Deregulation of idiotype expression. Induction of tolerance in an anti-idiotypic response.
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The induction of tolerance in an anti-idiotypic response was attempted by in vivo exposure to excess idiotype. Monoclonal immunoglobulin from the anti-p-azobenzenearsonate (ABA) hybridoma R16.7 was used as a representative of cross-reactive idiotype-positive (CRI+) antibodies because this hybridoma protein (HP) shares one or more closely related public idiotypic determinants with the serum CRI in A/J mice. Immunologic unresponsiveness was established by a single injection of the R16.7 idiotype and persisted for at least 6 wk. The level of circulating anti-idiotypic antibodies in tolerized A/J mice was significantly depressed after immunogenic challenge with eigher antigen, ABA-keyhole limpet hemocyanin (KLH), or the idiotype R16.7 HP. Experimental depletion of anti-idiotypic antibodies by tolerization allowed assessment of immunoregulation within this altered idiotype-anti-idiotype network. Deregulation of idiotype expression in tolerized mice challenged with ABA-KLH was manifest with up to 96% of the anti-ABA antibodies cross-reacting with the R16.7 idiotype. This selective enhancement of a major idiotype was accomplished without substantial alteration of the level of the overall anti-hapten response. Both the unresponsiveness established in anti-idiotypic antibody-producing cells and the enhanced synthesis in idiotype-producing cells were stable upon adoptive transfer into lethally irradiated, syngeneic recipients. Finally, previous immunization with the antigen ABA-KLH interfered with the induction of unresponsiveness to the idiotype. This interference is presumed to be mediated by prior activation of anti-idiotypic cells and/or antibody because injection of antigen with tolerogenic idiotype did not abrogate tolerance induction.Keywords:
Immunoglobulin Idiotypes
Hapten
Keyhole limpet hemocyanin
Idiotopes
Adoptive Cell Transfer
Anti-idiotypic antisera (a-Id) were prepared in SJL mice against the dextran B512 (Dex)-specific hybridoma antibody D.16.6 (mu, kappa) of C57BL/6 origin. Such a-Id were specific for the D.16.6 antibody, but the idiotypic determinants recognized were not hapten modifiable. The a-Id were used in radioimmunoassays (RIA) to study the genetic control of the expression of the D.16.6 idiotype (Id) in a variety of mouse strains. It was found that all mouse strains tested expressed this Id as a component of the normal background immunoglobulin (Ig) in their sera. Only in mice of the IgCHb haplotype, however, was the Id found in association with Dex-specific antibodies. Furthermore, even in IgCHb mouse strains, not all individuals expressed Id-positive anti-Dex antibodies. Because the D.16.6 Id is a "recurrent" natural Id, but a "non-dominant" Id in the Dex response of IgCHb mouse strains, these observations contradict our previous suggestions on the selection of "dominant" Id from the pool of "naturally" produced Ig.
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Previous reports have shown the A/J anti-para-azophenylarsonate (anti-Ar) antibodies that share a major cross-reactive idiotype (CRI) comprise a family of closely related but nonidentical molecules. Serological studies with CRI+ monoclonal anti-Ar antibodies have suggested the presence of a conserved idiotypic determinant within the family. The present study utilized monoclonal ant-idiotypic determinant within the family. The present study utilized monoclonal anti-idiotypic antibodies to define further the nature of the conserved idiotypic determinant. It was found that 8 of 10 CRI+ monoclonal antibodies possess an idiotypic determinant reactive with each of three monoclonal anti-idiotypic antibodies. In addition, approximately 60% of CRI+ serum anti-Ar antibodies reacted with one of the monoclonal anti-idiotypic preparations. The monoclonal anti-idiotypic antibodies react with an idiotope in the region of the hapten-binding site, as indicated by the ability of free haptens to inhibit idiotype-anti-idiotype interactions. Finally, two of three monoclonal anti-idiotypic antibodies suppressed the subsequent production of CRE+ serum anti-Ar antibodies when administered before antigen, without significantly affecting the total anti-Ar response.
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Hapten
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Hybridoma antibodies against the PC-binding T15 BALB/c myeloma protein were raised by cell fusion with anti-T15 A/He immune cells. The idiotype specificity of these monoclonal anti-T15 antibodies was determined with a panel of different myeloma and hybridoma immunoglobulins. Two types of anti-T15 antibodies are seen. One reacts with a number of different IgA myeloma proteins and with serum IgA of certain strains of mice; this reactivity most likely is due to allotypy. The other group consists of anti-T15 antibodies that are specific for the T15 idiotype and are therefore termed anti-idiotypic. The bindings of the anti-idiotype antibodies to T15 were specifically inhibited by T15 (F(ab')2 but not by other PC-binding myeloma proteins of different idiotypes. The relationship of the idiotype-specific anti-T15 antibodies to the PC-binding site of the T15 idiotype was analyzed by hapten inhibition of anti-idiotypic binding and by inhibition of BALB/c anti-PC splenic hemolytic plaque formation. Anti-T15 antibodies, for which the T15 binding is inhibited by PC or PC-BSA, also specifically inhibit anti-PC plaque formation. These antibodies are labeled site and near-site anti-idiotypic antibodies. Site and near-site-specific anti-idiotypic antibodies recognize different idiotopes on the T15 molecules. The possible differential biologic activities of these anti-idiotopes in idiotype network regulation is considered.
