Progress 01/01/09 to 12/31/13
Outputs
OUTPUTS: Recent work continues to demonstrate a role for hormone and hormone like molecules in forms of malnutrition like zinc deficiency and protein calorie deficiency. Leptin which controls feeding behavior was found to be high in malnutrition being also essential for development of lymphocytes, neutrophile and monocytes in the bone marrow. The latter is an important and novel new finding offering therapeutic possibilities. PARTICIPANTS: Nothing significant to report during this reporting period. TARGET AUDIENCES: The target audience would include clinicians and nutritionists. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
The children of Somalia are unfortunately repeating our studies that show a rapid and deleterious impact of malnutrition on immune defense. They have far more and more intense infections. The Gates Foundation, based on our work and that of the Blacks at John Hopkins, have a whole new program to provide zinc and other supplements to these children.
Publications
- No publications reported this period
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Progress 01/01/11 to 12/31/11
Outputs
OUTPUTS: Recent work continues to demonstrate a role for hormone and hormone like molecules in forms of malnutrition like zinc deficiency and protein calorie deficiency. Leptin which controls feeding behavior was found to be high in malnutrition being also essential for development of lymphocytes, neutrophils and monocytes in the bone marrow. The latter is an important and novel new finding offering therapeutic possibilities. PARTICIPANTS: Mark Trottier, Research Assistant Professor, Department of Biochemistry & Molecular Biology, Michigan State University, Afia Naaz, Research Associate, Department of Biochemistry & Molecular Biology, Michigan State University, Pandu Yenemula, College of Human Medicine, Department of Surgery, Michigan State University TARGET AUDIENCES: The target audience would include clinicians and nutritionists PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
The children of Somalia are unfortunately repeating our studies that show a rapid and deleterious impact of malnutrition on immune defense. They have far more and more intense infections. The Gates Foundation, based on our work and that of the Blacks at John Hopkins, have a whole new program to provide zinc and other supplements to these children.
Publications
- Fraker, Pamela J and Naaz, A.(2011) The role of leptin in immune cell development and innate immunity. In Adipokines, Prudy, editor, Science Publishers, London, UK, Chapter 30, 327
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Progress 01/01/10 to 12/31/10
Outputs
OUTPUTS: Our earlier work clearly demonstrated that modest periods of deficiencies in dietary zinc had deleterious effects on many immune defense systems which compromised health. We were the first lab to also demonstrate that the production of lymphocytes by the bone marrow was significantly reduced by malnutrition. More recently, studies of the morbidly obese after gastric bypass surgery indicate most patients are low in zinc in spite of being provided zinc supplements. This is due to reductions in the area of the gut needed for zinc absorption. We are currently investigating the extent and duration of this problem that could lead to more infections and poorer immune defense. PARTICIPANTS: Mark Trottier, Research Assistant Professor, Department of Biochemistry & Molecular Biology, Michigan State University Afia Naaz, Research Associate, Department of Biochemistry & Molecular Biology, Michigan State University Pandu Yenemula, College of Human Medicine, Department of Surgery, Michigan State University TARGET AUDIENCES: The target audience would include clinicians and nutritionists. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
Deficiencies in zinc are now known to be common among those who have chronic diseases and those who are undernourished . Thus the Gates Foundation has initiated a zinc supplemental program in Africa. Our studies demonstrating the deleterious impact of suboptimal dietary zinc on the immune defense system helped generate this outcome.
Publications
- Fraker, P and Naaz, A. 2010. Leptin modulation of the immune system, Chapter 8. In V Preedy (ed). Modern Insight into Disease From Molecules to Man: adipokines. Science Publishers, London, England (in press).
