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Leptin regulation of the immune response and the immunodeficiency of malnutrition ¹

Department of Veterans Affairs Medical Center, University of California, San Francisco, San Francisco, California, 94121, USA

²Correspondence: Amgen Inc., One Amgen Center Dr., MS/15–2B, Thousand Oaks, CA, 91320-1799, USA. E-mail: faggioni{at}amgen.com

	ABSTRACT

TOP ABSTRACT LEPTIN AND OBESITY: IS... LEPTIN IS A PLEIOTROPIC... LEPTIN FUNCTIONS A CYTOKINE LEPTIN AND THE INNATE... LEPTIN AND THE ACQUIRED... LEPTIN DEFICIENCY AS A... REFERENCES

 
Leptin is a 16 kDa protein mainly produced by adipose tissue in proportion to adipose tissue mass. Originally thought to be a satiety factor, leptin is a pleiotropic molecule. In addition to playing a role in energy regulation, leptin also regulates endocrine and immune functions. Both the structure of leptin and that of its receptor suggest that leptin might be classified as a cytokine. The secondary structure of leptin has similarities to the long-chain helical cytokines family, which includes interleukin 6 (IL-6), IL-11, CNTF, and LIF, and the leptin receptor is homologous to the gp-130 signal-transducing subunit of the IL-6-type cytokine receptors. Leptin plays a role in innate and acquired immunity. Leptin levels increase acutely during infection and inflammation, and may represent a protective component of the host response to inflammation. More important, leptin deficiency increases susceptibility to infectious and inflammatory stimuli and is associated with dysregulation of cytokine production. Leptin deficiency also causes a defect in hematopoiesis. Leptin regulates T cells responses, polarizing Th cells toward a Th1 phenotype. Low leptin levels occurring during starvation mediate the neuroendocrine and immune dysfunction of starvation.—Faggioni, R., Feingold, K. R., Grunfeld, C. Leptin regulation of the immune response and the immunodeficiency of malnutrition.

Key Words: starvation • macrophages • lymphocytes • pleiotropic molecule

	LEPTIN AND OBESITY: IS IT A SATIETY FACTOR?

TOP ABSTRACT LEPTIN AND OBESITY: IS... LEPTIN IS A PLEIOTROPIC... LEPTIN FUNCTIONS A CYTOKINE LEPTIN AND THE INNATE... LEPTIN AND THE ACQUIRED... LEPTIN DEFICIENCY AS A... REFERENCES

 
LEPTIN IS A 16 kDa protein synthesized mainly by adipose tissue and was originally identified as the gene defect responsible for the obesity syndrome in ob/ob mice in 1994 by Friedman and colleagues (1) . The genetic defect of ob/ob mice was first described in the 1950s as the spontaneous mutation that causes a severe obese phenotype due to both overeating and decreased energy expenditure (2) . The gene was named ob and the obese mice carrying the mutation were called ob/ob mice. The protein encoded by the ob gene was named leptin, from the Greek leptos, which means thin. Because a defect in leptin led to overeating and obesity, leptin was proposed to be a satiety factor.

Parabiotic animal experiments suggested that the ob/ob animals were unable to make a factor that results in overeating, but ob/ob mice could respond to such a factor from a parabiotic mate. Similar experiments suggested that db/db mice, which have a mutation in the db gene and display a phenotype identical to ob/ob mice, make the factor that is missing in ob/ob mice, but db/db mice cannot respond to it. Therefore, it was hypothesized that the db gene would encode for the ob receptor. After the cloning of leptin, the leptin receptor (OB-R) was cloned shortly thereafter by virtue of its high affinity to leptin through an expression cloning strategy (3) . The OB-R is indeed the product of the db gene and is abundant in the hypothalamus, an area in the brain involved in the control of food intake. Db/db mice were shown to have a deletion in the long isoform of the leptin receptor and to be resistant to leptin (4) .

Thus, both leptin-deficient and leptin receptor-deficient mice display identical severe hereditary obesity phenotype, characterized by increased food intake and body weight plus decreased energy expenditure (1 , 4 5 6) . Furthermore, administration of leptin reverses the obese phenotype in ob/ob mice and decreases food intake in normal mice. In contrast, db/db mice are resistant to the weight-reducing effects of leptin (7 8 9) .

