett, T. P., Schilling, E. M., Faunce, D. E., Choudhry, M. A., Witte, P. L., Kovacs, E. J. (2003) Aging enhances lymphocyte cytokine defects after injury FASEB J. 17,688-689[Abstract/Free Full Text]
    77. 77
  77. Adolfsson, O., Huber, B. T., Meydani, S. N. (2001) Vitamin E-enhanced IL-2 production in old mice: naïve but not memory T cells show increased cell division cycling and IL-2 producing capacity J. Immunol. 167,3809-3817[Abstract/Free Full Text]
    78. 78
  78. Haynes, L., Linton, P. J., Eaton, S. M., Tonkonogy, S. L., Swain, S. L. (1999) Interleukin 2, but not other common {gamma} chain-binding cytokines, can reverse the defect in generation of CD4 effector T cells from naïve T cells of aged mice J. Exp. Med. 190,1013-1024[Abstract/Free Full Text]
    79. 79
  79. Mascarucci, P., Taub, D., Saccani, S., Paloma, M. A., Dawson, H., Roth, G. S., Ingram, D. K., Lane, M. A. (2001) Age-related changes in cytokine production by leukocytes in rhesus monkeys Aging (Milano) 13,85-94[Medline]
    80. 80
  80. Glaser, R., Maccallum, R. C., Laskowski, B. F., Malarkey, W. B., Sheridan, J. F., Kiecott-Glaser, J. K. (2001) Evidence for a shift in the Th1- and Th2-cytokine response associated with chronic stress and aging J. Gerontol. A Biol. Sci. Med. Sci. 56,M477-M482[Abstract/Free Full Text]
    81. 81
  81. Renshaw, M., Rockwell, J., Engleman, C., Gewirtz, A., Katz, J., Sambhara, S. (2002) Cutting edge: impaired Toll-like receptor expression and function in aging J. Immunol. 169,4697-4701[Abstract/Free Full Text]
    82. 82
  82. Boehmer, E. D., Goral, J., Faunce, D. E., Kovacs, E. J. (2004) Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokines by production and mitogen-activated protein kinase expression J. Leukoc. Biol. 75,342-349[Abstract/Free Full Text]
    83. 83
  83. Beharka, A. A., Meydani, M., Wu, D., Leka, L. S., Meydani, A., Meydani, S. N. (2001) Interleukin-6 production does not increase with age J. Gerontol. A Biol. Sci. Med. Sci. 56,B81-B88[Abstract/Free Full Text]
    84. 84
  84. Bruunsgaard, H., Pedersen, B. K. (2003) Age-related inflammatory cytokines and disease Immunol. Allergy Clin. North Am. 23,15-39[CrossRef][Medline]
    85. 85
  85. Kovacs, E. J., Grabowski, K. A., Duffner, L. A., Plackett, T. P., Gergory, M. S. (2002) Survival and cell mediated immunity after burn injury in aged mice J. Amer. Aging Assoc. 25,3-10
    86. 86
  86. Saurwein-Teissl, M., Blasko, I., Zisterer, K., Neuman, B., Lang, B., Grubeck-Loebenstein, B. (2000) An imbalance between pro- and anti-inflammatory cytokines, a characteristic feature of old age Cytokine 12,1160-1161[CrossRef][Medline]
    87. 87
  87. Franceschi, C., Bonafe, M., Valensin, S., Olivieri, F., De Luca, M., Ottaviani, E., De Benedictis, G. (2000) Inflamm-aging: an evolutionary perspective on immunosenescence Ann. N. Y. Acad. Sci. 908,244-254[CrossRef][Medline]
    88. 88
  88. Ahluwalia, N., Mastro, A. M., Ball, R., Miles, M. P., Rajendra, R., Handte, G. (2001) Cytokine production by stimulated mononuclear cells did not change with aging in apparently healthy, well-nourished women Mech. Ageing Dev. 122,1269-1279[CrossRef][Medline]
    89. 89
  89. Chandra, R. K. (1997) Nutrition and the immune system: an introduction Am. J. Clin. Nutr. 66,460S-463S[Abstract/Free Full Text]
    90. 90
  90. Lesourd, B. M. (1997) Nutrition and immunity in the elderly: modification of immune responses with nutritional treatments Am. J. Clin. Nutr. 66,478S-484S[Abstract/Free Full Text]
    91. 91