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Progress 01/01/09 to 12/31/09
Outputs
OUTPUTS: In past studies of deficiencies in single nutrients, like zinc, as well as more complex deficiencies in protein energy, we showed that the stress axis was induced and produced elevated levels of glucocorticoids (Gc). The Gc in these types of deficiencies caused large reductions in the production of lymphocytes in the marrow. This, of course, compromised cell and antibody mediated responses in the host. However, in the last few years we have discovered an important protection is also put into place. Monocytes and granuloctyes that are part of the first line of defense survive in the marrow seemingly unaffected by Gc. PARTICIPANTS: Steve Seibold, Research Assistant Professor, Department of Chemistry, Michigan State University Michael Feig, Associate Professor, Departments of Biochemistry and Molecular Biology and Chemistry, Michigan State University Mikhail Kashlev, Department Head, National Cancer Institute, Frederick, MD Benoit Coulombe, Director of Proteomics, IRCM, Montreal, Canada TARGET AUDIENCES: The target audience is the transcription field, those interested in the synthesis of RNA from a DNA template. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
The role of zinc deficiency in malnutrition, defective immune function and chronic disease is widely recognized. The Gates Foundation is now providing zinc therapy to children to reduce diarrhea (a sign of zinc deficiency), and poor immune responses to vaccinations in order to diminish childhood mortality in Africa. Our work has been the underpinning of current recognition of the need to maintain zinc status in order to maintain immune defense.
Publications
- Fraker, P. and Naaz, N. (2009) Leptin modulation of immune function. Chapter 5. In: Modern Insight into Disease. Science Publishers, London, England (in press).
- Fraker, P. and Trottier, M. (2010) Glucocorticoid mediated survival of the precursors of granulocytes and monocytes. PNAS (accepted).
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Progress 01/01/08 to 12/31/08
Outputs
OUTPUTS: We have shown in the past that deficiencies in zinc and/or protein calories act as a nutritional stress. This results in the chronic production of glucocorticoids (Gc) that rapidly down regulate the production of lymphocytes possibly to spare nutrients. However, there was survival of the first line of defense,the phagocytic cells, which appears to be an important failsafe. This was an important new finding. Moreover we found that human phagocytic cells or neutrophils, were elevated in the blood as well as in the marrow where they were produced. In the latter case, a significant increase of 40% was noted which would provide Gc exposed subjects substantial temporary protection. Members of the anti apoptotic family, inhibitors of apoptosis, and heat shock protein also exhibited increased gene expression in these neutrophils. They are key to the survival neutrophils exposed to Gc in both humans and mice. PARTICIPANTS: Not relevant to this project. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
Malnutrition, including deficiencies in zinc, accompany many chronic diseases such as AIDS, cancers, GI disorders renal disease etc. These deficiencies quickly compromise immune defense causing increased infections in these patients that prolong their recovery. Our studies focus on the reprogramming of the immune system to respond to this stress with ongoing efforts made to find nutritional and immunological interventions.
Publications
- Trottier, M., Newstad, M., King, L., and Fraker, P. Natural glucocorticoids induce expansion of all developmental stages of murine bone marrow granulocytes without inhibiting function. PNAS 105, 2028-2033 (2008).
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Progress 01/01/07 to 12/31/07
Outputs
The loss of young developing lymphocytes in the marrow and thymus of zinc deficient (ZD) mice is very high (40-60%), it was remarkable to find that myelopoiesis (the production of neutrophils, monocytes, macrophages) not only remained normal but exhibited substantial enhancement in umbers in acute ZD and protein calorie malnutrition (PCM). Malnutrition constitutes a stress that also causes chronic elevation of glucocorticoids that can be immunosuppressive. To test the role of glucocorticoids alone on myelopoiesis we used our glucocorticoid implantation system which generates concentrations of steroids analogous to that observed in ZD. We noted 25-35% increase in the numbers of myelopoietic cells in the marrow of mice exposed to stress levels of glucocorticoids. Thus, the immune system reprograms itself so that the phagocytic cells that are the first line of immunodefense survive.
Impacts
Malnutrition, including deficiencies in zinc, accompany many chronic diseases such as AIDS, cancers, GI disorders renal disease etc. These deficiencies quickly compromise immune defense causing increased infections in these patients that prolong their recovery. Our studies focus on the reprogramming of the immune system to respond to this stress with ongoing efforts made to find nutritional and immunological interventions.
