Since the first report of hybridomas producing monoclonal antibodies by Kohler and Milstein in 1975, this technique has spread to nearly all areas of biological, biochemical, and biomedical research. Watching the use of these methods spread from immunologists to cell biologists, developmental biologists, biochemists and to other biological disciplines and observing the nearly logarithmic increase in publications using these reagents has been in itself fascinating and informative. An overview of the development of this technology and its applications is presented including the use of monoclonal antibodies to study cell surface molecules, differentiation antigens, receptors, and histocompatibility antigens. The use of these antibodies to analyze microorganisms and parasitic antigens as well as their use in the genetic analysis of human cell surface antigens and the detection of polymorphic variation in enzymes and other proteins is discussed. Examples of the application of monoclonal reagents to the study of tumor cell biology including the labeling of metastatic tumor cells and the detection of cell surface molecules implicated in the regulation of growth control and cell division are provided.

Hybridomas: a new dimension in biological analyses.

In 1975 Kohler and Milstein [1] reported an experimental method of obtaining hybrid plasmacytoma cell lines that make antibody against preselected antigens Their approach was suggested by the observation that hybrids made by fusing two antibody-producing cells continue to secrete the antibodies originally produced by each of the two parental cell types [2, 3] They carried this observation one step further and stimulated what may well become a revolution in the fields of serology, immunology, and cell biology They fused spleen cells, from a mouse immunized against sheep red blood cells, with P3X63Ag8, a plasmacytoma line As many as 10% of the hybrid clones were found to secrete antibody against sheep red blood cells into the culture medium [1] The frequency of hybrids making antibody against the recently injected antigen suggested a preferential fusion or hybrid formation with spleen cells recently stimulated by antigen Kohler, Milstein and co-workers used the same procedure (fig 1) to produce monoclonal antibodies against the hapten 2,4,6,-Trinitrophenyl, and mouse IgD [4, 5] They also reported mouse plasmacytoma x rat spleen cell hybrids making antibody against a rat histocompatibility antigen [6] and leukocyte differentiation antigens [7] It soon became clear that this technique of monoclonal antibody production is useful for producing antibodies against a wide range of antigens Effectively, what one does in this procedure is to immunize (usually a mouse or rat) with an antigen containing an array of antigenic determinants, allow the animal to respond, and then, use the spleen cells to generate hybrid plasmacytomas Each hybrid that secretes antibody to the antigen of interest is producing a single clonal component of the animal' s complex antibody response and is thus a so-called monoclonal antibody Preliminary to the production of hybrids making antibody against a chosen antigen, it is essential that there be available an assay procedure that enables the discrimination

Monoclonal antibodies. Hybrid myelomas--a revolution in serology and immunogenetics.

During an immune response, specific antibody variable region genes are diversified by a somatic point mutation process that generates de novo "foreign" V-region sequences. This creates an interesting problem in immune regulation because B cells are highly proficient at self-presenting V-region peptides in the context of class II MHC. Though our studies indicate that the corresponding T-cell repertoire attains a state of tolerance to germline-encoded antibody V-region diversity, it is presently unknown whether the same is true of mutationally generated diversity. On the basis of immunoregulatory considerations, we hypothesize that contact exclusion or tolerance normally precludes T cells from helping B cells via self-presented mutant V-region peptides. The lack of recurrent somatic mutations that create known T-cell epitopes in antibody V regions lends some support to this idea. In contrast, our studies of spontaneously autoreactive B cells in systemic autoimmune disease strongly suggest that precursors of such cells are recruited by T-cell help directed to self-presented mutant idiopeptides. Failures in tolerance or contact exclusion mechanisms may be responsible for this apparently abnormal event. In addition to their importance in immune regulation, somatic mutations or other differences from germline-encoded V-region sequence may be largely responsible for undesirable patient responses to therapeutic monoclonal antibodies. These reactions might be averted or diminished by inducing tolerance in the T-cell repertoire with synthetic peptide correlates of non-germline-encoded V-region sequences in humanized antibodies.

Somatic origin of T‐cell epitopes within antibody variable regions: significance to monoclonal therapy and genesis of systemic autoimmune disease

We have made several T-T hybridomas which secrete soluble factors capable of suppressing an in vitro antibody response to nitrophenol (NP), but not other unrelated antigens. These factors bind specifically to NP, and express determinants coded for in the I-J region of the mouse major histocompatibility complex. No determinants that cross-react with the constant regions of mouse immunoglobulins are present on the factors. Three sub-clones originating from the same initial culture well of hybridoma cells secrete factors which carry I-J determinants of different haplotypes. One clone expresses I-J determinants derived from the suppressor cell parent, another expresses I-J determinants derived from the tumour cell parent, and a third expresses both. This correlates exactly with I-J determinants expressed on the cell membrane, and suggests the participation of at least two genes in the determination of suppressor-factor structure.

T-cell hybridomas producing hapten-specific suppressor factors.

The initiation of most immune responses seems to involve a complex series of interactions between macrophages and various subsets of lymphoid cells [8, 23]. In many instances, it appears that the activity of a given cell population can be mimicked by a soluble mediator or 'factor'. Antigen-specific factors are of particular interest in that they exhibit the exquisite specificity characteristic of the immune system and hence may be the actual mediators of immune regulation at the molecular level. Whether they act in vivo as independent soluble moieties that in effect increase the functional radius of their parent regulator cell or perform while still attached to the cell membrane is not known. Whatever the case, there seems to be ample rationale to isolate these molecules and attempt to characterize their chemistry and mode of action. Scientific activity in this area has increased markedly in the past several years so that factors, which for a time fell into disrepute, appear to be respectable once more. It is not our intention to review this literature extensively [for this see 11, 12, 34, 46, 47], but rather to present an appraisal of the present state of the art highlighting areas which to us appear important or contentious and to indicate how antigen-specific helper factors (Hfs) may relate to the problem of cancer immunotherapy.

Specific helper factors

Different T cell functions, e.g. help, suppression and cytotoxicity are associated with different T cell subsets, bearing distinctive differentiation markers. Thus effector T cells mediating help are Ly 1+2−3− and may bear Ia determinants, those mediating suppression are Ly 1−2+3+, IJ+, and cytotoxic cells are Ly 1−2+3+ and do not bear Ia determinants (1). At least the cytotoxic effectors are Ly 6.2 positive, but they arise from Ly 6.2 negative precursors (2). Thus expression of certain differentiation markers (Ly 123) is associated with acquisition of the ability to perform a particular function, even before encounter with antigen, whilst others are expressed as a result of further differentiation, including clonal expansion, following response to antigen (e.g. Ly 6.2 and possibly Ia antigens).

T cell hybrids with T cell functions.

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T cell hybrids with T cell functions.