  91. Mazari, L., Lesourd, B. M. (1998) Nutrition influences on immune responses in healthy aged persons Mech. Ageing Dev. 104,25-40[CrossRef][Medline]
    92. 92
  92. Barbul, A., Regan, M. C. (1995) Immune involvement in wound healing Otolaryngol. Clin. North Am. 28,955-968[Medline]
    93. 93
  93. Swift, M. E., Burns, A. L., Gray, K. L., DiPietro, L. A. (2001) Age-related alterations in the inflammatory response to dermal injury J. Invest. Dermatol. 117,1027-1035[CrossRef][Medline]
    94. 94
  94. Shallo, H., Plackett, T. P., Heinrich, S. A., Kovacs, E. J. (2003) Monocyte chemoattractant protein-1 (MCP-1) and macrophage infiltration into the skin after burn injury in aged mice Burns 29,641-647[CrossRef][Medline]
    95. 95
  95. Ashcroft, G. S., Horan, M. A., Ferguson, M. W. J. (1998) Aging alters the inflammatory and endothelial cell adhesion molecule profiles during human cutaneous wound healing Lab. Invest. 78,47-58[Medline]
    96. 96
  96. Swift, M. E., Kleinman, H. K., DiPietro, L. A. (1999) Impaired wound repair and delayed angiogenesis in aged mice Lab. Invest. 79,1479-1487[Medline]
    97. 97
  97. Vitale, M., Zamai, L., Neri, L. M., Galanzi, A., Facchini, A., Rana, R., Cataldi, A., Papa, S. (1992) The impairment of natural killer function in the healthy aged is due to postbinding-deficient mechanism Cell. Immunol. 145,1-10[CrossRef][Medline]
    98. 98
  98. Ogata, K., Yokose, N., Tamura, H., An, E., Nakamura, K., Dan, K., Nomura, T. (1997) Natural killer cells in the late decades of human life Clin. Immunol. Immunopathol. 84,269-275[CrossRef][Medline]
    99. 99
  99. Mariani, E., Monaco, M. C. G., Cattini, L., Sinoppi, M., Facchini, A. (1994) Distribution and lytic activity of NK cell subsets in the elderly Mech. Ageing Dev. 76,177-187[CrossRef][Medline]
    100. 100
  100. Borrego, F., Alonso, M. C., Galiani, M. D., Carracedo, J., Ramirez, R., Ostos, B., Pena, J., Solana, R. (1999) NK phenotypic markers and IL2 response in NK cells from elderly people Exp. Gerontol. 34,253-265[CrossRef][Medline]
    101. 101
  101. McNerlan, S. E., Rea, I. M., Alexander, H. D., Morris, T. C. M. (1998) Changes in natural killer cells, the CD57CD8 subset, and related cytokines in healthy aging J. Clin. Immunol. 18,31-38[CrossRef][Medline]
    102. 102
  102. Mariani, E., Mariani, A. R., Meneghetti, A., Tarozzi, A., Cocco, L., Facchini, A. (1998) Age-dependent decrease of NK cell phosphoinositide turnover during spontaneous but not Fc-mediated cytolytic activity Int. Immunol. 10,981-989[Abstract/Free Full Text]
    103. 103
  103. Krishnaraj, R. (1997) Senescence and cytokines modulate the NK cell expression Mech. Ageing Dev. 96,89-101[CrossRef][Medline]
    104. 104
  104. Dussault, I., Miller, S. C. (1994) Decline in natural killer cell-mediated immunosurveillance in aging mice–a consequence of reduced cell production and tumor binding capacity Mech. Ageing Dev. 75,115-129[CrossRef][Medline]
    105. 105
  105. Kmiec, Z., Mysliwska, J., Rachon, D., Kotlarz, G., Sworczak, K., Mysliwski, A. (2001) Natural killer activity and thyroid hormone levels in young and elderly persons Gerontology 47,282-288[CrossRef][Medline]
    106. 106
  106. Mysliwska, J., Bryl, E., Zorena, K., Balon, J., Foerster, J., Mysliwski, A. (1997) Overactivity of tumor necrosis factor-{alpha} but not interleukin 6 is associated with low natural killer cytotoxic activity in the elderly Gerontology 43,158-167[Medline]
    107. 107
  107. Mysliwska, J., Mysliski, A., Romanowski, P., Bigda, J., Sosnowska, D., Foerster, J. (1992) Monocytes are responsible for depressed natural killer (NK) activity in both young and elderly low NK responders Gerontology 38,41-49[Medline]