Circulating leptin levels are directly related to adipose tissue mass (10 , 11) . High leptin levels signal the presence of sufficient energy stores to sites in the central nervous system, which respond by reducing appetite and increasing energy expenditure, preventing severe obesity (11) . Therefore, leptin signals the nutritional status from the periphery to the area of the brain involved in the homeostasis of energy balance. However, the primary function of leptin may not be as a satiety factor. Leptin treatment at physiological levels reduces eating (and increases energy expenditure) by ob/ob mice to the levels of normal mice, but it does not cause satiety (end of eating). Higher doses of leptin are required to decrease food intake in normal animals (7 8 9) The same relationships are true in humans with the ob gene defect and normal humans (12) . Finally, transgenic mice overexpressing leptin at very high levels have little fat when young, but achieve normal body composition by 30 wk (13) .

Leptin levels are also modulated acutely. For example, leptin levels change rapidly with feeding or fasting disproportionately to the changes in fat depot (14 , 15) . Therefore, leptin is not just a readout of the fat stores.

	LEPTIN IS A PLEIOTROPIC MOLECULE

TOP ABSTRACT LEPTIN AND OBESITY: IS... LEPTIN IS A PLEIOTROPIC... LEPTIN FUNCTIONS A CYTOKINE LEPTIN AND THE INNATE... LEPTIN AND THE ACQUIRED... LEPTIN DEFICIENCY AS A... REFERENCES

 
On the other hand, a pleiotropic role for leptin in mammalian physiology is clearly suggested by the complex syndrome exhibited by leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice. Those mice are not only obese, but have abnormalities in reproductive function, hormone levels, wound repair, bone structure, and immune function (16 17 18 19 20 21 22) .

The weight-regulating effects of leptin are mediated through the Ob-Rb form in the hypothalamus (23 , 24) . However, Ob-Rb is also present in several peripheral organs including the spleen, lung, and kidney (25 26 27) . Circulating mononuclear cells, T lymphocytes, and macrophages in addition to endothelial cells express the long isoform of the leptin receptor (28 29 30 31) . Therefore, the expression pattern of leptin receptor mRNAs is consistent with multiple targets for leptin’s action, well beyond the hypothalamus.

	LEPTIN FUNCTIONS A CYTOKINE

TOP ABSTRACT LEPTIN AND OBESITY: IS... LEPTIN IS A PLEIOTROPIC... LEPTIN FUNCTIONS A CYTOKINE LEPTIN AND THE INNATE... LEPTIN AND THE ACQUIRED... LEPTIN DEFICIENCY AS A... REFERENCES

 
The structure of leptin and its receptor suggest that leptin is a member of the cytokine family. Despite the absence of sequence similarity between leptin and other long-chain helical cytokines, there is a striking similarity in their tertiary structures (32) . Leptin has a four-helix bundle similar to that of the long-chain helical cytokine family, which also includes IL-6, IL-11, IL-12, leukemia inhibitory factor (LIF), G-CSF, CNTF, and oncostatin M.

The leptin receptor is a cytokine receptor and belongs to the class I cytokine receptor family that includes gp-130, the common signal-transducing component for the IL-6-related family of cytokines such as IL-6, IL-11, LIF, CNTF, and oncostatin M (3 , 4 , 33) . The OB-R is alternately spliced into at least five transcripts from the single db gene. These transcripts encode proteins called the long (OB-Rb), short (OB-Ra, -c, and -d), and soluble (OB-Re) forms of the leptin receptor with varying length of their cytoplasmic tail (4) . The complexity of the OB-R system is typical of the cytokine biology, where the signal triggered by the binding of a cytokine to its receptor(s) on target cells might be modulated by soluble receptors, decoy receptors, receptor antagonists, and binding proteins (see below).

OB-Rb is essential in mediating most of the biological effects of leptin (4 , 6) . OB-Rb is highly expressed in the hypothalamus (24) , but is also present in peripheral tissues, including those of the immune system such as spleen, thymus, lung, and leukocytes (25 , 27 28 29 , 34 , 35) .

The short isoform (Ob-Ra) is the most abundant isoform found in most tissues (3) . It is highly expressed in the choroid plexus where it is likely to function as a transporter across the blood–brain barrier, as its mutation in fa^k/fa^k rats leads to reduced levels of leptin in the cerebrospinal fluid (36) . Although evidence of signaling capabilities has been reported for Ob-Ra (37) , the role of the signal it triggers is still unclear; it remains to be determined whether it might also function as a decoy receptor or have a role as a ligand-passing receptor.