Idiotopes
Immunoglobulin Idiotypes
Phosphorylcholine
Paratope
Hapten
Myeloma protein
Polyclonal antibodies
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Abstract To analyze the idiotype (Id) of anti-Ia antibodies elicited during alloimmune responses, we produced syngeneic mouse anti-Id monoclonal antibodies (mAb) reactive with the Id of the 11-5.2.1.9 (11-5) mouse anti-I-Ak (BALB/c anti-CKB) mAb. Two such anti-Id mAb, IA2 (IgG2a) and IIID1 (IgG1), detect structurally related idiotopes located within the binding site of 11-5 for I-Ak antigens. A third anti-Id mAb, VC6 (IgG1), detects an idiotope located either inside or outside of, but presumably proximal to, the 11-5 antigen-binding site, because its expression correlates with the antigenic specificity of 11-5. None of the idiotopes detectable by these three anti-Id mAb are accessible when the binding site of 11-5 is occupied by an I-Ak molecule. The association constants of these anti-Id mAb for their cognate Fab-linked Id range from 2 X 10(9) to 1 X 10(10) M-1. The three anti-Id-producing hybridomas were found with a frequency of 0.008% among growing hybrid colonies. Even though these anti-Id mAb detect public idiotopes (IdX) on 11-5, they do not detect the presence of such IdX markers in the sera of five syngeneic BALB/c mice hyperimmunized with C3H (I-Ak) spleen cells. This suggests that 11-5 represents a BALB/c idiotype infrequently expressed by serum immunoglobulins. The 11-5 idiotopes detectable by IA2, IIID1, and VC6 seem to be conformationally determined by the interaction of 11-5 H and L chains and are not confined to one or the other of these subunit polypeptides. Thus, the expression of the 11-5 Id may be regulated by both VH and VL genes.
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We have previously shown that BALB/c antipneumococcal polysaccharide antibodies with phosphorylcholine (PC) specificity are self-binding, mediated by hypervariable sequence structure of the heavy chain. We extended the observation of self-binding anti-PC antibodies to naturally occurring human anti-PC antibodies. Anti-PC antibodies were purified from normal donor sera and shown to bind to monoclonal antiidiotypic anti-T15 antibodies originally raised against the murine T15 idiotype. These human antibodies are self-binding which is inhibitable by the PC hapten and the murine T15 (50-73)-derived Vh peptide. The anti-PC antibodies were further separated into id-positive and id-negative anti-PC antibodies. Only the T15 id-positive preparation was self-binding. These findings demonstrate an evolutionary, conserved biological property between mouse and man associated with a naturally occurring antibacterial antibody. This conserved biological and structural property may have been selected in evolution because it is part of an important immune defense mechanism against bacterial and other environmental pathogens.
Phosphorylcholine
Idiotopes
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Summary A hybrid cell line, 14A1, was produced that secretes antibodies reading with a monoclonal A/J anti‐p‐azobenzenearsonate (ABA) antibody. 7.1.3, previously shown to have all of the determinants of the cross‐reactive idiotype (CRI) defined by rabbit anti‐idiotype sera. 14A1 was detected using a sensitive assay that is specific for antibodies against idiotypic, but not allotypic nor isotypic, determinants. This was confirmed by demonstrating that 14A1 antibodies bind 7.1.3 but not other A/J monoclonal antibodies of the same class or CRI − monoclonal anti‐ABA antibodies. The idiotypic determinant recognized by 14A1 is located at or near the hapten‐binding site of 7.1.3, as ABA‐conjugated tyrosine is capable of blocking this interaction. Rabbit anti‐CRI antibodies are prevented from binding to 7.1.3 by the addition of 14A1, demonstrating the spatial proximity of the 14A1 idiotope with determinant(s) of the CRI. All A/J anti‐ABA antibodies that have the 14A1 idiotope are also CRI − , while anti‐ABA antibodies from other strains of mice do not express this idiotope. Furthermore, antibodies from A/J mice immunologically suppressed for the CRI also fail to interact with 14A1 antibodies. These results have implications both for the nature of the CRI and for the regulation of the immune response by anti‐idiotype antibodies.
