By David N. Leff
From birth to middle age, people are vaccinated against an array of childhood-to-adult diseases ¿ from whooping cough to flu shots late in life. Domestic animals, too, undergo immunization to protect them from veterinary infections. Why then was there no vaccine to immunize millions of animals exposed to mad cow disease in Britain, rather than slaughter vast herds against that bovine spongiform encephalopathy (BSE)?
By a similar token, how come there is no vaccine to protect people who caught the human equivalent of mad cow disease, called variant Creutzfelt-Jacob Disease (vCJD)? (See BioWorld Today, Aug. 16, 2001, p. 1)
Mad cow in cattle, Creutzfeldt-Jakob in humans ¿ and scrapie in goats, sheep and laboratory mice ¿ are all prion diseases. The mutated form of these proteinaceous particles, designated PrPSc, wreak highly contagious, death-dealing infection on their victims. But unlike viruses, bacteria and fungi, they infect by a unique, unbeatable tactic: PrPSc works by twisting the molecular structure of the normal, non-infective prion (PrPC by name), which inhabits every cell of every mammalian life form on earth.
Ergo, points out clinical neuropathologist Frank Heppner, a resident at the University of Zurich Hospital in Switzerland, ¿The basic problem with a vaccine until now was that the normal prion protein, PrPC, is a natural constituent of the body. And if immunized with something that belongs to your own body you won¿t get any immune response. This is good in general,¿ he pointed out, ¿because nature invented it by avoiding any sort of autoimmune diseases. If you vaccinate with something against yourself, or you make an antibody against that self-antigen, you would end up with something like autoimmune disease.
¿This phenomenon is called tolerance,¿ Heppner explained, ¿like a pregnant woman¿s tolerance of the unborn foreign body in her womb. And therefore it was not possible until now to raise any antibody titer against the normal prion. We tried to circumvent this obstacle, which is why we constructed transgenic mouse models.¿
Assembling An Antibody Blind To Self¿
Today¿s issue of Science, dated Sept. 6, 2001 (by online release), describes Heppner¿s end-run around the self-prion impasse. The article, of which he is first author, is titled: ¿Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies.¿ Its senior author is Adriano Aguzzi, director of the university¿s Institute of Neuropathology.
¿Our paper embodies two findings,¿ Heppner told BioWorld Today. ¿The most visible one, perhaps, is the fact that in principle we could demonstrate that the immune system is capable of preventing the pathogenesis of the prion disease, scrapie. We did not know the immune system can do something like that.
¿And the second insight,¿ he continued, ¿is that the organism of the mouse tolerates a certain amount of antibodies basically directed against the PrPC self-antigen ¿ which is the normal situation. We learned from this study that an organism tolerates a certain amount of self-antibodies. This is significant, if we think of classical immunization procedures.¿
In formulating the team¿s game plan, Heppner recounted, ¿We said, Okay, we want to express this particular antibody that certainly recognizes a self-protein, the normal prion protein. We want to circumvent it by transgenically expressing the antibody¿s corresponding gene and its variable region, which determines the antibody¿s antigen-recognition pattern.¿
¿We first generated these mice on a normal prion protein knockout background. This way we avoided having an antibody that recognizes self-antigen ¿ something like an autoimmune disease. Then we characterized those mice, and they did what they should do, which is expressing from early on a constant level of this antibody. The next step was to intercross these antibody-expressing transgenic mice with wild-type mice, which carried the normal prion protein. By doing so we re-introduced one allele of Prnp, the prion normal protein gene. That gave us the possibility of having some prion protein.
¿At this point we worried whether we still had an antibody at all. The immune system¿s B cells, which generate antibodies, if called upon to make an antibody against something expressed in the host¿s own body, are deleted. But we were lucky. We could see that these mice, having the prion protein, still had anti-PrP antibody titers. This confirmed that a kind of window allowed a certain amount of self-recognizing antibodies against the animals¿ own proteins.¿
Then, to enlist these transgenic animals as mouse models of prion disease, infected with PrPSc, the co-authors inoculated them with an infectious brain homogenate from mice infected with scrapie prions, originally developed by the Rocky Mountain Laboratory in Ft. Collins, Colo. ¿ a branch of the U.S. Centers for Disease Control and Prevention in Atlanta.
Vaccines Soon, Therapeutics Later
¿The pathological, disease-associated prions,¿ Heppner related, ¿after 234 days, were still not to be found in the brain, where infectious prions normally accumulate and exhibit their lethal effects. The presence of antibodies directed against normal PrPC prions was able to prevent the scrapie disease in those transgenic mice.
¿These first experiment,¿ he speculated, ¿seem to indicate that PrPC antibodies possibly masked the PrPC that is present on almost all cells. Thus, the infectious-disease PrPSc could not replicate because the normal PrPC ¿ which is the necessary target for conversion into PrPSc ¿ is no longer available.¿
In essence, those transgenic mice had been vaccinated against the scrapie infection. However, the Science paper concludes, ¿From an applied viewpoint, transgenesis is too elaborate as a defensive [vaccine] strategy against prions.¿
¿To make it more appliable,¿ Heppner suggested, ¿trying to do classical immunization, while bypassing this problem with self tolerance, there are some possible tricks immunologists can use. For example, offering the PrPC as a vaccine in a different context, so it¿s not recognized as its own self-protein. It¿s putting on a different coat, so to speak. Of course, we¿re going to go in this direction.
¿So far, we¿re talking about putative vaccination, not about therapy,¿ he added. ¿This antibody might well be used as therapy to get rid of prion diseases in general. One could imagine big immunization programs to make all cattle that are available in risky regions immune against this agent. By doing this, we could come back to humans, because if there¿s no more mad cow disease, we¿d have no new Creutzfeldt-Jakob variants any longer.¿