T cell vaccination benefits relapsing progressive multiple sclerosis patients: a randomized, double-blind clinical trial.

BACKGROUND: T-cell vaccination (TCV) for multiple sclerosis (MS) refers to treatment with autologous anti-myelin T-cells, attenuated by irradiation. Previously published clinical trials have been all open-labeled. AIM: To evaluate the safety and efficacy of TCV in progressive MS, in a double-blind, controlled clinical trial. METHODOLOGY: Twenty-six patients with relapsing-progressive MS were enrolled in the study (mean age: 39±9.8 years; mean EDSS: 4.4±1.7). T-cell lines reactive to 9 different peptides of the myelin antigens, MBP, MOG and PLP were raised from the patients' peripheral blood. The patients were randomized into two groups: 19 were treated with TCV (four subcutaneous injections of 10-30×10(6) T-cells, attenuated by irradiation, on days 1, 30, 90 and 180) and 7 patients were treated with sham injections. Twenty-four patients (17 in the TCV group and 7 in the placebo) were eligible for per-protocol analysis. RESULTS: At one year following the inclusion, an increase in the EDSS (+0.50) and an increase in 10-meter walking time (+0.18 sec), were observed in the placebo group; in the TCV group there was a decrease in the EDSS (-0.44; p<0.01) and in the 10-meter walking time (0.84 sec; p<0.005). Sixteen of the 17 patients (94.1%) in the TCV group remained relapse-free during the year of the study, as compared to 42.9% in the placebo group (p = 0.01 and p = 0.03 with adjustment). The proportion of patients with any relapse during the year of the study in the TCV-group, was reduced by 89.6%., as compared to the placebo-treated group. MRI parameters did not change significantly. CONCLUSIONS: This is the first controlled, double-blind trial with TCV in progressive MS. The results demonstrate the feasibility and safety of the procedure, and provide significant indications of clinical efficacy. Further studies with larger groups of subjects are warranted. TRIAL REGISTRATION: ClinicalTrials.gov NCT01448252.

Major CD4 epitopes involved in anti-CD4 T-cell autoimmunity in HIV-1 patients.

We studied HIV-positive and -negative subjects for T-cell reactivity to rCD4, and found that 80% of 25 tested HIV-infected patients and 25% of controls manifested T-cell proliferation responses to rCD4. We mapped the major CD4 immunogenic epitopes among the CD4+ responders of both groups by testing T-cell proliferation responses to 31 synthetic overlapping peptides from the human CD4 molecule. Such responses to p1, p4, p14, p21, p28 and p29 were significantly higher in the eight infected patients and, with the exception of p14, these peptides differed from those found in three HIV-negative controls (p11, p14 and p27). Peptides p1, p28 and p29 are major immunogenic epitopes. Our findings suggest: (1) that HIV infection is associated with T-cell reactivity to CD4; and (2) that the use of synthetic CD4 peptides to replace the complete CD4 molecule may therefore lead to a cost-effective T-cell vaccination for HIV-positive patients exhibiting anti-CD4 autoimmunity, as well as to the development of complimentary TCR peptides for future peptide vaccinations.

T-cell vaccination against anti-CD4 autoimmunity in HIV-1 subtypes B and C-infected patients--an extended open trial.

This study is an extended clinical trial of the one initiated and reported in the Journal of Clinical Virology 2004;31S:S48-54. Thirteen HIV-1 patients (eight subtype B and five subtype C) that manifested T-cell autoimmunity to recombinant human CD4 (rCD4) were treated with T-cell vaccine composed of glutaraldehyde-treated autologous anti-CD4 reactive T-cells and compared to historical seven non-vaccinated HIV-1-infected subjects. This study proved to be feasible and safe. Follow-up study revealed that 7/8 subtype B and 2/4 subtype C patients (one has just received the first TCV injection) responded with a persistent increase in their blood CD4 T-cell levels and four subtype B patients manifested decreased anti-CD4 autoimmunity. Despite highly active antiretroviral therapy (HAART), the persistence of CD4 T-cell lymphopenia may be associated with anti-CD4 autoimmunity. T-cell vaccination (TCV) may decrease such autoimmunity and elevate CD4 T-cell numbers.

T-cell vaccination against anti-CD4 autoimmunity in HIV-1 infected patients.

BACKGROUND: Highly active antiretroviral therapy (HAART) is frequently associated with only partial restoration of CD4 T-cell levels. Autoimmunity to CD4 T-cells may account for the persistence of the CD4 T-cell lymphopenia in such cases. OBJECTIVE: To document T-cell autoimmunity to CD4 in HIV-infected patients and to determine if T-cell vaccination against CD4 autoimmunity is feasible and safe. STUDY DESIGN: Seven out of 20 HIV-infected patients undergoing HAART who manifested T- cell reactivity to rCD4, gp120 and to recall antigens (Tetanus toxoid and Candida) were treated with T-cell vaccines composed of glutaraldehyde treated autologous, activated T-cells, and enriched in anti CD4-reactive T-cells. The response of the seven vaccinated patients was compared to seven non-vaccinated HIV-1 infected subjects. RESULTS: Five out of seven responded with a decrease in anti-CD4 autoimmunity, associated with a persistent increase in their CD4 T-cell levels; just one of the control patients showed increased CD4 levels. No change in HIV plasma viral loads and no adverse effects were detected in any of the T-cell vaccinated patients. CONCLUSIONS: The persistence of CD4 T-cell lymphopenia despite effective anti-retroviral treatment may be associated with anti-CD4 autoimmunity. T-cell vaccination with autologous autoimmune CD8 T-cells may decrease such autoimmunity and increase CD4 T-cell numbers.