Publications
- Trottier, M., Newstad, M., King, L. and Fraker, P. Natural glucocorticoids induce expansion of all developmental stages of murine bone marrow granulocytes without inhibiting function. (in press-PNAS) (2008)
- Claycombe, K., King, L. and Fraker, P. A role for leptin in sustaining lymphopoiesis and myelopoiesis. (in press-PNAS) (2008)
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Progress 01/01/06 to 12/31/06
Outputs
Short periods of deficiencies in zinc (ZD) substantially impair lymphocyte mediated responses in higher animals. ZD also has neuroendocrine affects that lead to elevated production of glucocorticoids that suppress production of lymphocytes. However, we have made the novel discovery that the first line of immune defense (eg. phagocytic cells) are able to survive these stresses. Indeed, neutrophils have longer half-lives and the number of their progenitors in the marrow increases 40-60%. This reprogramming of the immune system as nutrients decline fosters changes in gene expression in phagocytic cells that includes increased expression of anti-apoptotic genes like the inhibitors of caspases. These survival genes protect the phagocytic cells. Preliminary studies suggest that phagocytic cells in nutritionally stressed animals and humans may also be able to attack and kill pathogens very effectively .Thus intermediate protection of the host is provided.
Impacts
Greater numbers of infections of longer duration accompany many nutritional deficiencies including ZD. These deficiencies are a component of many diseases such as AIDS, cancer, GI disorders, renal disease, etc. Our studies now focus on the substantial reprogramming of the immune system which attempts to survive suboptimal nutriture by protecting the first line of defense which is a novel finding.
Publications
- Fraker, P. 2006. Roles for cell death in zinc deficiency. J Nutr. 135:359-362.
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Progress 01/01/05 to 12/31/05
Outputs
Thymic atrophy, lymphopenia, and compromised cell and antibody-mediated responses that cause increased rates of infections of longer duration are the immunological hallmarks of zinc deficiency (ZD) in humans and higher animals. This year a study was designed to determine whether or not more chronic zinc deficiency (ChrZD) had different impact on bone marrow function than acute forms. The thymus was the most sensitive primary tissue to ChrZd. By d 50 it had atrophied by 36 percent with significant loss of Pre-T cells via apoptosis. Signigicant reductions were also noted in the erythropoietic population by d 50. Conversely the marrow maintained myelopoiesis and B cell lymphopoiesis for the 50 d period indicating greater ability to survive a chronic zinc deficiency and exposure to glucocorticoids that accompany ZD. The anemia and T cell lymphopenia assoicated with ChrZD in both rodents and humans may result from a great sensitivity of their precursor cells to zinc
deficiency and elevated glucocorticoids.
Impacts
Malnutrition including deficiencies in zinc accompany many chronic diseases such as AIDS, cancers, GI disorders, renal disease etc. These deficiencies quickly compromise immune defense causing increased infections in these patients that prolong their recovery. Our studies focus on the reprogramming of the immune system to respond to this stress with ongoing efforts made to find nutritional and immunological interventions.
Publications
- Chronic Zinc Deficiency in Mice disrupted T cell Lymphopoiesis and erythropoietin while B cell lymphopoiesis and meyelopoiesis were maintained, J Amer College Nutr. 24:1-9, 2005
- Roles for Cell Death in Zinc Deficiency, J. Nutr. 135:359-362, 2005
- Zinc pyrithione induces apoptosis and increases expression of Bim, James Mann and Pam Fraker. Apoptosis 10:369-379, 2005
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Progress 01/01/04 to 12/31/04
Outputs
Thymic atrophy, lymphopenia, and compromised cell and antibody-mediated responses that cause increased rates of infections of longer duration are the immunological hallmarks of zinc deficiency (ZD) in humans and higher animals. This deficiency compromises the health not only of Americans with a poor diet but many who suffer from chronic disease. As the deficiency advances, a reprogramming of the immune system occurs, beginning with the activation of the stress axis and chronic production of glucocorticoids that accelerate apoptosis among pre-B and T cells. We have show that this reduced lymphopoiesis and causes atrophy of the thymus. In contrast, myelopoiesis is preserved, thereby providing protection for the first line of immune defense or innate immunity. Changes in gene expression for cytokines, DNA repair enzymes, zinc transporters, signaling molecules, etc., suggest that cells of the immune system are attempting to adapt to the stress of suboptimal zinc. Better
understanding of the molecular and cellular changes made in response to inadequate zinc should lead to the development of immunotherapeutic interventions.
