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RANTES polymorphism affects susceptibility to HIV and asthma
News & Comment
TRENDS in Immunology Vol.22 No.1 January 2001
13
In Brief
New drug delivery system developed to prevent immune activation Martin Garnett and colleagues (Nottingham University, UK) have developed drug delivery ‘particles’ that can travel through the bloodstream without being phagocytosed by macrophages. It is hoped that these particles can be used to deliver anti-cancer drugs to tumours or as a gene delivery system.The team bound together two polymers – polyethylene glycol (PEG), which is hydrophilic, and polylactic acid (PLA), which is hydrophobic – to produce a copolymer that spontaneously assembles into spheres in an aqueous medium. Because PEG is hydrophilic it does not readily bind to proteins in the blood, and so avoids opsonization.The group found that it was possible to create particles with a range of sizes and surface characteristics to determine which had the best properties for drug delivery. If DNA, which is negatively charged, is mixed with a positively charged polymer, the structure spontaneously forms a doughnut shape. If PEG is then fastened to the positively charged polymer, nanoparticles can be assembled with DNA inside. Garnett believes this gene delivery system could prove safer than viral vectors. HEM
Scientists finally develop transgenic Burkitt’s mice Siegfried Janz and colleagues1 (Laboratory of Genetics, NCI, Bethesda, MD) have developed a transgenic mouse model of Burkitt’s lymphoma – a disease that accounts for over half of all childhood cancers in Africa, and is now found in Western countries where it strikes AIDS patients. It is known that the cancer develops when the Myc gene (found on chromosome 8), which stimulates cell growth, is translocated to chromosome 14.This gene then comes under the regulatory control of genes of the immune system, leading to the uninhibited proliferation of B cells. However, scientists would like to know how other genetic mutations, environmental factors and Epstein–Barr virus, work together to cause Burkitt’s lymphoma.The new mouse model should help them achieve this and might also be used to test new treatments. HEM http://immunology.trends.com
1 Janz, S. et al. (2000) Burkitt’s lymphoma in the mouse. J. Exp. Med. 92, 1183–1190
RANTES polymorphism affects susceptibility to HIV and asthma A recent report1 has shown that a single nucleotide mutation at position 403 in the RANTES promoter gene (known as −403A) doubles susceptibility to HIV infection. Paradoxically, the genotype also slowed the progression to AIDS by about 40%. RANTES (regulated on activation, normalT expressed and secreted) is a chemokine that attracts inflammatory cells into areas of injury and normally binds to the same receptor (CCR5) that the HIV virus uses to gain entry to the target cell. It is already known that polymorphisms in CCR5 are associated with disease outcome. Bill Ollier and Ali Hajeer of the Arthritis Research Campaign (ARC) Epidemiology Unit at the University of Manchester, UK, have been looking at RANTES gene variations in blood from HIV-positive and HIV-resistant individuals for some years. In 1998 they filed a patent application on the variants of the RANTES gene and have worked in cooperation with David McDermott at the National Institute of Allergy and Infectious diseases who applied the Manchester group’s findings to the Multicenter Aids Cohort Study. The research team hypothesizes that overproduction of RANTES by the mutated gene increases inflammation and opens up the spaces between cells allowing virus to enter. However, the increased numbers of RANTES molecules compete with virus for the CCR5 receptor thereby slowing disease progression. Another finding was that the mutated gene was more common in those of African/American descent than in those of European descent. The Manchester group has also made an interesting link between RANTES polymorphisms and asthma. Their recent report2 shows that the rare variant of the RANTES gene is associated with high risk of asthma and severe airway obstruction. Hajeer explained that ‘patients with asthma who are homozygous for the RANTES mutation (−403A) are six times more likely to develop severe asthma than patients possessing the ‘normal’ gene.’ HEM
1 McDermott, D.H. et al. (2000) Chemokine RANTES promoter polymorphism affects risk of both HIV infection and disease progression in the Multicenter AIDS Cohort Study. AIDS 14, 2671–2678 2 Fryer, A.A. et al. (2000)The 403 G A promoter polymorphism in the RANTES gene is associated with atopy and asthma. Genes Immun. 509–514
Anti B cell therapy proves successful in severe cases of rheumatoid arthritis A team led by Jonathan Edwards (University College London, UK), has returned five refractory rheumatoid arthritis patients to ‘normal life’ for 18 months after total B-cell ablation. The team hypothesized that one way of preventing the vicious cycle in which autoreactive B cells [usually IgG rheumatoid factor (RF) committed] perpetuate their existence would be to use total/subtotal Bcell depletion. It had previously been shown in lymphoma patients that such depletion produces no clinically relevant immunosuppression.The results1, presented recently at the American College of Rheumatology (ACR), are so impressive that an international trial is now under way. The five patients who had erosive seropositive RA, and had failed to respond to five disease modifying antirheumatic drugs (DMARDS) underwent a three week course of B-cell depletion using monoclonal anti-CD20 (Rituximab), prednisolone and cyclophosphamide and were followed up for 17 months. Patients were scored on the ACR scoring system, which is based on patient responses and clinical findings. All patients achieved high ACR scores, ACR50 (indicating a 50% response) at six months, and three of those achieved ACR70.Two patients, who relapsed at seven and nine months, but were given further depletion therapy, have achieved ACR70 scores at one year along with the other three patients.The relapses coincided with the return of B cells, but only in cases where RF levels remained high. Adverse events were limited to respiratory tract episodes in two patients and mild thrombocytopenia in one. Edwards hopes that the second Phase of the trial will be completed in just under a year. He stated that if the results continued to be as positive as the early data suggest, therapy could become available within two years (safety and toxicity data on Rituximab
