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MOLECULAR MEDICINE TODAY, JUNE 1997 N e w s Vaccine for atherosclerosis A novel approach to increasing the serum levels of 'good' cholesterol, or high-density lipoproteins (HDLs), has been rewarded with a Small Business Innovation Research grant from the US National Institutes of Health (Bethesda, MD, USA). Researchers at T Cell Sciences, Inc. (Needham, MA, USA) will use the US $100 000 grant to refine their peptide and DNA vaccines that block the function of the cholesteryl ester aansfer protein (CETP) responsible for transferring cholesterol from HDLs to the other two forms in which it is transported, low-density lipoproteins (LDLs) and very low-density lipoproteins (VLDLs) (Box I). T Cell Science's vaccines are designed to stimulate the host's production of antibodies against CETP to interfere with its activity.The peptide vaccine includes part of the C-terminal antino acid sequence of CETP, which is "known to be directly involved in its cholesterol-transferfunction, as well as the sequence of a fragment of tetanus toxoid, which should increase the inmauneresponse generated. Transgenic mice that express human CETP, and wild-type rabbits were immunized with the vaccine; both groups of animals produced antibodies that were shown h~ vireo to bind to both human and rabbit CETP. In a hypercholesterolaemicrabbit model of atherosclerosis (in which rabbits are fed a high-cholesterol diet for 17 weeks), animals that had previously been immunized with the peptide vaccine had a significantlyreduced area of atherosclerotic lesions in the aorta (Fig. l). The experiments are now being expanded to include more animals and different variations of the vaccine; for example, coupling larger segments of recombinant human CETP sequence to an immunogenic carrier molecule, such as whole tetanus toxoid. T Cell Science's DNA vaccine is a plasmid construct containing nucleotide sequences that encode two regions of rabbit CETP and the tetanus toxoid fragment. When injected intramuscularlyin a small number of rabbits, the DNA vaccine directed expression of the chimeric peptide and elicited an immune response. Rabbits that produced antibodies against CETP showed a decrease in serum cholesterol and had fewer aortic lesions after being fed a high-cholesteroldiet compared with non- vaccinated animals. The new funding will be used to expand these experiments and to explore therapeutic versus prophylactic use of the vaccine. Gilbert Thompson (Professor of Clinical Lipidology, MRC Lipoprotein Team, Hammersmith Hospital, London, UK) comments that the idea of blocking CETP with antibodies is 'slightly simplistic', because there is controversy over 'whether CETP is a good guy or a bad guy' in terms of its contribution to a healthy lipid profile. Ross Figure 1. Effect of the CETP vaccine on atherosclerosis in rabbit aortas. One group of rabbits (a) was given the vaccine while the other (b) was not. Both groups were then fed a high-cholesterol diet for 17 weeks. Rabbit aortas were stained with Sudan IV, which stains atherosclerotic lesions red, and the stained areas were measured using planar morphometry. The area of the aorta covered with atherosclerotic lesions was 20% in the vaccinated group versus 45% in the non-vaccinated group. Kindly provided by Charles W. Rittershaus, T Cell Sciences, Needham, MA, USA. Milne (Professor of Pathology, Universityof Ottawa Heart Institute, Ottawa, Canada) agrees, but adds that the protectiveeffect of the vaccines against atherosclerotic lesions is very interesting.T Cell Sciences hope to decide on the most efficient construct for the DNA vaccine by the end of this year and also to find a developmentpartner to produce the vaccine for clinical trials, which could begin in 12-18 months. ., .- - . Approximately half the. mortadity, i n the Western world and Japan is due to atherosc!e- rosis, where fatty deposits clog the .inner walls of blood vessels, .leading.to ischaemic heart disease, ,myocardial iinfarction and cerebral vascular accidents. - ; : Known risk factors"for atherosclerosis in- clude a high-fat diet~ a high level of total circU- laling cholesterol, and a high fractiono f Cho- lesterol in the form of 10w-denSity lipoproteins (LDLs). By contrast, elevated serum high-den- sity lipoproteins (HDLs).appe~.. to Offer pro: tection against atherosderosis, HighJevds of HDLs are also associated with reduced activity of cholesteryl ester transfer protein (CETP), which normally wamfers.cholesteryl esters be- tween HDLs, LDLs and;very low:-density lip0- proteins (VLD~). In addition to the,s.indiesof immunization against CETP, the moleculfirapproaches to controlling serum, cholesterol! include the following . . . . -.,~ e:Stafins: clinically~ proven &Ugs>thatA'educe total cholesterol :and LDL in'-the bl0od,%y blocking de nowbiosynthesis of~cholesterolin the li~,er and"increasing ~cxiption. of LDL receptOrS. • ' " ' " • X~0geneic liver ~U ~lan~fi6ni'~S.'iS still .at :the researc k stage in ~bit m ,oddsbut has been shown to increase .expression. of,LDL receptors in the liver.-: • Inhibition o f microsomal-.triglyceride- trans- fer-protein: this>protein..is~involved in~ the.secre- ~ttonofqipoproteins, ~aCd~ly4hoSe~Contain- ing ap61ip0pr0tehiB,:fr0m~e'llver. Claire O'Brien l 01997 Elsevier Science Ltd 231
