- Email: [email protected]
Keeping infectious complications at bay with immunonutrition
News & Comment
soluble in water (unlike natural Aβ), includes the immunogenic Aβ1–11 and Aβ22–28 regions yet is entirely nontoxic and nonfibrillar. Repeated immunization with this Aβ-like peptide reduced amyloid deposition in brains of transgenic Tg2576 APP mice – animals frequently used as an AD model because of their similar brain pathology. After seven months from the beginning of the protocol, the immunized mice demonstrated a reduced burden of Aβ plaques in both the cortical and hippocampal regions of the brain.
TRENDS in Immunology Vol.22 No.10 October 2001
It remains to be seen whether this immunization method will also diminish the AD-like memory impairment observed in similar AD animal models. Hopefully, this new approach will open the door for safer human trials in AD patients. Jenner’s legacy seems to have been awakened and is thriving – this could trumpet the dawn of a new exciting chapter in modern medicine, where noninfectious diseases, possibly including stroke and nerve trauma2, will become treatable by vaccination.
543
1 Sigurdsson, E.M. et al. (2001) Immunization with a nontoxic/nonfibrillar amyloid-β homologous peptide reduces Alzheimer’s disease-associated pathology in transgenic mice. Am. J. Pathol. 159, 439–447 2 Schwartz, M. and Kipnis, J. (2001) Protective autoimmunity: regulation and prospects for vaccination after brain and spinal cord injuries. Trends Mol. Med. 7, 252–258
David Gurwitz* [email protected] *This article also appears in the September issue of Trends in Molecular Medicine.
In Brief
3000 genes are induced when dendritic cells encounter live bacteria Using microarray technologies, it is now possible to analyze the expression of thousands of genes during the activation of immune cells. A recent report by Paola Ricciardi-Castagnoli and co-workers at the University of Milano-Bicocca, Italy demonstrates the usefulness of this approach when addressing how dendritic cells (DCs) respond to live Gram-negative bacteria. Using the D1 DC line (which shows similar maturation in culture to that observed for fresh bone-marrow-derived DCs), they have shown that expression of ≈3000 genes is induced upon incubation with live E. coli. These genes include those involved in cytoskeletal rearrangements, antigen processing, control of migration and apoptosis, and inflammatory responses. Most interestingly, expression of IL-2 was found to be induced rapidly. This did not occur in macrophages and the authors conclude that DCs are involved uniquely in T-cell priming. The usefulness of analysis of global gene expression for immunologists continues to become apparent. Nat. Immunol. (2001) 2, 882–888 LON
Mannose-binding lectin shows its value The plasma protein mannose-binding lectin (MBL) binds to carbohydrate moieties found http://immunology.trends.com
on the surface of a range of microorganisms. Once bound, the protein activates complement, leading to increased phagocytosis and lysis of the foreign surface. Low levels of MBL are common to all populations, but the relative importance of this component of the innate immune system and the significance of its plasma levels are still being described. Its relationship to disease severity and risk of autoimmunity are also being explored. A Danish group led by Niels Peterslund reported in the Lancet that patients with levels of MBL <0.5 mgl−1 are more likely to suffer from significant infection following chemotherapy for cancer. Infusions of synthetic MBL are being tested, and there is now a potential for ameliorating the clinical course of some patients following such treatments. CAM
A new generation of isoformselective PI 3-K inhibitors At least one ‘Holy Grail’ for many pharmaceutical research divisions has been to identify therapeutically useful selective PI 3-K inhibitors. There are several different, but closely related, PI 3-Ks, which are thought to have distinct biological roles. However, until now, medicinal chemists and biomedical researchers alike have been frustrated by the available pharmacological inhibitors, which are unable to distinguish the different isoforms of PI 3-K adequately. Fortunately, there seems to be light at the end of the tunnel; researchers at Thrombogenix Pty Ltd, Victoria, Australia have now reported the discovery of compounds with anti-thrombrotic properties that inhibit PI 3-Kα and PI 3-Kβ selectively, and might be of potential use for