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Hapten
Immunoglobulin Idiotypes
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AbstractThe immune reponse to the phosphorylcholine (PC) hapten elicited by PC-keyhole limpet hemocyanin (KLH) is composed of 2 groups of antibodies with specificity to either PC or phenylphosphorylcholine which were designated as group I and II anti-PC antibodies, respectively. We demonstrate that anti-PC IgE antibody expression is restricted to group II antibodies and does not display the T15 idiotype. Accordingly anti-PC IgE antibodies recognize the same epitope (PC-phenyl) as IgG1, IgG2a and IgG2b antibodies which is different from that (PC) recognized by IgM and IgG3 antibodies. A monoclonal anti-PC IgE antibody, representing group II characteristics was established. From amino acid sequences of light chains of purified group I and II antibodies from serum as well as of monoclonal representatives thereof it appears that both populations are relatively homogenous and represent independent clonal expressions. Nevertheless the formation of anti-PC IgE antibodies in mice can be suppressed by isologous anti-T15 anti-idiotypic antiserum. This antiserum, however, crossreacts with different anti-PC antibodies including monoclonal group II anti-PC IgE antibodies and is composed of a large number of anti-idiotopes. An analyses performed with monoclonal anti-T15 idiotopes demonstrates that some but not all antibodies suppress the formation of anti-PC IgE. We conclude that syngeneically induced anti-idiotypic interactions may display regulation of a wide range of specificities affecting responses to various antigenic determinants.
Idiotopes
Immunoglobulin Idiotypes
Phosphorylcholine
Hapten
Keyhole limpet hemocyanin
Polyclonal antibodies
Hemocyanin
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Five murine monoclonal antibody (mAb) anti-idiotypes (id), shown in the accompanying report by binding studies to be reactive with five different id on a single member of the 5AF6 family of BALB/c antibodies against the p-azophenylarsonate (Ar) hapten, were used to examine the distribution of their recognized id among anti-Ar in BALB/c and other mouse strains immunized with keyhole limpet hemocyanin-Ar (KLH-Ar). Differences in id expression in BALB/c and other strains substantiate that all five monoclonal anti-id reacted with different id. This suggests that the anti-id repertoire for a single antibody molecule may be extensive. Two of the anti-id reacted with id that were found in virtually all KLH-Ar immunized BALB/c mice, but constituted only a subset (approximately 33%) of the antibodies representing the 5AF6 family. The other three anti-id reacted with id infrequently expressed among BALB/c anti-Ar. Other mouse strains producing 5AF6 family anti-Ar antibodies also produced antibodies recognized by mAb 2CB8 and 6BA1; however, the three id infrequently expressed in BALB/c mice were produced in higher quantities and in a greater percent of mice. Monoclonal anti-id were capable of suppressing a portion but not all of the 5AF6 family of anti-Ar antibodies. Four of the five anti-id suppressed a greater fraction of the 5AF6 family than that id represented in a normal immune response, suggesting that suppression was mediated via an id other than that recognized by these monoclonal anti-id. Overall, the results indicate that an extensive repertoire of anti-id can be produced against a single id antibody, but suppression induced by treatment with these anti-id in this model is presumably mediated via another as yet unidentified id determinant(s).
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Hapten
Keyhole limpet hemocyanin
Immunoglobulin Idiotypes
BALB/c
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Many monoclonal antibodies that react with the lacto-N-fucopentaose III (LNF III) antigenic determinant, Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-3Gal beta 1-4Glc, have been described recently. The terminal trisaccharide of this determinant, fucosyllactosamine, is present on glycolipids and glycoproteins and on the surface of granulocytes, monocytes, and other cells. To study the structural and genetic diversity of these antibodies, syngeneic anti-idiotypic monoclonal antibodies were produced in BALB/c mice against PMN 6, a monoclonal antibody directed against this sequence. Anti-idiotypic antibodies 6B1 and 6C4 reacted with 50% of a panel of 20 anti-LNF III monoclonal antibodies, whereas 6A3 reacted strongly only with PMN 6. This indicates that the determinants recognized by 6C4 and 6B1 represent major cross-reactive idiotopes of this family of antibodies. The binding of idiotypic antibodies to a glycolipid bearing this antigenic determinant was completely inhibited by the three anti-idiotypic antibodies, 6A3, 6B1, and 6C4. The idiotopes could be demonstrated on the heavy chain of the monoclonal antibodies by an antibody transfer technique when mild reducing conditions were employed, but a high concentration of reducing agent destroyed the idiotypic determinants. This suggests that the anti-idiotypic antibodies recognize conformational structures expressed on the heavy chain molecules. The binding of 18 monoclonal antibodies to two glycolipid antigens and to a fucosyllactosamine-bovine serum albumin conjugate was compared. Antibodies that possessed the 6C4 cross-reactive idiotope bound to fucosyllactosamine-bovine serum albumin more weakly than idiotype-negative antibodies (p = 0.001). This suggests that the 6C4-positive antibodies might represent germline structures.
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