Ten Belgian men and women with multiple sclerosis havereceived injections of a putative prototype vaccine that someday may prevent or treat the perplexing autoimmune disease.The subcutaneous inoculations consisted of seeing-eye, self-Tcells programmed to destroy the autoreactive T cells thatattack myelin tissue and cause multiple sclerosis (MS).
The Phase I trial is aimed only at gaining new knowledge ofthis dire in-teraction, the immediate cause of multiple sclerosis.The root cause that drives these berserk T cells into savagingthe myelin sheath enveloping brain and spinal cord nerve cellsis still anybody's guess.
Neuroimmunologist Jingwu Zhang, for one, has an educatedguess. Zhang, who heads the multiple sclerosis unit of the semi-private Willems Research Institute in Haasselt, Belgium, is thelead author of a paper in last week's Science, "RestrictedDepletion of Human Myelin Basic Protein-Reactive T Cells by TCell Vaccination."
MS is a chronic, inflammatory autoimmune disease that strikespeople in the prime of life with recurring and intensifyingbouts of paralysis, tremor, slurred speech, muscle weakness,impaired vision and poor coordina-tion. Increasingly, throughthe decades-long course of the on/off relaps-ing/remittingversion of the disease, T cells reactive to myelin basic protein(MBP) switch from the resting to the activated state.
To counterattack the myelin-munching auto-reactive T cellsturned on by MBP antigen or other unknown factors, Zhang andhis co-workers devised a system for immunizing MS patientsagainst these single-target autoimmune T lymphocytes. Theirvac-cine consisted of BMP-reactive T cells attenuated byirradiation. "Otherwise," Zhang told BioWorld, "they would bepathogenic, and induce the disease."
Half a dozen patients, three men and three women; three ofthem with relapsing and remitting MS; three with progressivedisease; volunteered to try the vaccine. Each received a seriesof three subcutaneous shots two or three months apart ofirradiated, anti-clonotypic clones of their own cultured T cells,activated with MBP antigen-presenting cells four days beforeinjection. As controls, the patients also received non-specificprecursor T cells.
After the second inoculation, all six patients showedprogressively fewer cir-culating MBP-reactive T cells. This,Zhang noted, "suggested that the vaccine was indeedstimulating a regulatory reaction" on the part of the clonotypiccells. In other words, the regulatory T cell lines, isolated fromthe recipients and cloned, inhibited the patients' ownautoreactive T cells.
This concept, he continued, "has led to the paradigm of T cellvaccination, in which attenuated MBP-autoreactive T cells up-regulate clonotypic regulatory networks to prevent and treat"the disease.
The Phase I vaccine trial, Zhang explained, was "carried out inpatients with MS because regulation of MBP-reactive T cellshas potential therapeutic consequences."
But he added bluntly, "no conclusion as to treatment efficacycan be drawn from the present study."
In trying to define the molecular target within the T cellreceptor, Zhang said, "We have some idea (unpublished) as towhere that target sequence might be located."
Paradoxically, he points out, "T cell reactivity to MBP is notspecific to MS. We and others have found that you can alsogenerate MBP-reactive cells from normal, healthy individuals."
The key to this apparent contradiction, he discovered, is not thepresence of those myelin-hungry T cells, but their prior status:activated in MS, resting in normals. "If not activated, Zhangexplained, "those cells cannot get into the brain and induce thedisease."
Since submitting his report to Science early last May, Zhang'sgroup has added another four MS patients to its Phase I study."The data from these additional ones, are more or less the sameas reported in this paper," he said.
Now the researchers are ready to undertake a Phase II clinicaltrial, enrolling 20 or 30 MS subjects. Ready, willing but notable, he said, "we are trying to raise some more money to startthis second-phase study," Zhang said, "which will be morefocused on the clinical aspect."
He is looking for financial support from industry andapproaching biotechnology companies and other fundingsources in Europe. At 500,000 Belgian francs per patient (U.S.$14,700), this works out at $294,000 for 20 patients; $441,000for 30.
"They will be very selected patients," Zhang said, "early cases,with very frequent nuclear magnetic imaging to monitorchanges in the brain."
He added: "I think this T cell vaccination has a lot of future, notonly for MS but for other autoimmune diseases in general."
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.