    108. 108
  108. Ravaglia, G., Forti, P., Maioli, F., Bastagli, L., Facchini, A., Mariani, E., Savarino, L., Sassi, S., Cucinotta, D., Lenaz, G. (2000) Effects of micronutrient status on natural killer cell immune function in healthy free-living subjects aged ≥90 y Am. J. Clin. Nutr. 71,590-598[Abstract/Free Full Text]
    109. 109
  109. De La Fuente, M., Miquel, J., Catalan, M. P., Victor, V. M., Guayerbas, N. (2002) The amount of thiolic antioxidant ingestion needed to improve several immune functions is higher in aged than in adult mice Free Radic. Res. 36,119-126[CrossRef][Medline]
    110. 110
  110. Mikael, N., Mirza, N. M., Zaharian, B. I., Deulofeut, H., Salazar, M., Yunis, E. J., Dubey, D. P. (1994) Genetic control of the decline of natural killer cell activity in aging mice Growth Dev. Aging 58,3-12[Medline]
    111. 111
  111. Hsueh, C-M., Chen, S-F., Ghanta, V. K., Hiramoto, R. N. (1996) Involvement of cytokine gene expression in the age-dependent decline of NK cell response Cell. Immunol. 173,221-229[CrossRef][Medline]
    112. 112
  112. Plett, A., Murasko, D. M. (2000) Genetic differences in the age-associated decrease in inducibility of natural killer cells by interferon-{alpha}/ß Mech. Ageing Dev. 112,197-215[CrossRef][Medline]
    113. 113
  113. Fernandes, G., Gupta, S. (1981) Natural killing and antibody-dependent cytotoxicity by lymphocyte subpopulations in young and aging humans J. Clin. Immunol. 1,141-148[CrossRef][Medline]
    114. 114
  114. Edwards, D. L., Avis, F. P. (1979) Antibody-dependent cellular cytotoxicity effector cell capacity among normal individuals J. Immunol. 123,1887-1893[Abstract/Free Full Text]
    115. 115
  115. Edwards, B. K., Howe, H. L., Ries, L. A., Thun, M. J., Rosenberg, H. M., Yancik, R., Wingo, P. A., Jemal, A., Feigal, E. G. (2002) Annual report to the nation on the status of cancer, 1973–1999, featuring implications of age and aging on U.S. cancer burden Cancer 94,2766-2792[CrossRef][Medline]
    116. 116
  116. Jemal, A., Murray, T., Samuels, A., Ghafoor, A., Ward, E., Thun, M. J. (2003) Cancer statistics, 2003 CA Cancer J. Clin. 53,5-26[Abstract/Free Full Text]
    117. 117
  117. Albright, J. W., Albright, J. F. (1998) Impaired natural killer cell function as a consequence of aging Exp. Gerontol. 33,13-25[CrossRef][Medline]
    118. 118
  118. Ogata, K., An, E., Shioi, Y., Nakamura, K., Luo, S., Yokose, N., Minami, S., Dan, K. (2001) Association between natural killer cell activity and infection in immunologically normal elderly people Clin. Exp. Immunol. 124,392-397[CrossRef][Medline]
    119. 119
  119. Exley, M., Garcia, J., Balk, S. P., Porcelli, S. (1997) Requirements for CD1d recognition by human invariant V{alpha}24+ CD4–CD8– T cells J. Exp. Med. 186,109-120[Abstract/Free Full Text]
    120. 120
  120. Faunce, D. E., Gamelli, R. L., Choudhry, M. A., Kovacs, E. J. (2003) A role for CD1d-restricted NKT cells in injury-associated T cell suppression J. Leukoc. Biol. 73,747-755[Abstract/Free Full Text]
    121. 121
  121. Gansert, J. L., Kiessler, V., Engele, M., Wittke, F., Rollinghoff, M., Krensky, A. M., Porcelli, S. A., Modlin, R. L., Stenger, S. (2003) Human NKT cells express granulysin and exhibit antimycobacterial activity J. Immunol. 170,3154-3161[Abstract/Free Full Text]
    122. 122
  122. Shao, H., Van Kaer, L., Sun, S. L., Kaplan, H. J., Sun, D. (2003) Infiltration of the inflamed eye by NKT cells in a rat model of experimental autoimmune uveitis J. Autoimmun. 21,37-45[CrossRef][Medline]