Leptin circulates both in free form and bound to its soluble receptor OB-Re (38) . OB-Re appears to act as a carrier, since the binding of leptin to it delays its clearance from circulation and potentiates its effect on food intake (39) . Other cytokine receptors such as tumor necrosis factor (TNF) also use their soluble receptors as binding proteins (40) .

A leptin binding protein (OB-BP) with no similarity to the previously reported leptin receptor has recently been cloned (41) . High levels of OB-BP mRNA are detectable in placenta and moderate expression in spleen, peripheral blood leukocytes, and small intestine (41) . Although a role for OB-BP in leptin physiology has not been demonstrated, a role as a molecular sink to regulate leptin serum levels has been proposed. However, the major binding protein in plasma is OB-Re, not OB-BP (42) .

OB-Rb shares the same signal transduction pathway with gp-130-like cytokines (33) . It activates Janus kinase/signal transducers and activators of transcription (STAT) as well as mitogen-activated protein kinase signal transduction pathways (24) . In common with cytokine-transducing pathways, leptin induces expression of SOCS (suppressor of cytokine signaling)-3 mRNA in the hypothalamus (43) . SOCS proteins are thought to function as inducible intracellular negative regulators of cytokine signal transduction. Accordingly, transfection data suggest that SOCS-3 is an inhibitor of leptin signaling (43) .

Thus, in that leptin is structurally related to the cytokine family and its signal-transducing pathway is typical of a cytokine, it was important to investigate whether leptin was also regulated as a cytokine during the immune response.

	LEPTIN AND THE INNATE IMMUNE RESPONSE

TOP ABSTRACT LEPTIN AND OBESITY: IS... LEPTIN IS A PLEIOTROPIC... LEPTIN FUNCTIONS A CYTOKINE LEPTIN AND THE INNATE... LEPTIN AND THE ACQUIRED... LEPTIN DEFICIENCY AS A... REFERENCES

 
Cytokines orchestrate the host response to infectious and inflammatory stimuli. The induction of a cytokine cascade, which includes TNF, IL-6, and IL-1, leads to pathophysiological changes such as hypoglycemia, induction of acute-phase response (APR) proteins, and anorexia (44) . The leptin receptor is homologous to gp-130, the signaling transducing subunit of IL-6 family cytokines, which are important mediators of the APR (44) . As predicted from structural homology, leptin expression is regulated during the APR. Leptin levels are acutely increased by inflammatory and infectious stimuli such as lipopolysaccharide (LPS), turpentine, and cytokines (45 46 47) . The increase in leptin production during local and systemic inflammation does not occur in IL-1ß-deficient mice (47) and is blocked by soluble IL-1R in rats (48) . Therefore, during infection and inflammation, leptin expression is modulated in a manner similar to the cytokine response to infection and injury. Increased leptin levels also occur during experimental peritonitis induced by cecal ligation puncture and this increase is partially mediated by TNF (49) . Furthermore, leptin levels are elevated during carrageenan induced rat paw edema and carrageenan-induced pleurisy (50) . Thus, the overall increase in leptin during infection and inflammation indicates that leptin is part of the immune response and host defense mechanisms.

Because leptin is involved in the regulation of food intake and anorexia is a prominent feature of the APR, a role for leptin in the anorexia of infection and inflammation was proposed (45) . Despite its role in the control of food intake, however, leptin is not essential for the anorexia of inflammation (51) . In fact, LPS-induced anorexia is not attenuated by the absence of leptin. In contrast to other members of the IL-6 family, leptin does not induce APR proteins (52 , 53) , but does mediate other aspects of the host immune response.

