"Friend" vs. "Foe" or "Self" vs. "Them" are the themes most peoplethink of when they think of the immune system. Under normalcircumstances, immune cells blend into the ranks of the compleximmune network, rising in numbers only when called on to protectthe body from invasion by outsiders. But when cells of the immunesystem turn traitorous and attack "self," the result is an autoimmunedisease. If the target of the turncoat immune cells is a component ofthe cells that support and insulate neurons, the autoimmune disease ismultiple sclerosis (MS).
In this month's issue of Nature Medicine, Arthur Vandenbark and hiscolleagues report the promising results of a preliminary clinical trialthat appeared to successfully turn "self" against "traitor."
In "Treatment of multiple sclerosis with T-cell receptor peptides:Results of a double-blind pilot trial," the researchers report that theywere able to boost T cells that recognized a peptide present onturncoat T cells that attack myelin basic protein (MBP), an importantcomponent of the cells damaged in MS. By vaccinating MS patientswith a piece of the peptide, called Vbeta5.2, which is expressed onthe harmful T cells, the scientists have raised hopes of some dayrecruiting the immune system itself in the fight against autoimmunediseases.
"This paper lends support to the idea that there is a natural regulationof inflammatory cells and that in most patients who get MS, thatregulation isn't sufficient to control the course of the disease," saidVandenbark, of the Veterans Affairs Medical Center and the OregonHealth Sciences University, in Portland, Ore.
The peptide vaccine was administered with the intent of amplifyingthe normal immune regulatory system. "Conceptually this is a fairlylimited vaccine. We are really focusing now on T cells that attackmyelin, a subset of those that attach MBP, and a subset of those thatexpress a common receptor for MBP," Vandenbark said.
Neuroimmunologist Trevor Owen, of McGill University, co-authoreda commentary on the study in the same issue of Nature Medicine. "Itappears to be a useful study and a good beginning," Owen toldBioWorld Today. "But there is a tone of a note of caution in ourcommentary. When you look at the clinical data, it is clear that somebenefit was obtained. But it is clear that for some other patients therewas no benefit. So this approach seems to have at least not done anyharm and maybe achieved a slight improvement in a group ofpatients."
In the study, five of nine patients who received injections of a slightlymodified form of the natural peptide responded favorably. During theyear long study, they showed reduced response to MBP and remainedclinically stable without side effects. One of eight subjects whoreceived the natural or unmodified version of the peptide showedsimilar positive responses. None of the six subjects who receivedplacebo responded.
Vandenbark has a good explanation for the results Owen referred to.The peptide that produced the most encouraging results differed fromthe native form by just one amino acid substitution. This substitutedpeptide was included in the trial to overcome any possibleimmunologic tolerance to the natural peptide vaccine.
"That is very exciting because it opens the door to designing evenbetter substitutions," Vandenbark said. "We are very interested infollowing up the different substitutions in different positions in themolecule to see if we can improve upon this particular substitution."
Owen acknowledged that "there does appear to be somecorrespondence and effect. It gives you confidence that it is worthpursing this line of investigation. Really I think this is the first trial ofsuch a technique in an MS patient group."
The promising approach used in the pilot human clinical study wasspearheaded by animal experiments guided by Vandenbark'scolleague and collaborator Halina Offner, a co-author of the NatureMedicine paper. That work showed that the peptides could be used astherapy. "This was a major step because it shows you can actuallyinfluence the pathogenic mechanism once it has started. There are notmany things immunologically that work as therapies. Most areassociated with preventing disease. They are not as effective once adisease has already started. This represented something new, in away: that we could use a small peptide segment of a T-cell receptor,that it would boost this regulatory system. And then we would getregulation that was sufficient to block the pathogenic sequence,"Vandenbark said.
The group from Oregon is working closely with ConnectiveTherapeutics Inc. in Palo Alto, Calif., which owns the patent rights tothe work. The company now is planning larger scale clinical trials.The approach of recruiting one type of immune cell to attack anothertype may have an additional benefit, referred to as a "bystanderresponse."
According to results presented in the report, the T-cells induced toattack errant immune cells following administration of the vaccineappear to release IL-10, a powerful cytokine. "IL-10 release couldaffect other inflammatory cells in the vicinity of its release even ifthey do not initiate the release," Vandenbark explained. And, now ofcourse, other peptides on harmful T cells are also potential targets. Ifother families of molecules are also shown to be involved in MS,then it is reasonable to consider making peptide vaccines directedagainst them. "I would think that eventually," Vandenbark said, "wewould have some sort of cocktail of peptides each of which would bedirected at some subgroup of the MS population."
Other diseases that might be candidates for this type of vaccinationtherapy include rheumatoid arthritis and diabetes. n
-- Dean A. Haycock Special To BioWorld Today
(c) 1997 American Health Consultants. All rights reserved.