    123. 123
  123. Sonoda, K. H., Faunce, D. E., Taniguchi, M., Exley, M., Balk, S., Stein-Streilein, J. (2001) NK T cell-derived IL-10 is essential for the differentiation of antigen-specific T regulatory cells in systemic tolerance J. Immunol. 166,42-50[Abstract/Free Full Text]
    124. 124
  124. Moore, K. W., O’Garra, A., de Waal Malefyt, R., Vieira, P., Mosmann, T. R. (1993) Interleukin-10 Annu. Rev. Immunol. 11,165-190[CrossRef][Medline]
    125. 125
  125. Dawson, H. D., Ross, A. C. (1999) Chronic marginal vitamin A status affects the distribution and function of T cells and natural T cells in aging Lewis rats J. Nutr. 129,1782-1790[Abstract/Free Full Text]
    126. 126
  126. Miyaji, C., Wantanabe, H., Toma, H., Akisaka, M., Tomiyama, K., Sato, Y., Abo, T. (2000) Functinal alterations of granulocytes, NK cells, and natural killer T cells in Centenarians Hum. Immunol. 61,908-916[CrossRef][Medline]
    127. 127
  127. Tsukahara, A., Seki, S., Iiai, T., Moroda, T., Watanabe, H., Suzuki, S., Tada, T., Hiraide, H., Hatakeyama, K., Abo, T. (1997) Mouse liver T cells: their change with aging and in comparison with peripheral T cells Hepatology 26,301-309[CrossRef][Medline]
    128. 128
  128. Poynter, M. E., Mu, H-H., Chen, X-P., Daynes, R. A. (1997) Activation of NK1.1+ T cells in vitro and their possible role in age-associated changes in inducible IL-4 production Cell. Immunol. 179,22-29[CrossRef][Medline]
    129. 129
  129. Dubey, D. P., Husain, Z., Levitan, E., Zurakowski, D., Mirza, N., Younes, S., Coronell, C., Yunis, D., Yunis, E. J. (2000) The MHC influences NK and NKT cell functions associated with immune abnormalities and lifespan Mech. Ageing Dev. 113,117-134[CrossRef][Medline]
    130. 130
  130. Inui, T., Nakagawa, R., Ohkura, S., Habu, Y., Koike, Y., Motoki, K., Kuranaga, N., Fukasawa, M., Shinomiya, N., Seki, S. (2002) Age-associated augmentation of the synthetic ligand-mediated function of mouse NK1.1 Ag+ T cells: their cytokine production and hepatotoxicity in vivo and in vitro J. Immunol. 169,6127-6132[Abstract/Free Full Text]
    131. 131
  131. Leite-de-Moraes, M. C., Herbelin, A., Gouarin, C., Koezuka, Y., Schneider, E., Dy, M. (2000) Fas/Fas ligand interactions promote activation-induced cell death of NK T lymphocytes J. Immunol. 164,4367-4371[Abstract/Free Full Text]
    132. 132
  132. McGeer, P. L., Rogers, J., McGeer, E. G. (1994) Neuroimmune mechanisms in Alzheimer disease pathogenesis Alzheimer Dis. Assoc. Disord. 8,149-158[Medline]
    133. 133
  133. Rogers, J., Schultz, J., Brachova, L., Lue, L. F., Webster, S., Bradt, B., Cooper, N. R., Moss, D. E. (1992) Complement activation and ß-amyloid-mediated neurotoxicity in Alzheimer’s disease Res. Immunol. 143,624-630[CrossRef][Medline]
    134. 134
  134. Lue, L. F., Rydel, R., Brigham, E. F., Yang, L. B., Hampel, H., Murphy, G. M., Jr, Brachova, L., Yan, S. D., Walker, D. G., Shen, Y., Rogers, J. (2001) Inflammatory repertoire of Alzheimer’s disease and nondemented elderly microglia in vitro Glia 35,72-79[CrossRef][Medline]
    135. 135
  135. Nagaki, K., Hiramatsu, S., Inai, S., Sasaki, A. (1980) The effect of aging on complement activity (CH50) and complement protein levels J. Clin. Lab. Immunol. 3,45-50[Medline]
    136. 136
  136. Oyeyink, G. O., Salimonu, L. S. (1999) Levels of complement components, immunoglobulins and acute phase proteins in plasma during aging in Nigeria Afr. J. Med. Med. Sci. 28,177-180[Medline]
    137. 137