the treatment of patients with cardiovascular diseases. The idea of isoform-specific PI 3-K inhibitors now seems to be reality and might lead to the novel therapy of other PI-3-K-dependent conditions, such as respiratory diseases, inflammatory disorders, cancers and diseases linked to the disordered function of white blood cells. World Intellectual Property Organisation (2001) International Publication Number WO01/53266 A1 SW
Keeping infectious complications at bay with immunonutrition Certain nutrients have been shown to influence immunological and inflammatory responses in humans, and a new term, immunonutrition, has been coined for the study of foodstuffs complimented with substances that might enhance immunity. This concept is being used by several food companies to promote their products, both for humans and household pets. Whether immunonutrition translates into quantifiable changes in immunity during illness is uncertain still. A recent report by D. Heyland and colleagues at the Kingston General Hospital in Canada analyzed systematically a total of 2419 patients in 22 randomized trials, which compared the use of immunonutrition with
1471-4906/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
544
News & Comment
standard enteral nutrition in surgical and critically ill patients. The studies involved enteral nutrition supplemented with some combination of arginine, glutamine, nucleotides and omega-3 fatty acids compared with standard nutrition. The outcomes measured included infectious complications and mortality rates. The authors found that the use of commercial formulations with high arginine content was associated with a significant reduction in infectious complications, and a trend towards a lower mortality rate compared with other ‘immune-enhancing’ diets, particularly in surgical patients, rather than in the critically ill. They conclude that the studies suggest immunonutrition might decrease infectious complications but is not associated with an overall advantage in terms of mortality. J. Am. Med. Assoc. (2001) 286, 944–953 LON
Do you need tomatoes in your salad? Previous research has suggested that a diet rich in tomato products, which contain the antioxidants lycopene and β-carotene, might help to protect infectionfighting white blood cells from the damage inflicted on them by free-radical particles, particularly, in the elderly. However, recent evidence from a controlled study by British researchers indicates that no beneficial (or adverse) effects on immune status whatsoever can be observed in people over the age of 65 who are taking the dietary supplements lycopene or β-carotene! Eur. J. Clin. Nutr. (2001) 55, 627–635 SW
Dynamic duos regulate autoimmune disorders A connection has been identified between two molecules that might be involved in some forms of arterial disease and autoimmune disorders. The lipid lysophosphatidylcholine (LPC) is a product of membrane-lipid metabolism during inflammatory events and has been implicated in the development of atherosclerosis and autoimmune diseases, such as lupus. The lymphocyte orphan receptor G2A has also been considered a possible regulator of autoimmune diseases, http://immunology.trends.com
TRENDS in Immunology Vol.22 No.10 October 2001
because mice that lack this receptor develop autoimmune symptoms and T cells from these mice are hyperproliferative. Researchers at the Cleveland Clinic Foundation, Ohio, USA now report that LPC is a high-affinity ligand for G2A and that this interaction might help to regulate the inflammation that underpins atherosclerosis and several autoimmune diseases. G2A might act as a sensor of LPC at sites of inflammation to limit the expansion of tissue-infiltrating cell populations and progression to autoimmune disease. However, when levels of G2A are too low, the immune system can kick-in. This work supports the growing realization that lymphocyte responses are regulated by more than antigen-presenting cells, antigen or the limited production of chemokines. Science (2001) 293, 702–705 SW
