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

Reginald Gorczynski,Geoffrey Hoffmann

doi:10.2196/ijmr.7612

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.

Highlights

Much research on antiidiotypic antibodies has been focused on such antibodies mimicking the shape of the antigen, and being able to substitute for the antigen (Charmat et al, 1984, Guillet et al, 1985, Urbain et al, 1979) An antibody specific for an antigen X has a V region that is anti-X, and we say it has an anti-X idiotype
Second symmetry antiidiotypes are for example A anti-anti-A antibodies that are present in an A anti-B serum, that are specific for B anti-A antibodies, that in turn are present in a B anti-A immune response
It has previously been shown that immunization of a strain A mouse with lymphocytes of a strain B can induce the production of both antigen-specific (A anti-B) and antiidiotypic (A antianti-A) antibodies (Hoffmann et al, 1986)

Summary

Introduction

Much research on antiidiotypic antibodies has been focused on such antibodies mimicking the shape of the antigen, and being able to substitute for the antigen (Charmat et al, 1984, Guillet et al, 1985, Urbain et al, 1979) An antibody specific for an antigen X has a V region that is anti-X, and we say it has an anti-X idiotype. If we immunize a rabbit with an anti-X antibody together with an adjuvant the rabbit may make anti-anti-X antiidiotypic antibodies. Such antiidiotypic antibodies play no role in the immune network theory that has been developed in a series of papers and a monograph published from 1975 to the present (Hoffmann et al, 1986; Hoffmann, 1994; Hoffmann, 2008; Leung and Hoffmann, 2014). The antiidiotypes that play a role in the symmetrical immune network theory are of two types, namely second symmetry antiidiotypes (Hoffmann et al, 1986) and co-selection antiidiotypes (Hoffmann, 1994). Co-selection antiidiotypes are expressed by lymphocytes that are co-selected (mutually selected) with antigen-specific lymphocytes

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