  137. Menzel, E. J., Zlabinger, G. J., Dunky, A., Steffen, C. (1988) Autoimmunity and T-cell subpopulations in old age Arch. Gerontol. Geriatr. 7,249-260[CrossRef][Medline]
    138. 138
  138. Bellavia, D., Frada, G., Di Franco, P., Feo, S., Franceschi, C., Sansoni, P., Brai, M. (1999) C4, BF, C3 allele distribution and complement activities in healthy aged people and Centenarians J. Gerontol. A Biol. Sci. Med. Sci. 54,B150-B153[Abstract]
    139. 139
  139. Esparza-Gordillo, J., Soria, J. M., Buil, A., Souto, J. C., Almasy, L., Blangero, J., Fontcuberta, L., de Cordoba, S. R. (2003) Genetic determinants of variation in the plasma levels of the C4-binding protein (C4BP) in Spanish families Immunogenetics 54,862-866[Medline]
    140. 140
  140. Ogata, R. T., Mathias, P., Bradt, B. M., Cooper, N. R. (1993) Murine C4b-binding protein: mapping of the ligand binding site and the N-terminus of the pre-protein J. Immunol. 150,2273-2280[Abstract]
    141. 141
  141. Lavery, L. W., Goyns, M. H. (2002) Decline in the expression of C4 binding protein {alpha}-chain gene during ageing of the rat liver Biogerontology 3,207-211[CrossRef][Medline]
    142. 142
  142. Cannon, J. G., Fiatarone, M. A., Fielding, R. A., Evans, W. J. (1994) Aging and stress-induced changes in complement activation and neutrophil mobilization J. Appl. Physiol. 76,2616-2620[Abstract/Free Full Text]
    143. 143
  143. Kyrkanides, S., O’Banion, M. K., Whiteley, P. E., Daeschner, J. C., Olschowka, J. A. (2001) Enhanced glial activation and expression of specific CNS inflammation-related molecules in aged versus young rats following cortical stab injury J. Neuroimmunol. 119,269-277[CrossRef][Medline]
    144. 144
  144. Hazlett, L. D., Masinick-McClellan, S. A., Barrett, R. P. (1999) Complement defects in aged mice compromise phagocytosis of Pseudomonas aeruginosa Curr. Eye Res. 19,26-32[CrossRef][Medline]



This article has been cited by other articles:


Home page
 J. Virol.Home page
T. Baas, A. Roberts, T. H. Teal, L. Vogel, J. Chen, T. M. Tumpey, M. G. Katze, and K. Subbarao
Genomic Analysis Reveals Age-Dependent Innate Immune Responses to Severe Acute Respiratory Syndrome Coronavirus
J. Virol., October 1, 2008; 82(19): 9465 - 9476.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
K.-F. Kong, K. Delroux, X. Wang, F. Qian, A. Arjona, S. E. Malawista, E. Fikrig, and R. R. Montgomery
Dysregulation of TLR3 Impairs the Innate Immune Response to West Nile Virus in the Elderly
J. Virol., August 1, 2008; 82(15): 7613 - 7623.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
C. S. Lages, I. Suffia, P. A. Velilla, B. Huang, G. Warshaw, D. A. Hildeman, Y. Belkaid, and C. Chougnet
Functional Regulatory T Cells Accumulate in Aged Hosts and Promote Chronic Infectious Disease Reactivation
J. Immunol., August 1, 2008; 181(3): 1835 - 1848.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
E. J. Albert and J. S. Marshall
Aging in the absence of TLR2 is associated with reduced IFN-{gamma} responses in the large intestine and increased severity of induced colitis
J. Leukoc. Biol., April 1, 2008; 83(4): 833 - 842.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
S. K. Mathur, E. A. Schwantes, N. N. Jarjour, and W. W. Busse
Age-Related Changes in Eosinophil Function in Human Subjects
Chest, February 1, 2008; 133(2): 412 - 419.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
R. A. J. Signer, E. Montecino-Rodriguez, O. N. Witte, J. McLaughlin, and K. Dorshkind
Age-related defects in B lymphopoiesis underlie the myeloid dominance of adult leukemia
Blood, September 15, 2007; 110(6): 1831 - 1839.