Complement modulates induction of autoimmune myocarditis Inflammation of the heart muscle (myocarditis) is associated with infection by coxsackie virus (CB3) and is a frequent cause of cardiac failure in young adults. Researchers, led by Noel White at the Johns Hopkins Medical School in Baltimore, USA, have shown that mice whose complement systems were inhibited, and which were then infected with coxsackie virus, did not develop myocarditis. By contrast, the majority of mice with an intact complement system developed the disease. The findings indicate that an overactive complement system might be a sign that a patient is more susceptible to myocarditis, and might offer an insight into new lines of therapy for this and other autoimmune diseases. Nat. Immunol. (2001) 2, 739–745 SW
Natural anti-HIV antibodies Researchers at the Rockefeller University in New York, USA and the Institute for Human Genetics and Biochemistry in Switzerland have discovered HIV-fighting antibodies as a component of the body’s innate immune system. These antibodies defend against infection with HIV by binding to the HIV
protein Tat. The researchers suspect that a person infected with HIV develops fullblown AIDS as the body begins to lose its innate immunity to the virus. Therefore, if adequate levels of the innate antibodies could be restored, it might be possible to prevent HIV-related illness. This discovery might open the door to a new approach to the treatment of HIV infection. Exp. Hematol. (2001) 29, 1004–1009 SW
Endocannabinoid receptors and cirrhosis Advanced liver cirrhosis is associated with generalized vasodilation of unknown origin, which contributes to mortality. Patients with cirrhotic livers are endotoxemic and the activation of vascular cannabinoid CB1 receptors has been implicated in endotoxininduced hypotension. Georges Kunos from the NIH in Bethesda, MA, USA and his collaborators have shown that monocytes derived from patients with cirrhotic livers produce significantly higher levels of the endogenous cannabinoid anandamide compared with those derived from control patients. Moreover, transfer of these monocytes resulted in hypotension in recipient rats that could be reversed by a CB1 antagonist. Also, isolated vascular endothelial cells from human cirrhotic livers express much higher levels of endocannabinoid receptors than noncirrhotic controls. Thus, endocannabinoid receptor antagonists might be a novel therapeutic approach for the management of patients with advanced liver cirrhosis. Nat. Med. (2001) 7, 827–832 SW
Reducing allergy: environmental or cellular strategies? Exposure to allergens in utero and during the first year of life contributes to sensitization in a dose-dependent fashion. The link between this sensitization and the development of asthma or eczema is unclear. The National Asthma Campaign study group in Manchester, UK, randomized couples who had atopy themselves to undergo a reduction in exposure to environmental allergens or have routine management prior to and following pregnancy. There were significant reductions in respiratory problems during the first year of life in infants whose parents had decreased exposure. There was no effect on rates of eczema. Before recommending
1471-4906/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
soluble in water (unlike natural Aβ), includes the immunogenic Aβ1–11 and Aβ22–28 regions yet is entirely nontoxic and nonfibrillar. Repeated immunization with this Aβ-like peptide reduced amyloid deposition in brains of transgenic Tg2576 APP mice – animals frequently used as an AD model because of their similar brain pathology. After seven months from the beginning of the protocol, the immunized mice demonstrated a reduced burden of Aβ plaques in both the cortical and hippocampal regions of the brain.
TRENDS in Immunology Vol.22 No.10 October 2001
It remains to be seen whether this immunization method will also diminish the AD-like memory impairment observed in similar AD animal models. Hopefully, this new approach will open the door for safer human trials in AD patients. Jenner’s legacy seems to have been awakened and is thriving – this could trumpet the dawn of a new exciting chapter in modern medicine, where noninfectious diseases, possibly including stroke and nerve trauma2, will become treatable by vaccination.
543
1 Sigurdsson, E.M. et al. (2001) Immunization with a nontoxic/nonfibrillar amyloid-β homologous peptide reduces Alzheimer’s disease-associated pathology in transgenic mice. Am. J. Pathol. 159, 439–447 2 Schwartz, M. and Kipnis, J. (2001) Protective autoimmunity: regulation and prospects for vaccination after brain and spinal cord injuries. Trends Mol. Med. 7, 252–258
David Gurwitz* [email protected] *This article also appears in the September issue of Trends in Molecular Medicine.
