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Immune system network theory leads to a new symmetry, namely that the antibodies produced in an allogeneic A anti-B immune response (where A and B are, say, two different mouse strains), should have complementary shapes to the antibodies in a B anti-A response. That is, A anti-B is anti-(B anti-A). This symmetry is due to the existence of two readily separable populations of antibodies that are present in alloantisera: anti-foreign and anti-anti-self antibodies. The theoretical basis for the symmetry is described, and results indicating the presence of anti-anti-self antibodies in each of 12 alloantisera (six made in B10-congenic strains, and six made with the unrelated chains CBA, SJL, and C57BL/6) are reported. The finding that hyperimmune alloantisera routinely contain anti-anti-self antibodies suggests that network regulation plays an important role in maintaining self-tolerance during responses to allogeneic cells. We further show that A anti-B serum absorbed against B can specifically prolong the survival of A grafts in a B strain animal. We suggest that this result can be interpreted as being due to A anti-(B anti-A) antibodies preventing B anti-A cells from rejecting the A grafts. We call this phenomenon "reverse enhancement" because it involves the converse antiserum to that used in conventional enhancement of graft survival by specific antibodies.

We define experimentally measurable similarity coefficients S[A,B/C] that specify the extent to which a pair of substances, A and B, are similar in the context of a diverse reagent, C, which can be a non-immune serum. We describe how this definition can be applied to mixtures of antibodies, for example the antibodies of two serum samples, A and B. A "distance coefficient" D[A,B/C] between two sera, A and B, in the context of C, is defined as one minus the similarity coefficient of the two sera in the same context. We discuss the problem of the experimental measurement of these coefficients, and the possible use of the coefficients in the diagnosis and prognosis of disease conditions.

A microcomputer-controlled device was built that automatically prepares small volumes of mixtures of up to eight reagents. The operation of the system is fast, flexible, and reliable, thus making possible the routine use of experimental protocols that require large numbers of small volume reagent samples, each having a different composition. In particular, the software we developed for this device handles the preparation of three-antibody staining solutions to be used in triple labeling immunofluorescent flow cytometry experiments that involve only two fluorochromes. In this role, the device is known as an "Immunofluorescence Tomograph."

A mechanism is suggested for the regulation of the immune response that involves antigen-binding and anti-idiotypic lymphocytes. The cross-linking of receptors is postulated to be a general mechanism for triggering T cells, B cells and cytotoxic effector cells (e.g. macrophages). A key role in regulation is ascribed to antigen-specific T cell-dependent factors, which are assumed to be able to block the receptors of both T cells and B cells of the anti-idiotypic specificities. The simple postulates of the model lead to feasible mechanisms for the helper, suppressor and killer roles of T cells, cellular and humoral immune responses, low zone tolerance and the tolerogenic effects of monomers, immune memory, antigenic competition, the abrogation of tolerance with cross-reacting antigens, the usefulness of the switch from IgM to IgG, and self-tolerance to both serum antigens and cell surface antigens. Biological roles are suggested for one of the Ia antigens and beta 2-microglobulin. The theory leads to a number of predictions, which can be tested experimentally. A simple mathematical model is included, which provides an indication of how the theory may be further developed on a quantitative basis.

The problem of the simultaneous use in flow cytometry of N greater than 2 antibodies in conjunction with two fluorochromes was investigated. Theoretical analysis led to a labeling procedure and reconstruction formula that allow N-dimensional labeling distributions to be obtained from two-dimensional fluorescence distributions. The general problem of M greater than or equal to 2 fluorochromes and N greater than M antibodies was shown to be reducible to the case of two fluorochromes. The method was tested by a triple labeling analysis of murine thymocytes.

A monoclonal antibody (Fd-B2) to ferredoxin, which bears an idiotype scarcely expressed in any of a wide variety of mouse strains, is able to markedly enhance the response to ferredoxin of both high-responder and intermediate-responder strains. A rabbit anti-idiotype serum to Fd-B2 also specifically enhances the response to ferredoxin in such mice. Most remarkably, the treatment of nonresponder T cells by either the idiotype (Fd-B2) plus complement or anti-idiotype antiserum plus complement causes them to be responsive in adoptive transfer experiments. The two responding populations (idiotype-treated and anti-idiotype-treated) can then be combined to reconstitute the nonresponsive state. When the nonresponders are treated with either Fd-B2 idiotype plus complement or anti-idiotype plus complement and subsequently respond, the idiotype of the anti-ferredoxin antibody produced does not bear the Fd-B2 idiotype. We interpret the results as being consistent with a model in which the unresponsive state for ferredoxin is a state of high network connectivity of the ferredoxin-specific T cells.