Impacts
Malnutrition including deficiencies in zinc accompany many chronic diseases such as AIDS, cancers, GI disorders, renal disease etc. These deficiencies quickly compromise immune defense causing increased infections in these patients that prolong their recovery. Our studies focus on the reprogramming of the immune system to respond to this stress with ongoing efforts made to find nutritional and immunological interventions.
Publications
- Fraker, P. and Lill-Elghanian, D. The many roles for apoptosis in immunity as modified by aging and nutritional status. J. Nutr., Health & Aging 8, 129-136 (2004)
- Fraker, P. Reprogramming of the immune system during zinc deficiency. Annual Review of Nutrition 24, 227-298 (2004)
- Mann, J. and Fraker, P. Zinc induced apoptosis among cells of the immune system. (in press-Apoptosis) (2004)
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Progress 01/01/03 to 12/31/03
Outputs
Lymphopoiesis: The role of apoptosis in disrupting lymphopoiesis will be further defined in vivo using a transgenic mouse over-expressing the anti-apoptotic protein Bcl-2 in cells of the B-lineage allowing us the production of lymphocytes to compare the survival of protected pre B cells versus unprotected pre T cells during zinc deficiency (ZD). Pro B cells which accumulated in ZD mice will be examined for expression of Pax 5, a transcription factor key to B cell development. We suspect it is low in pro B cells from ZD mice allowing them to engage in lineage reversal joining the ever increasing pool of myeloid cells. We also suspect phenotypic analysis of progenitor cells in ZD mice will show they are also skewed towards myelopoiesis.
Impacts
Many chronic diseases such as AIDS, some cancers, colitis, irritable bowel syndrome, renal disease, reduces assimilation of zinc from the diet. This compromises immune defense in these patients. Better understanding of how suboptimal zinc alters the production of lymphocytes will lead to nutrition and immunological interventions for these subjects.
Publications
- Huang, Z. and Fraker, P. The impact of low protein diets on hematopoiesis. J. Nutr. (in press) (2003).
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Progress 01/01/02 to 12/31/02
Outputs
The objective of the research of this past year was to determine why phagocytic or myeloid cells that are key to the first line of host defense survived zinc deficiency (ZD) in the young adult mouse. Although short periods of ZD caused substantial losses of T and B lymphocytes, the phagocytic cells of the first line of defense survived both suboptimal zinc and the endogenously produced glucocorticoids (Gc) that are usually immunosuppressive. Our first goal was to study the effect of Gc on neutrophils. The approach used was to begin by incubating neutrophils and myeloid cell lines such as U937 and HL-60 with various doses of Gc. The following was observed. All of the myeloids survived culture in Gc to include high doses. Surprisingly, their half life was extended. Using Western analysis, we observed the receptor for Gc was rapidly down regulated in all of the above cells within a half an hour. This is a unique finding since this receptor in most other kinds of cells is
not down-regulated until after 12-24 hours. We used PCR to demonstrate that the message RNA for the receptor remained unchanged. Thus we are in the process of determining whether or not this important receptor is removed by proteolytic digestion. In sum the ability of phagocytic cells to survive exposure to immunosuppressive glucocorticoids by rapidly down regulating their receptors for glucocorticoids is an important immunological and medical finding.
Impacts
Our finding that phogocytic cells survive exposure to immunosuppressive concentrations of glucocorticoids by down regulating the steriod receptor is of potential medical importance. It may for example explain why some inflammatory responses seen in asthma, arthritis, autoimmunity, etc; show poor responses to treatment with pharmacological versions of the glucocorticoids such as prednisone, dexamethasone, hydrocortisone, etc. This information suggests that drugs other than glucocorticoids that can reduce inflammatory responses need to be considered and developed if we are to be able to reduce inflammatory responses initiated by myeloid cells.
Publications
- Islam, Z., Pestka, J., King, L., and Fraker, P. Modulation of immune system by mycotoxins. Toxicology & Applied Pharmacol. 180, 43-55 (2002).