In Brief
3000 genes are induced when dendritic cells encounter live bacteria Using microarray technologies, it is now possible to analyze the expression of thousands of genes during the activation of immune cells. A recent report by Paola Ricciardi-Castagnoli and co-workers at the University of Milano-Bicocca, Italy demonstrates the usefulness of this approach when addressing how dendritic cells (DCs) respond to live Gram-negative bacteria. Using the D1 DC line (which shows similar maturation in culture to that observed for fresh bone-marrow-derived DCs), they have shown that expression of ≈3000 genes is induced upon incubation with live E. coli. These genes include those involved in cytoskeletal rearrangements, antigen processing, control of migration and apoptosis, and inflammatory responses. Most interestingly, expression of IL-2 was found to be induced rapidly. This did not occur in macrophages and the authors conclude that DCs are involved uniquely in T-cell priming. The usefulness of analysis of global gene expression for immunologists continues to become apparent. Nat. Immunol. (2001) 2, 882–888 LON
Mannose-binding lectin shows its value The plasma protein mannose-binding lectin (MBL) binds to carbohydrate moieties found http://immunology.trends.com
on the surface of a range of microorganisms. Once bound, the protein activates complement, leading to increased phagocytosis and lysis of the foreign surface. Low levels of MBL are common to all populations, but the relative importance of this component of the innate immune system and the significance of its plasma levels are still being described. Its relationship to disease severity and risk of autoimmunity are also being explored. A Danish group led by Niels Peterslund reported in the Lancet that patients with levels of MBL <0.5 mgl−1 are more likely to suffer from significant infection following chemotherapy for cancer. Infusions of synthetic MBL are being tested, and there is now a potential for ameliorating the clinical course of some patients following such treatments. CAM
A new generation of isoformselective PI 3-K inhibitors At least one ‘Holy Grail’ for many pharmaceutical research divisions has been to identify therapeutically useful selective PI 3-K inhibitors. There are several different, but closely related, PI 3-Ks, which are thought to have distinct biological roles. However, until now, medicinal chemists and biomedical researchers alike have been frustrated by the available pharmacological inhibitors, which are unable to distinguish the different isoforms of PI 3-K adequately. Fortunately, there seems to be light at the end of the tunnel; researchers at Thrombogenix Pty Ltd, Victoria, Australia have now reported the discovery of compounds with anti-thrombrotic properties that inhibit PI 3-Kα and PI 3-Kβ selectively, and might be of potential use for
the treatment of patients with cardiovascular diseases. The idea of isoform-specific PI 3-K inhibitors now seems to be reality and might lead to the novel therapy of other PI-3-K-dependent conditions, such as respiratory diseases, inflammatory disorders, cancers and diseases linked to the disordered function of white blood cells. World Intellectual Property Organisation (2001) International Publication Number WO01/53266 A1 SW
Keeping infectious complications at bay with immunonutrition Certain nutrients have been shown to influence immunological and inflammatory responses in humans, and a new term, immunonutrition, has been coined for the study of foodstuffs complimented with substances that might enhance immunity. This concept is being used by several food companies to promote their products, both for humans and household pets. Whether immunonutrition translates into quantifiable changes in immunity during illness is uncertain still. A recent report by D. Heyland and colleagues at the Kingston General Hospital in Canada analyzed systematically a total of 2419 patients in 22 randomized trials, which compared the use of immunonutrition with
1471-4906/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.
