Mouse idiotypes

Not only has linkage been observed, but also associations at the molecule level between the idiotype of a homogeneous streptococcal antibody and the allotypes of the strain in which it was induced. Eichmann showed that idiotypically related antibodies produced in allotypically heterozygous mice always had the same allotype-idiotype combination. This finding indicates that the mouse idiotypes, like rabbit Vh allotypes, are usually synthesized from information present on the same chromosome as the Ch gene with which they are genetically transmitted. The bulk of genetic data obtained in mouse idiotypic studies is consistent with that obtained in studies with Vh allotypes. One of the few cases where unique information has been obtained will be described here. 

One such case involved investigation of the linkage between two different mouse idiotypes (A5A and ARS), both linked to the A/J Ch allotype . The observation of a crossover between the ASA idiotype and the BALB/c allotype in one male mouse provided the opportunity to test linkage between these two idiotypes. The crossover mouse was bred and the new haplotype (allogroup) was shown to be inherited without the ARS idiotype. On the basis of these data, the chromosomes of the BALB/c, A/J and recombinant might be represented ... 

The assay principle should, however, be applicable to any target hapten, unlike assays based on a chemical modification. Cloning efficiency of the hybridoma-secreting anti-idiotype antibodies would be in a practical range, and much higher than that of anti-metatype antibodies. We (Kl) established four kinds of a-type and two kinds of /3-type anti-idiotype antibodies after three fusion experiments, each using spleen cells from one immunized mouse. Barnard et al. (Bl, B3, B4)... 

Kuettner, M.G., Wang, A.-L., Nisonoff, A. (1972). Quantitative investigations of idiotypic antibodies. VI. Idiotypic specificity as a potential genetic marker for the variable regions of mouse immunoglobulin polypeptide chains. J. Exp. Med.135,579-595. 

Siekevitz, M., Huang, S.Y., Gefter, M.L. (1983). The genetic basis of antibody production a single heavy chain variable region gene encodes all molecules bearing the dominant anti-arsonate idiotype in the strain A mouse. Eur. J. Immunol. 13, 123-132. 

Fab (50 kd) and scFv (27 kd) antibody fragments have shorter plasma half-lives (0.5 to 21 hours) because of more rapid glomerular filtration and clearance [7], Plasma clearance, particularly of the xenogenic (usually mouse) portions of humanized and/or chimeric monoclonal antibodies, might be accelerated by development of anti-mouse (or other species), anti-isotypic, anti-idiotypic, or anti-allotypic antibodies that foster immune complex formation or reticuloendothelial clearance via several different FcR forms or elicit allergic or anaphylactic responses [7,8]. 

Five of the phosphocholine mouse myeloma H chains have Asx 31 while the remaining three and the human protein have Asp. Position 31 is seen to be a surface residue. If the remaining five proteins with Asx are found also to have Asp, it will probably not be in idiotypic4 determinant since the different phosphocholine-binding myeloma proteins have distinct idiotypic specificities although it could also exert a conformational role on other residues in the CDR. 

Capra et al. (1977) have found the three CDR of the light chains of mouse anti-p-azo-phenylarsonate antibodies having a cross-reacting idiotype to be identical despite the presence of 16 substitutions in the framework. The framework substitutions were associated with at least two, and probably with more than three, distinct light chains the inability to obtain overlap peptides did not permit determination of the exact number of light chains. 

Lymberi P, Hirsch F, Kuhn J, et al. 1986. Autoimmunity induced by HgCl2 in Brown-Norway rats—part II. Monoclonal antibodies sharing specificities and idiotypes with mouse natural monoclonal antibodies. 

A mouse model of lymphoma was used in pre-clinical studies to validate the vaccination procedure using a tobacco-derived idiotype-specific single-chain variable region fragment of the immunoglobulin from the cancerous mouse B-cell lymphoma [236]. Non-vaccinated mice died within 3 weeks of tumor injection, while 80% of the vaccinated mice were protected from the cancer and survived. 

A number of different mouse myeloma proteins [IgA(/f)] have the capacity to bind phosphorylcholine (77,92-94). There is evidence that some of these proteins, which arose independently in different mice, may be very similar or identical in structure. This evidence includes idiotypic specificity and partial sequence analyses (Chapter 11). These proteins also react with pneumococcal type C polysaccharide, which contains haptenic determinants resembling phosphorylcholine. There exist other mouse myeloma proteins which are also reactive with phosphorylcholine but which differ in structure, as shown by differences in their idiotypic determinants, affinities for various haptens related to phosphorylcholine, and partial amino acid sequences. Leon and Young (92) recognized three classes of myeloma proteins with antiphosphorylcholine activity. Class 1 is characterized by a fairly high affinity for choline as well as phosphorylcholine the other two classes do not combine well with choline. Classes 2 and 3 are distinguished by differences in affinity for phosphonocholine. Leon and Young identified four proteins in class 3 all of these had previously been shown by Potter and Liebermann (77)... 

Within an animal more than one precursor cell may express the same genetic information. Evidence for this is the fact that a relatively small number of cells taken from an inbred mouse may sometimes express idiotypes characteristic of that strain, either in culture or after adoptive transfer. Thus, in vivo, there may be more than one clone synthesizing molecules of the same idiotype. It is probable, however, that only closely related structural genes encode molecules with shared idiotype, and the number of such genes may be small for a given idiotype. In humans and rabbits, in which adoptive transfer experiments are not feasible, there is no direct evidence on this point. 

Additional evidence for the importance of antigenic valence is the finding of Potter et al. (34) and Potter and Lieberman (35) that Fab fragments of mouse myeloma proteins often fail to precipitate with antiidiotypic antibodies which form precipitates with the intact myeloma protein. Also, Harboe et al. (36) reported inhibition of the precipitation of monoclonal IgM by its antiidiotypic antiserum in the presence of the 7 S subunit of the IgM the latter would necessarily have a lower antigenic valence. Increased precipitability by the indirect method has also been observed in quantitative studies of certain rabbit allotypic specificities (37). The fact that Fab fragments sometimes form precipitates with antiidiotypic antibodies and sometimes inhibit precipitation is attributable to variation in the number of idiotypic determinants recognized by different antisera. 

Cosenza and Kohler (47,48) and Sher and Cohn (49) found that antiidiotypic antibodies to the myeloma proteins, TEPC 15 or SI07, which have antipneumococcal (antiphosphorylcholine) activity, almost completely inhibit plaque formation by spleen cells from BALB/c mice immunized with heat-killed strain R36A pneumococci. Erythrocytes used in the plaque-forming tests could be coated either with pneumococcal C-polysaccharide or with phosphorylcholine, with similar results. These significant experiments indicated that nearly all the antibodies produced by BALB/c mice in the primary in vitro response to the pneumococcal polysaccharide shju-e idiotype with a group of mouse... 

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