Eight multiple sclerosis sufferers in Belgium are betterfor having volunteered to test a novel vaccine againsttheir disease. Indirectly, they owe their favorableresponses to rats.

These animals readily succumb to experimental allergicencephalomyelitis (EAE), an artificial disorder of thecentral nervous system that closely resembles multiplesclerosis. Their own brain tissue injected into the rodent'sbrain reproduces the central nervous system defects, andsymptoms, of multiple sclerosis in humans.

In the blood of such sick animals, pathologists havefound T lymphocytes programmed to aim theirautoimmune weaponry at myelin-basic protein, (MBP).This substance clads neuronal fibers with myelin, whichprotects them in the manner of an insulating sheath. Inmultiple sclerosis, this sheath is slowly, progressively,destroyed by demyelination.

MBP-targeting T cells from such EAE-stricken rats willinduce the disease to healthy animals. But if the MBP-specific T lymphocytes are first attenuated, the transplantcannot trigger the disease.

Ergo, reasoned Belgian immunologist Jef Raus and hisco-workers, if T cells are at the root of multiple sclerosispathogenesis, removing them from a patient's bloodmight mitigate their disease, which is marked byintermittent bouts of exacerbation _ severe paralyticsymptoms _ and remission.

"So based on those early findings," Raus told BioWorldToday, we started looking at MBP-specific T cells inmultiple sclerosis patients. We were very happy when wefound these," he continued, "but to our disappointment,we found the same cells, at the same frequency, innormal, healthy individuals."

But with a difference: "In multiple sclerosis patients,"Raus said, "these T lymphocytes are activated _ why andhow, we don't know." What they did know was thatinterleukin-2 receptors go up in activated T cells.

That difference between healthy and multiple sclerosisindividuals, Raus pointed out, "is very important, becausenormally lymphocytes cannot cross the blood-brainbarrier. Activated lymphocytes can." This explains howthey can attack the myelin-basic protein in the centralnervous system.

Raus, who directs the semi-private Dr. L. WillemsInstitute in Diepenbeek, Belgium, noted another crucialdistinction between healthy and multiple sclerosis T cells."We found that in multiple sclerosis patients, contrary tonormal individuals," he said, "their BMP-targeted T cellsundergo a clonal expansion. That is, these T cellsoriginate from relatively few clones of progenitor cells."

By examining the sequences of T cell receptors, he andhis group found that "most of them came from patientswith two clones, in some from three, a few from fiveclones at most." This finding had weighty clinicalconsequences down the line.

Patients' Own Pathogenic Lymphocytes Make Vaccine

"In normal individuals," Raus observed, "these MBP-specific T cells originate from a larger variety of clones."

In an informal Phase I trial, he and his team drew bloodfrom eight multiple sclerosis patients with relapse-remitting disease. They isolated their one, two or threeclones of MBP-specific T cells, grew them up to a countof 50 million per clone, irradiated them to preventsubsequent proliferation, and re-injected this inoculuminto the volunteer subjects.

Their clinical results, two to three years following thisvaccination, appear in the current issue of The Lancet,dated Sept. 23, 1995.

Five of the eight vaccinees, in the two years prior totreatment, experienced 16 relapses; in the two years post-vaccination, only three.

In their five matched but unvaccinated control patients,relapses during these four years decreased from 12 to 10.In this cohort, brain lesion size, by magnetic resonanceimaging, increased 39.5 percent, compared with eightpercent among the vaccinated.

After three 15-million T cell injections over six months,Raus recalled, "the MBP-specific T cells in these fivepatients dropped to an unmeasurable level. Only cellsfrom the clones we had used in the vaccine wereeliminated from their peripheral blood.

Negative Results Produce Positive Lesson

Those three had one exacerbation each after vaccination,and showed a rise in MBP-specific T cells. "So youwould say," Raus said, "that not all those T cells wereeliminated." Those three individuals turned out to havehad five T-cell clones, of which only three had beenremoved, processed and returned. "What we saw," heexplained, "was that after vaccination, the two remainingclones, which were present at very low frequency, startedproliferating.

"This is the first time," Raus observed, "that anexacerbation directly correlated with a rise in MBP-specific T cells."

He cloned the remaining MBP-specific T cells thatincreased during the relapses, made a vaccine, and a yearand a half ago gave it to these three patients. "Sincethen," Raus observed, "we haven't seen anyexacerbation."

Meanwhile, at the beginning of 1995, he and his grouplaunched a larger, 25-patient, pilot trial of their T cellvaccine. It is enrolling subjects very early in the course oftheir multiple sclerosis, Raus said, "because we expectthat the T cell vaccination will stabilize their disease.Preparation of the vaccine takes two to four months,which means that the last group of the 25 received theirfirst injection last month. But some have already gotthree."

It's his ambition to do a double-blind Phase II study with100 patients, 50 vaccinees and 50 controls. "But we don'thave any money," he explained, "to finance such ablinded study," and added, "The vaccine alone costs theequivalent of $20,000 per patient. And as twenty of the25 have found the money to pay for their own treatment,it is ethically not feasible to put any of them in a controlgroup."

His institute is in the process of applying to patent thetechnology to make the vaccine, in Europe and the U.S.European patent law prevents patenting the clinicalprocedure, so they are applying for this protection only inthe U.S.

"We have contacts with large pharmaceuticalcompanies," Raus said, "to sponsor this Phase II trial, andof course acquire the rights for the vaccine treatment."One such prospect, he recalled, "was rather interested, butdecided not to get involved in the field of central nervoussystem disease." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.