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New immunosuppressive agent found in Korean soil samples
SCIENCE AND MEDICINE
New immunosuppressive agent found in Korean soil samples
R
esearchers have isolated a potent new immunosuppressive agent from bacteria growing in forest soil on Cheju Island, Korea. “Tautomycetin, which specifically induces apoptosis in activated T cells, is in late-phase preclinical trials and early phase I trials”, explains researcher Sang-Kyou Lee (Yonsei University, Korea). “Hopefully, it will be developed as an immunosuppressive agent for the treatment of graft rejection and autoimmune diseases in the near future.” Organ transplantation is the standard treatment for many forms of terminal organ failure. Induction of T-cell-mediated immune responses to the highly polymorphic MHC molecules expressed on the graft is the major barrier to successful transplantation. Precise HLA typing has greatly reduced the incidence of graft rejection, but genetic differences at other loci can also trigger rejection. Organ transplant recipients are generally treated with immunosuppressive drugs such as ciclosporin A
and FK506 (tacrolimus). However, these two drugs, which inhibit the induction of IL-2 expression, do not affect only T cells, explains Lee. “They also have severe cytotoxic effects on kidney and liver, and increase cancer susceptibility.” To find immunosuppressants specific for activated T cells, Lee developed a semi-high-throughput screening system for candidate compounds affecting the T-cell activation signal transduction pathway. “We discovered tautomycetin about 5 years ago by screening extracts of actinomycete strains”, he explains. Tautomycetin, he reports, inhibits T-cell proliferation in vitro at concentrations 100-fold lower than those needed to achieve maximal inhibition with ciclosporin A (Proc Natl Acad Sci; published online July 29, 2002; DOI: 10.1073/pnas.162522099). “Tautomycetin induces apoptosis of activated T cells and we have proposed several mechanisms by which this could occur. For example, it could indirectly induce apoptosis by preventing the early
T-cell activation pathway and creating intracellular stress, which could then activate mitochondriamediated apoptosis signalling.” The researchers also report that heterotopic cardiac allografts in tautomycetin-treated rats survived for more than 160 days with no obvious side-effects. They now plan to monitor graft survival for longer and to modify tautomycetin to optimise its drug formulation and immunosuppressive activity. Barry Kahan (University of Texas-Houston Medical School, TX, USA) comments that this is an interesting paper, “but whether tautomycetin will be clinically useful will depend on its side-effect profile and whether it exerts synergistic actions with other immunosuppressive drugs”. Lee responds that “in our hands, combination therapy with tautomycetin and much lower doses of ciclosporin A and other immunosuppressants than are currently used has been successful”. Jane Bradbury
Don’t remove amalgam fillings, urges American Dental Association
THE LANCET • Vol 360 • August 3, 2002 • www.thelancet.com
remove fillings, you risk damaging the teeth. Each time you replace a filling it has to be a little bit larger. And the more often we surgically intervene on a tooth, the higher the risk of adverse reactions or the need for a root canal. Plus, it could cost tens of thousands of dollars to do this in some cases. So patients are making this large investment and not really seeing any relief”, he emphasises. The US National Institutes of Health are 2 years into a 7-year, multicentre clinical trial of children aged 6 to 10 years to see whether any adverse health effects result from amalgam fillings (http://www.clinicaltrials.gov; search on “amalgam”). “Of course, they can’t release any findings yet, but they have told us that there are no indications right now that would cause them to discontinue the trial”, says Eichmiller. “And we know from the recent oestrogen trial [see Lancet 2002; 360: 146] that if there were any adverse responses, they’d pull the plug in a hurry, especially in children.”
Science Photo Library
mercury vapour may be released by he American Dental Association amalgam fillings as a result of (ADA) has launched a media vigorous chewing and grinding, “a campaign aimed at discouraging person would have to have almost patients from having amalgam 500 amalgam fillings in his mouth to [silver-coloured] fillings removed and see subtle symptoms, even if he were physicians from recommending the most mercury-sensitive patient”, the intervention, says Frederick asserts Eichmiller. Eichmiller (Paffenbarger Research Center, Gaithersburg, MD, USA). “We’re seeing more and more patients with multiple sclerosis, Rights were not granted to Alzheimer’s disease, and autism include this image in thinking that the conditions can be electronic media. Please corrected by removing amalgams. Their physicians don’t know how refer to the printed journal. to advise them, and so they say ‘go ahead and try it’ when the evidence isn’t there. So patients are being given false hope, plus there are risks and often huge costs associated with removing and replacing the fillings”, he warns. Concerns about amalgam arose Removal of amalgam fillings discouraged in large part because the material The ADA Code of Ethics prohibits contains mercury, explains member dentists from telling Eichmiller. But when mercury is patients that removal of any type of mixed with such metals as silver, “it dental filling will cure various forms a stable alloy, similar to the diseases because such a statement way that sodium and chlorine—both cannot be substantiated scienhazardous in their pure state—comtifically, Eichmiller continues. bine to form ordinary table salt.” Furthermore, “every time you Although a “minute” amount of
T
Marilynn Larkin
393
For personal use. Only reproduce with permission from The Lancet Publishing Group.