- King, L. and Fraker, P. Zinc deficiency in mice alters myelopoiesis and hematopoiesis. J. Nutr. (In press) (2002).
- King, L., and Fraker P. A distinct role for apoptosis in the changes in lymphopoiesis and myelopoiesis created by deficiencies in zinc. FASEB J. 15, 2572-2578 (2001).
- Laakko, T., King, L. and Fraker, P. Versatility of meracyanine 540 for the flow cytometric detection of apoptosis in human and murine cells. J. Immunol. Meth. 261, 129-139 (2002).
- Laakko, T. and Fraker, P. Rapid changes in lymphopoietic and granulopoietic compartments of the marrow caused by stress levels of corticosterone. Immunology 105, 1-15 (2002).
- Lill-Elghanian, Schwartz, K., King, L. and Fraker, P. Glucocorticoid-induced apoptosis in early B-cells from human bone marrow. Exper. Biol. Medicine 227, 753-762 (2002).
- Fraker, P. and Lill-Elghanian, D. The many roles for apoptosis in immunity as modified by aging and nutritional status. J. Nutr., Health & Aging (in press) (2002).
- King, L., Osati-Ashtiani, F. and Fraker, P. A distinct role apoptosis in the loss of precursor lymphocytes during zinc deficiency. J. Nutr. 132, 974-979 (2002).
- Laakko, T. and Fraker, P. Interleukin 7 mediated protection of pro and pre B-cells from the adverse effects of corticosterone. Cell Immunol. Accepted with minor revisions (2002).
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Progress 01/01/01 to 12/31/01
Outputs
Zinc deficiency is a prevalent nutritional problem in the USA especially among children of low income families, the frail elderly, and those with chronic diseases. Lymphopenia is a characteristic of zinc deficiency which is associated with massive loss of pre-B and pre-T cells from the primary lymphoid organs of zinc deficient mice which have elevated serum corticosterone (CS) that compromises immune defense. Whether this naturally elevated glucocorticoid level is associated with increased apoptotic loss of pre-T cells in the thymus of mice is examined here in A/J and CAF1/J mice. In three experiments, partially atrophied thymuses were removed from 20 marginally zinc deficient young adult mice (ZD) and cultured for six hours in parallel with thymocytes prepared from 17 adequately fed mice. Thymocyte immunophenotyping combined with flow cytometric cell cycle analysis were used to identify the degree of apoptotic cell death among thymocytes of the two dietary groups
which were compared in the absence of in vivo phagocytosis. The data show that apoptosis was enhanced 50-300% among pre-T cells (CD4+CD8+) prepared from ZD mice. This resulted in a 38% depletion of the thymic pre-T cell compartment and correlated with an 80% decrease in thymic cell number. Pro-T cells (CD4- CD8-) and mature T cells (CD4+CD8- , CD4- CD8+), which express higher levels of Bcl-2 protein, survived ZD to a greater extent and formed a higher proportion of the remaining thymocyte population in ZD mice. Collectively, these data show that heightened degrees of apoptotic cell death induced in vivo by CS disrupted thymic T cell lymphopoiesis, identifies the means of disruption of marrow B cell lymphopoiesis, and explains the appearance of lymphopenia.
Impacts
This work provides the first mechanistic explanation for the rapid and adverse effects of suboptimal dietary zinc on the immune system. It now opens the way for patient intervention to include blocking of glucocorticoid production to reduce apoptosis among cells of the immune system.
Publications
- King, L. and Fraker P. 2001. A distinct role for apoptosis in the changes in lymphopoiesis and myelopoiesis created by deficiencies in zinc. FASEB J. 15:2572-2578.
- King, L., Osati-Ashtiani, F. and Fraker, P. 2002. A distinct role apoptosis in the loss of precursor lymphocytes during zinc deficiency. J. Nutr. in press.