544
News & Comment
standard enteral nutrition in surgical and critically ill patients. The studies involved enteral nutrition supplemented with some combination of arginine, glutamine, nucleotides and omega-3 fatty acids compared with standard nutrition. The outcomes measured included infectious complications and mortality rates. The authors found that the use of commercial formulations with high arginine content was associated with a significant reduction in infectious complications, and a trend towards a lower mortality rate compared with other ‘immune-enhancing’ diets, particularly in surgical patients, rather than in the critically ill. They conclude that the studies suggest immunonutrition might decrease infectious complications but is not associated with an overall advantage in terms of mortality. J. Am. Med. Assoc. (2001) 286, 944–953 LON
Do you need tomatoes in your salad? Previous research has suggested that a diet rich in tomato products, which contain the antioxidants lycopene and β-carotene, might help to protect infectionfighting white blood cells from the damage inflicted on them by free-radical particles, particularly, in the elderly. However, recent evidence from a controlled study by British researchers indicates that no beneficial (or adverse) effects on immune status whatsoever can be observed in people over the age of 65 who are taking the dietary supplements lycopene or β-carotene! Eur. J. Clin. Nutr. (2001) 55, 627–635 SW
Dynamic duos regulate autoimmune disorders A connection has been identified between two molecules that might be involved in some forms of arterial disease and autoimmune disorders. The lipid lysophosphatidylcholine (LPC) is a product of membrane-lipid metabolism during inflammatory events and has been implicated in the development of atherosclerosis and autoimmune diseases, such as lupus. The lymphocyte orphan receptor G2A has also been considered a possible regulator of autoimmune diseases, http://immunology.trends.com
TRENDS in Immunology Vol.22 No.10 October 2001
because mice that lack this receptor develop autoimmune symptoms and T cells from these mice are hyperproliferative. Researchers at the Cleveland Clinic Foundation, Ohio, USA now report that LPC is a high-affinity ligand for G2A and that this interaction might help to regulate the inflammation that underpins atherosclerosis and several autoimmune diseases. G2A might act as a sensor of LPC at sites of inflammation to limit the expansion of tissue-infiltrating cell populations and progression to autoimmune disease. However, when levels of G2A are too low, the immune system can kick-in. This work supports the growing realization that lymphocyte responses are regulated by more than antigen-presenting cells, antigen or the limited production of chemokines. Science (2001) 293, 702–705 SW
Complement modulates induction of autoimmune myocarditis Inflammation of the heart muscle (myocarditis) is associated with infection by coxsackie virus (CB3) and is a frequent cause of cardiac failure in young adults. Researchers, led by Noel White at the Johns Hopkins Medical School in Baltimore, USA, have shown that mice whose complement systems were inhibited, and which were then infected with coxsackie virus, did not develop myocarditis. By contrast, the majority of mice with an intact complement system developed the disease. The findings indicate that an overactive complement system might be a sign that a patient is more susceptible to myocarditis, and might offer an insight into new lines of therapy for this and other autoimmune diseases. Nat. Immunol. (2001) 2, 739–745 SW
Natural anti-HIV antibodies Researchers at the Rockefeller University in New York, USA and the Institute for Human Genetics and Biochemistry in Switzerland have discovered HIV-fighting antibodies as a component of the body’s innate immune system. These antibodies defend against infection with HIV by binding to the HIV
protein Tat. The researchers suspect that a person infected with HIV develops fullblown AIDS as the body begins to lose its innate immunity to the virus. Therefore, if adequate levels of the innate antibodies could be restored, it might be possible to prevent HIV-related illness. This discovery might open the door to a new approach to the treatment of HIV infection. Exp. Hematol. (2001) 29, 1004–1009 SW
Endocannabinoid receptors and cirrhosis Advanced liver cirrhosis is associated with generalized vasodilation of unknown origin, which contributes to mortality. Patients with cirrhotic livers are endotoxemic and the activation of vascular cannabinoid CB1 receptors has been implicated in endotoxininduced hypotension. Georges Kunos from the NIH in Bethesda, MA, USA and his collaborators have shown that monocytes derived from patients with cirrhotic livers produce significantly higher levels of the endogenous cannabinoid anandamide compared with those derived from control patients. Moreover, transfer of these monocytes resulted in hypotension in recipient rats that could be reversed by a CB1 antagonist. Also, isolated vascular endothelial cells from human cirrhotic livers express much higher levels of endocannabinoid receptors than noncirrhotic controls. Thus, endocannabinoid receptor antagonists might be a novel therapeutic approach for the management of patients with advanced liver cirrhosis. Nat. Med. (2001) 7, 827–832 SW
Reducing allergy: environmental or cellular strategies? Exposure to allergens in utero and during the first year of life contributes to sensitization in a dose-dependent fashion. The link between this sensitization and the development of asthma or eczema is unclear. The National Asthma Campaign study group in Manchester, UK, randomized couples who had atopy themselves to undergo a reduction in exposure to environmental allergens or have routine management prior to and following pregnancy. There were significant reductions in respiratory problems during the first year of life in infants whose parents had decreased exposure. There was no effect on rates of eczema. Before recommending
1471-4906/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved.