Heinz Kohler

Internal antigen and immune network.

Summary The network hypothesis postulates the existence of internal idiotopic structures which mimic nominal antigens. Experimental evidence for idiotope internal antigen is presented and its implication for the Network hypothesis is discussed. The exploitation of the internal idiotope antigens (or preparation of vaccines) is a realistic possibility.

Autoantibodies Against Ig Immunoglobulin Framework Epitopes

The concept of antibodies against antibodies is now more than 40 years old. In 1955 Slater et al. (1) reported that a rabbit antiserum against a human myeloma protein continued to react with the immunizing myeloma protein after extensive absorption on normal human immunoglobulins (Igs). This experiment showed for the first time that it is possible to induce antibodies specific for unique epitopes (idiotopes) on another antibody. It was not clear, however, that such antiantibodies were present or could be induced in the same species and individual which served as the source of the immunogenic Ig. In 1957, Milgrom and Dubiski (2) concluded from experiments in rabbits that the immunoglobulins of an individuals own body may become antigenic. Ten years later, the concept of antiantibodies blossomed, as many laboratories began work on idio-types and anti-idiotypes, including auto-anti-idiotypic immune responses, which provided the experimental support for Niels Jerne’s network theory (see ref. 3).

Anti-Idiotypic Tumor Vaccines

Host defense against cancer is known to be usually insufficient to halt the growth and the dissemination of the tumor. This may be due to ineffective stimulation of the lymphocyte clones, which have the potential to mount a response to tumor-associated antigens (TAAs) (1) or due to suppression of cytotoxic T lymphocyte activity by progressive tumor growth (2). A common explanation for the absence of antitumor immunity is that the immune system has been tolerized by the tumor antigen (3–6); however, the exact mechanisms of suppression of immunity against TAAs are not known. Since stimulation of dormant antitumor-specific immunity with nominal tumor antigens has had only limited success, an alternative approach to immunize experimental animals or cancer patients with “internal image” (Ab2β or “network” antigens) (7), that is, anti-idiotypic (anti-Id or Ab2) antibodies, has been applied. This method may be effective in breaking tumor antigen-induced tolerance by presenting the critical TAA epitope in a different molecular environment to the tolerized host (8) and may thus break tolerance in tumor-specific immunity. Furthermore, the anti-Id antibodies, the so-called network antigens (7), are the most promising because they are not dependent on genetic idiotypic availability. Consequently, network antigens for a given tumor species would be effective in outbred populations.