Results of a phase I clinical trial of a T-cell receptor vaccine in patients with multiple sclerosis. II. Comparative analysis of TCR utilization in CSF T-cell populations before and after vaccination with a TCRV beta 6 CDR2 peptide.
We report here the results of a phase I trial of a T-cell receptor (TCR) V beta 6 CDR2 region peptide vaccine in 10 patients with multiple sclerosis who showed biased over-representations of V beta 6 mRNA among T-cells in their cerebrospinal fluids (CSF). One group of 5 patients was immunized twice during a four week period with 100 micrograms of the TCRV beta 6 peptide 39-LGQGPEF LTYFQNEAQLEKS-58 emulsified in incomplete Freund's adjuvant (IFA); the second group of 5 MS patients received 300 micrograms of the same peptide in IFA over a similar time period. Patients were monitored for adverse events, immunogenicity of the peptide and changes in their CSF T-cell populations. The results indicate that this peptide was immunogenic (T-cell proliferation assays and recall DTH responses) in some of the patients, although none of the immunized patients produced detectable anti-peptide antibodies. More importantly, we show that the 5 patients treated with higher doses of the vaccine displayed a slight decrease in CSF cellularity, a lack of growth of CSF cells in cytokine supplemented expansion cultures that implies a significant absence of a subset of activated CD4 T-cells and a marked diminution in V beta 6 mRNA levels among T-cells in these cultures. By comparison, in 5 patients receiving the lower dosage of the vaccine, CSF cellularity was the same or slightly increased over pre-vaccination levels, CSF cells from 1 patient failed to grow in expansion cultures and cultured CSF cells from 2 patients underwent a change from an oligoclonal V beta 6 pattern to one that was more polyclonal. These results justify a more through exploration of the use of TCR peptide vaccines as a possible therapeutic treatment for MS.
Gold
D P
DP
Sidney Kimmel Cancer Center, San Diego, CA 92121, USA.
Smith
R A
RA
Golding
A B
AB
Morgan
E E
EE
Dafashy
T
T
Nelson
J
J
Smith
L
L
Diveley
J
J
Laxer
J A
JA
Richieri
S P
SP
Carlo
D J
DJ
Brostoff
S W
SW
Wilson
D B
DB
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D005260:Female; D006801:Humans; D008875:Middle Aged; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000276:immunology / Q000628:therapy*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014611:Vaccination
D016693:Receptors, Antigen, T-Cell, alpha-beta