Toward a New Kind of Vaccine: A Logical Extension of the Symmetrical Immune Network Theory

Abstract

BackgroundThe symmetrical immune network theory, developed in 1975, is based on the existence of specific T cell factors and hypothesizes that normal IgG immune responses comprise the production of 2 kinds of antibodies, namely antigen-specific antibodies and anti-idiotypic antibodies.ObjectiveThe aim of this study was to confirm the existence of specific T cells factors and to show that immunization of C3H mice with BL/6 skin or using nominal antigen for immunization (Tetanus Toxoid) induced production of antigen-specific (anti-BL/6 or antitetanus) antibodies plus anti-idiotypic antibodies (C3H anti-anti-C3H). Subsequently, we investigated the role of combinations of antigen-specific and anti-idiotype antibodies in a variety of animal models of clinical diseases.MethodsAntigen-specific antibodies were produced by conventional immunization of mice (eg, with tetanus toxoid or by skin allografting). Subsequent anti-idiotypic antibodies were derived by exhaustive absorption of antigen-specific antibody, with confirmation of anti-idiotypic specificity by binding to relevant target antigen-specific antibodies in an enzyme-linked immunosorbent assay (ELISA). Antigen-specific plus anti-idiotypic antibodies were then used to modulate skin allograft survival, dextran sulfate sodium (DSS)-induced colitis, ovalbumin (OVA)-induced IgE production, and breast cancer growth in mice.ResultsInfusions of anti-BL/6 antibodies together with BL/6 anti-anti-BL/6 antibodies specifically suppressed (>85%) an immune response to BL/6 lymphocytes in C3H mice. The two kinds of antibodies with complementary specificity are hypothesized to stimulate 2 populations of T lymphocytes. Coselection of these 2 populations leads to a new stable steady state of the system with diminished reactivity to BL/6 tissue. A combination of anti-C3H and C3H anti‑anti-C3H IgG antibodies down-regulated inflammation in a mouse model of inflammatory bowel disease (>75%) and attenuated anti-IgE production and sensitization to produce IL4 cytokines (>70%) in an OVA-allergy model. Combination of C3H anti‑BL/6 and BL/6 anti-anti-BL/6 antibodies decreased tumor growth and metastases (>705) in an EMT6 transplantable breast cancer model.ConclusionsUse of a combination of antigen-specific and anti-idiotypic antibodies has potential as a new class of vaccines.

Mechanism(s) of prolonged attenuation of allergic responses after modulation of idiotypic regulatory network

“…Importantly, the antigen-specific regulation seen was independent of the specific antigens used to prepare the polyclonal immune Ig. One possible mechanism to help explain these effects involved the perturbation of regulatory T cell networks [19–21]. Such a concept is consistent with other data favouring a role for Tregs in control of allergic reactivity [22].…”

“…The protocol used to immunize naïve BALB/c mice to produce IgE against OVA was a modification of that described elsewhere [19]. 8 mice per group received 10 μg OVA emulsified in alum intraperitoneally (ip) in 0.2 ml PBS at days 0, day 14, 28 and 42 (see Fig.…”

“…A control group received no OVA immunization. In some cases, as documented in the text, groups of animals received weekly intramuscular (im) injections, beginning at day 7 post first OVA immunization, of 75 μg of pooled polyclonal anti-idiotype Ig [C3H anti–anti-C3H Ig (C3H anti-BL/6 absorbed with BL/6)] and 10 μg pooled polyclonal BL/6 anti-C3H immune Ig [19]. Other groups received 75 μg of human IMIG or 10 μg human anti-Tet Ig (both from GRIFOLS, Canada [23]).…”

“…Given this background it is evident that there remains an unmet need to develop novel therapies. We have recently reported on the use of a combined injection of polyclonal anti-idiotype antibodies, along with polyclonal immune antibodies, as a treatment aimed at “re-setting” immune regulatory networks in rodents [19]. This treatment led to a marked attenuation of a variety of immune reactivities, including decreased inflammatory cytokines and inflammatory colitis; suppression of skin graft rejection in a transplant model; and decreased IgE and IL-4 production as a marker of attenuation of allergen-induced Th2 activity in a rodent model (sensitization of mice to ovalbumin, OVA).…”

“…More recently we have extended these studies to show that attenuation of allergic responses (skin reactivity to peanut butter sensitization) can also be suppressed in Beagle dogs using the same methodological approach [23, 24]. Our hypothesis predicted that similar immunoregulation would be seen using treatment not just with immune Ig and anti-idiotype Ig from the same species (homologous), but across species (heterologous Ig treatment) [19–21, 23].…”