That leptin regulates inflammatory responses is clearly indicated by the increased sensitivity to proinflammatory monocyte/macrophage-activating stimuli observed in ob/ob mice (54 , 55) . Leptin deficiency exacerbates susceptibility to LPS- and TNF-induced lethality and liver injury (54 55 56) . Thus, a functional leptin system appears to be a protective component of the host response to inflammation. An increased number of circulating monocytes is present in ob/ob mice (57) and might account, at least in part, for the increased sensitivity to LPS or TNF. In addition, macrophages from leptin-deficient mice have impaired phagocytic functions since they cannot clear and kill circulating Escherichia coli as efficiently as normal mice (30 , 56) . Thus, leptin regulates important macrophage functions, and chronic leptin deficiency may alter the phenotype of macrophages. In fact, macrophages from leptin-deficient mice appear to be constitutively activated. Macrophages from ob/ob mice show increased basal expression of IL-6 and cyclooxygenase-2 and produce more PGE₂, superoxide, and hydrogen peroxide (58) ._. This is consistent with the observation that the phenotype associated with leptin deficiency resembles normal mice primed with Propionibacterium acnes, a treatment that increases sensitivity to LPS (59) .

In addition to modulating phagocytosis and cytokine production by macrophages, leptin has recently been shown to regulate another aspect of the nonspecific immune response. Functional OB-R was detected on the polymorphonuclear neutrophil (PMN) membrane and shown to enhance oxidative species production by stimulated PMNs (60) . Thus, leptin might modulate PMN functions by regulating their oxidative capacity.

Dysregulation in cytokine induction after LPS stimulation also contributes to the increased susceptibility to LPS toxicity observed in ob/ob mice. Lower levels of anti-inflammatory cytokines, such as IL-10, IL-6, and IL-1Ra, and higher levels of the proinflammatory cytokines IL-12, IL-18, and interferon (IFN-) have been detected after LPS in ob/ob mice (54 , 56 , 59) . No conclusive data are available on TNF levels after LPS, as they have been found to be either unchanged or decreased in ob/ob mice (30 , 51) . Therefore, it appears that a defect in leptin production is associated with a shift of the immune response toward a proinflammatory phenotype as consequence of the up-regulation of proinflammatory and down-regulation of anti-inflammatory cytokines. However, contrasting data have been obtained in vitro. In macrophages from control mice, high doses of leptin up-regulate LPS-induced production of TNF, IL-12, and IL-6 as well as phagocytosis, which would suggest that leptin itself has some proinflammatory properties (30) . On the other hand, leptin also induces expression and secretion of IL-1Ra by human monocytes in vitro, suggesting an anti-inflammatory action of leptin (61) . This latter result is consistent with the reduced levels of IL-1Ra detected in ob/ob mice after LPS (54) .

Data regarding the regulation of leptin expression in response to infection and inflammation in humans are even more divergent. Although cytokines have been shown to acutely increase leptin levels in humans (62 , 63) , LPS does not appear to modulate circulating leptin levels (64) . Other acute inflammatory stimuli such as surgical cholecystectomy have been shown to increase leptin levels in humans (65) . However, in chronic inflammatory and infectious diseases such as AIDS, rheumatoid arthritis, and inflammatory bowel disease, no changes in leptin levels have been observed (66 67 68) . Conflicting data have also been found for leptin levels during sepsis. No changes in serum leptin levels were detected in the study published by Carlson et al. (69) . On the other hand, leptin levels were found to be elevated in patients with sepsis (70) . Two independent studies show a positive correlation between leptin levels and survival (71 , 72) . In one human family, genetic leptin deficiency is associated with high mortality, as 7 of 11 affected members died of infection in childhood (73) , supporting the concept that leptin induction represents a protective component of the immune response.

	LEPTIN AND THE ACQUIRED IMMUNE RESPONSE

TOP ABSTRACT LEPTIN AND OBESITY: IS... LEPTIN IS A PLEIOTROPIC... LEPTIN FUNCTIONS A CYTOKINE LEPTIN AND THE INNATE... LEPTIN AND THE ACQUIRED... LEPTIN DEFICIENCY AS A... REFERENCES

 
Leptin plays a role in T cell-mediated immunity, as suggested by the ob/ob mice phenotype. They have reduced sensitivity to T cell-activating stimuli, in contrast to the increased sensitivity to proinflammatory monocyte/macrophage-activating stimuli, particularly LPS and TNF-, discussed above (54 , 55) . Ob/ob mice have lymphoid atrophy accompanied by decreases in the number of circulating lymphocytes and increases in the number of circulating monocytes (18 , 57) . As a result, the absence of leptin reduces sensitivity to T cell-activating stimuli and enhances responses to monocyte activators. Ob/ob mice are protected from liver damage in the concanavalin A (Con A) model of T cell-mediated hepatitis (57) . This effect is associated with reduced induction of TNF- and IL-18. Exogenous leptin replacement normalized their lymphocyte and monocyte populations and restored the responsiveness of ob/ob mice to Con A (18 , 57) .