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Progress 01/01/00 to 12/31/00
Outputs
The recent enrichment of animal chows with very high concentration of zinc (120 ppm where 6 is required for growth in mice) prevented our lab from carrying out the previous acute studies of zinc deficiency (ZD) in young mice. The latter were complete in 30 days; however, studies with mice apparently preloaded with zinc began to take almost twice as long. This initial, unfortunate, turn of events has taught us many important things. First, the body may be able to store more zinc in liver and bone than previously thought. We also reaffirmed an early observation made by nutritionists in the 70's that if a diet was high in calcium it would reduce the time needed to make rodents ZD perhaps by slowing the release of stored zinc from the bone. The slow or chronic model of ZD (50-60 days) yielded mice only marginally ZD with minimal changes in the marrow and thymus compared to what was observed in acute ZD. However, even in the changing model there was the beginning of an
activation of the stress axis with a threefold elevator in glucocorticoids observed in the blood of deficient mice. Future experiments include extending studies of chronic ZD using diet with more than adequate but moderate Ca++ concentration to 70-80 days. We suspect that effects of longer, more prolonged period of ZD may give some immune outcome as chronic or rapid ZD. In other words, when zinc deficits reach a certain point in the body, whether achieved in 30or 90 days, the effects on the primary tissues of the immune system, e.g., marrow and thymus, that are responsible for producing adequate numbers of lymphocytes may be the same. Previous studies of acute ZD indicate that it induced endogenous production of glucocorticoids that, in turn, initiated greatly heightened apoptosis that virtually eliminated young precursor T and B-cells. The latter is the underlying mechanism for the cause of lymphopenia. We completed studies that demonstrate that ZD causes marked changes in
hematopoietic processes in the marrow. The compartment responsible for regeneration of lymphocytes was depleted by half. Greatly increased apoptosis or cell death was the underlying cause. Conversely, the myeloid compartments that provide phagocytic cells increased. This appears to be an important new adaptive response to protect the first line of immune defense during malnutrition.
Impacts
We have demonstrated that the cause of the rapid decline in production of lymphocytes during forms of malnutrition is due to heightened cell death or apoptosis. The mechanism for this 30 year old observation has been defined.
Publications
- Fraker, P., King, L., Laakko, T. and Vollmer, T. 2000. The dynamic link between the integrity of the immune system and zinc status. J. Nutr. 130:13995-1465.
- King, L. and Fraker, P. 2000. Variations in cell cycle status of lymphopoietic and myelopoietic cells created by zinc deficiency. J. Infect. Diseases.
- Fraker, P. 1999. Impact of nutritional status on the immune response. Nutrition and Immunology, Chapter 12:47-156.
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Progress 01/01/99 to 12/31/99
Outputs
High rates of infection and disease and heightened mortality are outcomes of many nutritional deficiencies including zinc deficiency. For over a decade it was evident that reduced numbers of circulating lymphocytes were the underlying cause of reduced immune defense in zinc deficient humans and animals. Using the young adult mouse as a model, the first comprehensive studies of the effects of a nutritional deficiency on lymphopoiesis (production of lymphocytes) and other functions of the bone marrow were initiated. As little as 30 days of suboptimal intake of zinc reduced the number of precursor T and B-cells by 40 to70% in the adult mouse. Recent experiments demonstrate that the loss of those precursor cells was due to heightened levels of cell death or apoptosis induced by suboptimal zinc. This provides a key mechanism that explains the rapid depletion of lymphocytes during zinc deficiency. 0f equal interest is the recent observation that the phagocytic cells which
are the first line of immune defense are able to survive zinc deficiency. This represents a major shift in the composition of the marrow that may represent a very important adaptive response to malnutrition.
Impacts
Suboptimal zinc status has been noted in low income American children, pregnant teenagers, the frail elderly and those with chronic diseases such as cancer, AIDS, sickle cell anemia, gastrointestinal disorders, etc. Our finding that zinc deficiency caused rapid reductions in the production of lymphocytes while preserving production of phagocytic cells represents the discovery of a very important immune adaptive response not noted previously. Moreover, these findings open the way for immunotherapy of malnourished or zinc deficient subjects.
Publications
- Fraker, P. 1999. Impact of nutritional status on the immune response. Nutrition and Immunology, Chapter 12, 147-156pp.
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