[Abstract] [Full Text] [PDF]

Home page
 Toxicol SciHome page
I. Dublineau, L. Grandcolas, S. Grison, C. Baudelin, F. Paquet, P. Voisin, J. Aigueperse, and P. Gourmelon
Modifications of Inflammatory Pathways in Rat Intestine Following Chronic Ingestion of Depleted Uranium
Toxicol. Sci., August 1, 2007; 98(2): 458 - 468.
[Abstract] [Full Text] [PDF]

Home page
 Journals of Gerontology Series A: Biological Sciences and Medical SciencesHome page
C. F. Hodkinson, M. Kelly, H. D. Alexander, I. Bradbury, P. J. Robson, M. P. Bonham, J. M. O'Connor, C. Coudray, J. J. Strain, and J. M. W. Wallace
Effect of Zinc Supplementation on the Immune Status of Healthy Older Individuals Aged 55-70 Years: The ZENITH Study
J. Gerontol. A Biol. Sci. Med. Sci., June 1, 2007; 62(6): 598 - 608.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
L. Zhao, L. Sun, H. Wang, H. Ma, G. Liu, and Y. Zhao
Changes of CD4+CD25+Foxp3+ regulatory T cells in aged Balb/c mice
J. Leukoc. Biol., June 1, 2007; 81(6): 1386 - 1394.
[Abstract] [Full Text] [PDF]

Home page
 J Med MicrobiolHome page
C. Murciano, E. Villamon, A. Yanez, J.-E. O'Connor, D. Gozalbo, and M. L. Gil
Impaired immune response to Candida albicans in aged mice.
J. Med. Microbiol., December 1, 2006; 55(Pt 12): 1649 - 1656.
[Abstract] [Full Text] [PDF]

Home page
 Journals of Gerontology Series A: Biological Sciences and Medical SciencesHome page
C. F. Hodkinson, J. M. O'Connor, H. D. Alexander, I. Bradbury, M. P. Bonham, B. M. Hannigan, W. S. Gilmore, J. J. Strain, and J. M. W. Wallace
Whole Blood Analysis of Phagocytosis, Apoptosis, Cytokine Production, and Leukocyte Subsets in Healthy Older Men and Women: The ZENITH Study.
J. Gerontol. A Biol. Sci. Med. Sci., September 1, 2006; 61(9): 907 - 917.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
R. L. Chelvarajan, Y. Liu, D. Popa, M. L. Getchell, T. V. Getchell, A. J. Stromberg, and S. Bondada
Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages
J. Leukoc. Biol., June 1, 2006; 79(6): 1314 - 1327.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
K. Shimizu, R. N. Mitchell, and P. Libby
Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms
Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 987 - 994.
[Abstract] [Full Text] [PDF]

Home page
 Infect. Immun.Home page
G. Sen, Q. Chen, and C. M. Snapper
Immunization of Aged Mice with a Pneumococcal Conjugate Vaccine Combined with an Unmethylated CpG-Containing Oligodeoxynucleotide Restores Defective Immunoglobulin G Antipolysaccharide Responses and Specific CD4+-T-Cell Priming to Young Adult Levels
Infect. Immun., April 1, 2006; 74(4): 2177 - 2186.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
R. D. Stout, C. Jiang, B. Matta, I. Tietzel, S. K. Watkins, and J. Suttles
Macrophages Sequentially Change Their Functional Phenotype in Response to Changes in Microenvironmental Influences
J. Immunol., July 1, 2005; 175(1): 342 - 349.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
D. Alignani, B. Maletto, M. Liscovsky, A. Ropolo, G. Moron, and M. C. Pistoresi-Palencia
Orally administered OVA/CpG-ODN induces specific mucosal and systemic immune response in young and aged mice
J. Leukoc. Biol., June 1, 2005; 77(6): 898 - 905.
[Abstract] [Full Text] [PDF]

Home page
 Hum ReprodHome page
R. Rai, G. Sacks, and G. Trew
Natural killer cells and reproductive failure--theory, practice and prejudice
Hum. Reprod., May 1, 2005; 20(5): 1123 - 1126.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.1103592v1
76/2/291    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Plackett, T. P.
Right arrow Articles by Kovacs, E. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Plackett, T. P.
Right arrow Articles by Kovacs, E. J.