The lymphopenia of ob/ob mice also results in defective cell-mediated immunity, as they have impaired delayed type hypersensitivity (DTH) reaction (18 , 28) . Therefore, leptin acts as a regulator of T cell-mediated inflammation in vivo.

The defect in hematopoiesis observed in ob/ob mice probably involves anti-apoptotic and proliferative activities of leptin, described in several cell types. For example, leptin protects thymocytes from steroid-induced apoptosis in vitro (18) . The rise in leptin during the APR may ameliorate the reduction of lymphocytes induced by the hypercortisolism of the APR. Other effects of leptin on lymphocytes include 1) enhancing the alloproliferative response of human peripheral blood lymphocytes by acting on naive T lymphocytes (28) ; 2) enhancing phytohemagglutinin- and concanavalin A-induced proliferation of human T lymphocytes (29) ; 3) increasing the expression of activation markers CD69, CD25, and CD71 in CD4⁺ and CD8⁺ cells (29) ; 4) regulating cytokines production by T lymphocytes; 5) polarizing T helper (Th) cells toward a Th1 phenotype by enhancing proliferation and IL-2 production of naive T cells (28) ; 6) increasing INF- and inhibiting IL-4 production in memory CD4⁺ T cells; and 7) up-regulating the expression of adhesion molecules, such as VLA-2 and ICAM-1, on CD4⁺ T cells (28) . Thus, leptin regulates important aspects of immunity by regulating both the number and activation of T lymphocytes.

Consequently, leptin deficiency will ameliorate diseases where T cell function is essential for pathology. For example, a role for leptin was recently found in the pathogenesis of inflammatory bowel disease, a Th1-mediated disease. Elevated leptin levels have been detected in the circulation during experimental intestinal inflammation in rats and correlate with the degree of inflammation (74) . The increase is transient and limited to the early stages of inflammation. The decrease in leptin levels over time might account for the discrepancies in leptin levels measured in patients with inflammatory bowel disease (68) . Furthermore, leptin deficiency attenuates the severity of intestinal inflammation and reduces IL-18 expression in the colon epithelium (75) . Leptin deficiency in some pathological states is associated with reduced production of several proinflammatory mediators, such as TNF, IFN-, and IL-18 (75) . The ability of leptin deficiency to ameliorate the inflammation of T cell-mediated diseases should be contrasted to the worsening of the inflammatory diseases by leptin deficiency where T cells play a role in inhibiting toxicity (such as the toxicity from LPS activation of macrophages, as discussed above).

OB-Rb is expressed on endothelial cells and leptin has been proposed to play role in angiogenesis (31) . Leptin induces keratinocytes proliferation in vitro and promotes wound re-epithelialization in vivo (19) . Furthermore, leptin-deficient mice are characterized by a severe delay in wound healing (20) . Thus, by virtue of its mitogenic and angiogenic activities, leptin might play an important role in tissue regeneration during the host response to inflammation and infection.

	LEPTIN DEFICIENCY AS A MEDIATOR OF THE IMMUNE SUPPRESSION OF STARVATION

TOP ABSTRACT LEPTIN AND OBESITY: IS... LEPTIN IS A PLEIOTROPIC... LEPTIN FUNCTIONS A CYTOKINE LEPTIN AND THE INNATE... LEPTIN AND THE ACQUIRED... LEPTIN DEFICIENCY AS A... REFERENCES

 
Malnutrition is known to induce a state of immunodeficiency and a predisposition to death from infectious diseases (76) . During fasting or starvation, leptin levels drop disproportionately to the decrease in adipose tissue mass and the correlation between leptin levels and fat stores is lost (14) . Therefore, leptin during starvation is not merely a readout of the energy reserve, but is indeed a neuroendocrine signal that is crucial for the brain to initiate the adaptive responses to starvation. The adaptation of the organism to starvation is characterized by metabolic, endocrine, and immunological changes. Suppression of immune, reproductive and thyroid function, and stimulation of the hypothalamus-pituitary-adrenal (HPA) axis are among the changes induced by starvation (77) . Furthermore, starvation suppresses immunity, particularly T lymphocyte responses, and decreases resistance to infection (78 79 80) . In ob/ob mice, leptin deficiency leads to a complex syndrome characterized by most of the signs and symptoms of early starvation such as abnormal reproductive function, decreased thyroid hormone levels, increased cortisol levels and decreased activity (81) . Likewise, the immunological abnormalities of ob/ob are similar to those of starved mice. Like starved mice, ob/ob mice are more susceptible to infectious stimuli and have thymic atrophy and decreased T lymphocyte responses, such as DTH reaction (18 , 28 , 57) .