New immunosuppressive agent found in Korean soil samples
R
esearchers have isolated a potent new immunosuppressive agent from bacteria growing in forest soil on Cheju Island, Korea. “Tautomycetin, which specifically induces apoptosis in activated T cells, is in late-phase preclinical trials and early phase I trials”, explains researcher Sang-Kyou Lee (Yonsei University, Korea). “Hopefully, it will be developed as an immunosuppressive agent for the treatment of graft rejection and autoimmune diseases in the near future.” Organ transplantation is the standard treatment for many forms of terminal organ failure. Induction of T-cell-mediated immune responses to the highly polymorphic MHC molecules expressed on the graft is the major barrier to successful transplantation. Precise HLA typing has greatly reduced the incidence of graft rejection, but genetic differences at other loci can also trigger rejection. Organ transplant recipients are generally treated with immunosuppressive drugs such as ciclosporin A
and FK506 (tacrolimus). However, these two drugs, which inhibit the induction of IL-2 expression, do not affect only T cells, explains Lee. “They also have severe cytotoxic effects on kidney and liver, and increase cancer susceptibility.” To find immunosuppressants specific for activated T cells, Lee developed a semi-high-throughput screening system for candidate compounds affecting the T-cell activation signal transduction pathway. “We discovered tautomycetin about 5 years ago by screening extracts of actinomycete strains”, he explains. Tautomycetin, he reports, inhibits T-cell proliferation in vitro at concentrations 100-fold lower than those needed to achieve maximal inhibition with ciclosporin A (Proc Natl Acad Sci; published online July 29, 2002; DOI: 10.1073/pnas.162522099). “Tautomycetin induces apoptosis of activated T cells and we have proposed several mechanisms by which this could occur. For example, it could indirectly induce apoptosis by preventing the early
T-cell activation pathway and creating intracellular stress, which could then activate mitochondriamediated apoptosis signalling.” The researchers also report that heterotopic cardiac allografts in tautomycetin-treated rats survived for more than 160 days with no obvious side-effects. They now plan to monitor graft survival for longer and to modify tautomycetin to optimise its drug formulation and immunosuppressive activity. Barry Kahan (University of Texas-Houston Medical School, TX, USA) comments that this is an interesting paper, “but whether tautomycetin will be clinically useful will depend on its side-effect profile and whether it exerts synergistic actions with other immunosuppressive drugs”. Lee responds that “in our hands, combination therapy with tautomycetin and much lower doses of ciclosporin A and other immunosuppressants than are currently used has been successful”. Jane Bradbury
Don’t remove amalgam fillings, urges American Dental Association
THE LANCET • Vol 360 • August 3, 2002 • www.thelancet.com
remove fillings, you risk damaging the teeth. Each time you replace a filling it has to be a little bit larger. And the more often we surgically intervene on a tooth, the higher the risk of adverse reactions or the need for a root canal. Plus, it could cost tens of thousands of dollars to do this in some cases. So patients are making this large investment and not really seeing any relief”, he emphasises. The US National Institutes of Health are 2 years into a 7-year, multicentre clinical trial of children aged 6 to 10 years to see whether any adverse health effects result from amalgam fillings (http://www.clinicaltrials.gov; search on “amalgam”). “Of course, they can’t release any findings yet, but they have told us that there are no indications right now that would cause them to discontinue the trial”, says Eichmiller. “And we know from the recent oestrogen trial [see Lancet 2002; 360: 146] that if there were any adverse responses, they’d pull the plug in a hurry, especially in children.”
Science Photo Library
mercury vapour may be released by he American Dental Association amalgam fillings as a result of (ADA) has launched a media vigorous chewing and grinding, “a campaign aimed at discouraging person would have to have almost patients from having amalgam 500 amalgam fillings in his mouth to [silver-coloured] fillings removed and see subtle symptoms, even if he were physicians from recommending the most mercury-sensitive patient”, the intervention, says Frederick asserts Eichmiller. Eichmiller (Paffenbarger Research Center, Gaithersburg, MD, USA). “We’re seeing more and more patients with multiple sclerosis, Rights were not granted to Alzheimer’s disease, and autism include this image in thinking that the conditions can be electronic media. Please corrected by removing amalgams. Their physicians don’t know how refer to the printed journal. to advise them, and so they say ‘go ahead and try it’ when the evidence isn’t there. So patients are being given false hope, plus there are risks and often huge costs associated with removing and replacing the fillings”, he warns. Concerns about amalgam arose Removal of amalgam fillings discouraged in large part because the material The ADA Code of Ethics prohibits contains mercury, explains member dentists from telling Eichmiller. But when mercury is patients that removal of any type of mixed with such metals as silver, “it dental filling will cure various forms a stable alloy, similar to the diseases because such a statement way that sodium and chlorine—both cannot be substantiated scienhazardous in their pure state—comtifically, Eichmiller continues. bine to form ordinary table salt.” Furthermore, “every time you Although a “minute” amount of
T
Marilynn Larkin
393
For personal use. Only reproduce with permission from The Lancet Publishing Group.