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.

Autologous T-cell vaccination for multiple sclerosis: a perspective on progress.

T-cell vaccination (TCV) is a unique approach to induce immune regulation that may have importance in the treatment of autoimmune diseases, including multiple sclerosis (MS). TCV employs a classic vaccine strategy of injecting an attenuated form of the disease-causing agent--in this case, myelin-reactive T cells--that have been selected and expanded from each MS donor and then re-injected after irradiation to induce protective immunity. This anti-T-cell immunity consistently results in selective deletion or regulation of the targeted pathogenic T cells in vivo. Longitudinal studies have established that TCV is safe and often results in a reduced relapse rate and clinical stability or improvement, at least temporarily, in the majority of treated MS patients. These results lend direct support to the involvement of inflammatory myelin-reactive T cells in the MS disease process. However, these hopeful trends reported in a number of pilot trials await validation in larger proof-of-principle trials that are now in progress.

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.

Autoimmunity, alloimmunization and immunotherapy of AIDS.

The nature of clinical and physiological manifestations associated with HIV infection suggests that AIDS is an autoimmune disease. The conventional immunotherapeutic approaches aimed at enhancing the immune response against HIV have repeatedly failed when applied in the clinical practice. The results of several dozen therapeutic AIDS vaccine trials have consistently shown that while in vitro measured HIV-specific immune responses were evident as a result of vaccination the clinical improvement has been seldom observed. The clinical benefit, however, was invariably associated with the usage of vaccines that acted in accord with the principles of alloimmunization. The majority of these vaccines were derived from the blood of HIV carriers or a cell culture and thus they inherently contained alloantigens unrelated to HIV. The clinical experience with alloimmunization in a range of autoimmune diseases indicates that immune tolerization is an active immune process with benefits the vaccinees. The alloimmunization, which primarily induces tolerance rather than immune activation, might be a better strategy for the immunotherapy of AIDS.

Clinical experience with therapeutic AIDS vaccines.

Recently, there has been a renewed interest in therapeutic vaccination as an adjunct or alternative to current treatment options for HIV. The first immunotherapeutic trial relevant to this topic was published in 1983. Since then, several dozen therapeutic vaccine trials have been carried out. The results have consistently shown that although in vitro-measured HIV-specific immune responses were evident as a result of vaccination, clinical improvement has been seldom observed. The instances of apparent clinical benefit however, were invariably associated with the usage of vaccines that acted in accord with the principles of allo- or autoimmunization. The majority of these vaccines were derived from the blood of HIV carriers or a cell culture and therefore inherently contained host-cell antigens unrelated to HIV. These observations raise the issue of whether this clinically successful approach has been unduly neglected. Most commercial vaccines on the market today are made the old-fashioned way, but very little support or attention has been given to the development of such vaccines for AIDS therapy. The current strategy, biased toward vaccines which have shown little evidence of clinical efficacy, is shortsighted and needs to be revised.

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.

Characterization of new monoclonal antibodies that discriminate between soluble and membrane CD4 and compete with human anti-CD4 autoimmune sera.

In this report we present results on immunization of hu-CD4 C57Black/6J transgenic mice with HIV-1 gp120(451) complexed with its receptor protein, CD4. In addition to development of anti-gp120 antibodies, these mice also produced two anti-CD4 monoclonal antibodies, designated T6 and T9. Both these antibodies recognize soluble CD4 but not membrane associated CD4. Their corresponding epitopes map to the D3-D4 domains of CD4. These characteristics are very similar to the HIV related anti-CD4 autoimmunity found in 10-15% of HIV-1 infected people. Therefore, 208 HIV-1 positive patients were screened for anti-CD4 humoral response of which 27 were found positive (13%). Sixteen of these patients were then tested for their ability to compete with the T6 and T9 anti-CD4 monoclonal antibodies. In such experiments saturating amounts of either T6 or T9 antibodies were able to prevent 20-80% of the human serum binding to immobilized soluble CD4 in competitive ELISA tests. The T6 and T9 antibodies therefore help to define distinct CD4 epitopes associated with clinical anti-CD4 autoimmunity.

T cells and autoantibodies to human HSP70 in type 1 diabetes in children.

We studied T-cell proliferative responses (stimulation index: SI) and autoantibodies to human HSP60, HSP70 and HSP90 proteins in 25 children (mean age 10.1+/-3.8 years) newly diagnosed with Type 1 diabetes. The control group for T cells included 25 adults and three pediatric donors without Type 1 diabetes. Controls for antibodies included 10 pediatric subjects. The T-cell responses to HSP70 of the test group (mean SI=4.5+/-3.1) were significantly greater than those of the control group (meanSI=1.4+/-0.6; p<0.0001); the incidence of HSP70 responders was (85%) compared to 14% in the control group. All but three of the Type 1 children who responded to HSP70 also responded to HSP60 (85%). The T-cell responses of the Type 1 group to HSP90 (mean SI=1.7+/-1.1) were similar to those of the control group (mean SI=1.5+/-0.7). We mapped HSP70 epitopes recognized by T cells in seven subjects using overlapping peptides of the molecule. Among the Type 1 subjects, IgG seropositivity was 45% to HSP60, 30% to HSP70, and 15% to HSP90. Thus, we conclude that children with newly diagnosed Type 1 diabetes manifest heightened T-cell autoimmunity to HSP70 and HSP60, but not to HSP90.