Leptin administration reverses the neuroendocrine and immunological changes of starved mice as well as of ob/ob mice, indicating that leptin deficiency mediates hormonal and immune abnormalities in both (14 , 18 , 54 , 57) . The decrease in leptin during starvation increases susceptibility to LPS and TNF induced lethality whereas leptin administration reverses those changes despite ongoing starvation, suggesting that the absence of leptin plays a role in the immune dysfunction of starvation (82) . Thus, the increased susceptibility to LPS and TNF and restoration by leptin in starvation parallel that found in ob/ob mice (54) . Exogenous leptin administration also reverses the inhibitory effect of starvation on the development of a DTH reaction and protects from starvation-induced lymphoid atrophy (18) . Similar restoration of DTH is observed when leptin is administered to ob/ob mice (18) .

Low leptin levels and hypercortisolemia are prominent features of starvation, and both leptin and glucocorticoids have been shown to have immunomodulating properties. Furthermore, a regulatory loop exists between the HPA axis and circulating leptin. In mice, adrenalectomy decreases basal leptin levels and corticosterone replacement therapy restores circulating leptin to physiological levels (83) . As observed in ob/ob mice, leptin deficiency results in chronic HPA axis activation, which is reversed by leptin treatment (84) . Fasting leads to low leptin levels and HPA activation. Leptin administration during fasting substantially prevents the activation of the HPA axis (14 , 85) , and the reduction in hypercortisolemia might mediate some of the immunosuppression due to the low levels of leptin during starvation. However, leptin directly prevents in vitro steroid-induced apoptosis of thymocytes (18) . It is therefore likely that the effects of leptin on immune system are both direct and mediated by leptin’s modulation of glucocorticoid levels.

Thus, the decrease in leptin levels during starvation provides a potential mechanism for increased susceptibility to infection and the decreased T cell responses secondary to malnutrition. Whether leptin can be used therapeutically to reverse such immune dysfunction remains to be demonstrated.

In addition to genetic leptin deficiency (which is rare in humans) and leptin deficiency secondary to malnutrition, another pathological condition is characterized by low leptin levels: lipodystrophy. There are congenital and acquired syndromes of lipodystrophy (86) . One case showed leukocyte defects (87) . Transgenic mice with congenital generalized lipodystrophy are leptin deficient; leptin treatment reduced their insulin resistance but did not restore insulin sensitivity to normal. It would informative to characterize the immune response in these mice (88) . Furthermore, lipodystrophy has been reported in patients treated with highly active antiretroviral therapy, and may be accompanied by dyslipidemia and insulin resistance (89) . A dramatic polarization to TNF synthesis was observed in CD4 and CD8 T cells from patients treated with such antiretroviral therapy (90) . Many patients with antiretroviral therapy-induced lipodystrophy have low levels of fat (89) and decreased leptin levels. Thus, it is tempting to speculate that leptin deficiency might contribute to the dysregulation of TNF production or metabolic changes. Experimental protocols are under way to treat humans with lipodystrophy using leptin (NIH Protocol # 00-DK-0146).

Even though leptin has shown limited efficacy as an anti-obesity strategy, it may have therapeutic potential in diseases/conditions characterized by low leptin levels, such as malnutrition and lipodystrophy.

	ACKNOWLEDGMENTS

 
This work was supported by grants from National Institutes of Health (RO1-DK-40990 and RO1-DK-49448), the Research Service of the Department of Veterans Affairs, and the UCSF AIDS Clinical Research Center.

	FOOTNOTES

 
¹ From the FASEB 2001 Symposium "Nutrients as Regulators of the Immune System." Chairs: S. Meydani and K. Erickson.

	REFERENCES

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