TRENDS in Immunology Vol.22 No.1 January 2001
13
In Brief
New drug delivery system developed to prevent immune activation Martin Garnett and colleagues (Nottingham University, UK) have developed drug delivery ‘particles’ that can travel through the bloodstream without being phagocytosed by macrophages. It is hoped that these particles can be used to deliver anti-cancer drugs to tumours or as a gene delivery system.The team bound together two polymers – polyethylene glycol (PEG), which is hydrophilic, and polylactic acid (PLA), which is hydrophobic – to produce a copolymer that spontaneously assembles into spheres in an aqueous medium. Because PEG is hydrophilic it does not readily bind to proteins in the blood, and so avoids opsonization.The group found that it was possible to create particles with a range of sizes and surface characteristics to determine which had the best properties for drug delivery. If DNA, which is negatively charged, is mixed with a positively charged polymer, the structure spontaneously forms a doughnut shape. If PEG is then fastened to the positively charged polymer, nanoparticles can be assembled with DNA inside. Garnett believes this gene delivery system could prove safer than viral vectors. HEM
Scientists finally develop transgenic Burkitt’s mice Siegfried Janz and colleagues1 (Laboratory of Genetics, NCI, Bethesda, MD) have developed a transgenic mouse model of Burkitt’s lymphoma – a disease that accounts for over half of all childhood cancers in Africa, and is now found in Western countries where it strikes AIDS patients. It is known that the cancer develops when the Myc gene (found on chromosome 8), which stimulates cell growth, is translocated to chromosome 14.This gene then comes under the regulatory control of genes of the immune system, leading to the uninhibited proliferation of B cells. However, scientists would like to know how other genetic mutations, environmental factors and Epstein–Barr virus, work together to cause Burkitt’s lymphoma.The new mouse model should help them achieve this and might also be used to test new treatments. HEM http://immunology.trends.com
1 Janz, S. et al. (2000) Burkitt’s lymphoma in the mouse. J. Exp. Med. 92, 1183–1190
RANTES polymorphism affects susceptibility to HIV and asthma A recent report1 has shown that a single nucleotide mutation at position 403 in the RANTES promoter gene (known as −403A) doubles susceptibility to HIV infection. Paradoxically, the genotype also slowed the progression to AIDS by about 40%. RANTES (regulated on activation, normalT expressed and secreted) is a chemokine that attracts inflammatory cells into areas of injury and normally binds to the same receptor (CCR5) that the HIV virus uses to gain entry to the target cell. It is already known that polymorphisms in CCR5 are associated with disease outcome. Bill Ollier and Ali Hajeer of the Arthritis Research Campaign (ARC) Epidemiology Unit at the University of Manchester, UK, have been looking at RANTES gene variations in blood from HIV-positive and HIV-resistant individuals for some years. In 1998 they filed a patent application on the variants of the RANTES gene and have worked in cooperation with David McDermott at the National Institute of Allergy and Infectious diseases who applied the Manchester group’s findings to the Multicenter Aids Cohort Study. The research team hypothesizes that overproduction of RANTES by the mutated gene increases inflammation and opens up the spaces between cells allowing virus to enter. However, the increased numbers of RANTES molecules compete with virus for the CCR5 receptor thereby slowing disease progression. Another finding was that the mutated gene was more common in those of African/American descent than in those of European descent. The Manchester group has also made an interesting link between RANTES polymorphisms and asthma. Their recent report2 shows that the rare variant of the RANTES gene is associated with high risk of asthma and severe airway obstruction. Hajeer explained that ‘patients with asthma who are homozygous for the RANTES mutation (−403A) are six times more likely to develop severe asthma than patients possessing the ‘normal’ gene.’ HEM
1 McDermott, D.H. et al. (2000) Chemokine RANTES promoter polymorphism affects risk of both HIV infection and disease progression in the Multicenter AIDS Cohort Study. AIDS 14, 2671–2678 2 Fryer, A.A. et al. (2000)The 403 G A promoter polymorphism in the RANTES gene is associated with atopy and asthma. Genes Immun. 509–514
Anti B cell therapy proves successful in severe cases of rheumatoid arthritis A team led by Jonathan Edwards (University College London, UK), has returned five refractory rheumatoid arthritis patients to ‘normal life’ for 18 months after total B-cell ablation. The team hypothesized that one way of preventing the vicious cycle in which autoreactive B cells [usually IgG rheumatoid factor (RF) committed] perpetuate their existence would be to use total/subtotal Bcell depletion. It had previously been shown in lymphoma patients that such depletion produces no clinically relevant immunosuppression.The results1, presented recently at the American College of Rheumatology (ACR), are so impressive that an international trial is now under way. The five patients who had erosive seropositive RA, and had failed to respond to five disease modifying antirheumatic drugs (DMARDS) underwent a three week course of B-cell depletion using monoclonal anti-CD20 (Rituximab), prednisolone and cyclophosphamide and were followed up for 17 months. Patients were scored on the ACR scoring system, which is based on patient responses and clinical findings. All patients achieved high ACR scores, ACR50 (indicating a 50% response) at six months, and three of those achieved ACR70.Two patients, who relapsed at seven and nine months, but were given further depletion therapy, have achieved ACR70 scores at one year along with the other three patients.The relapses coincided with the return of B cells, but only in cases where RF levels remained high. Adverse events were limited to respiratory tract episodes in two patients and mild thrombocytopenia in one. Edwards hopes that the second Phase of the trial will be completed in just under a year. He stated that if the results continued to be as positive as the early data suggest, therapy could become available within two years (safety and toxicity data on Rituximab