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Biomedical subjects

A Nisonoff

Publications and source records attributed to A Nisonoff.

At least 91 records · Page 5Linked to original sources
PubMed1979

Antigen- and receptor-driven regulatory mechanisms. I. Induction of suppressor T cells with anti-idiotypic antibodies.

Delayed-type hypersensitivity (DTH) to the azobenzenearsonate (ABA) hapten can be readily induced in A/J mice injecting ABA-coupled syngeneic spleen cells subcutaneously. To further characterize this T-cell-dependent immunological phenomenon, the effect of passively administered anti-cross-reactive idiotype common to anti-ABA antibodies of A/J mice (CRI) antibodies on the development of ABA-specific DTH was investigated. Animals given daily injections (of minute amounts) of anti-CRI antibodies subsequent to immunization with ABA-coupled cells show significant reduction of ABA specific responses. This inhibition is antigen specific and requires the intact immunoglobulin molecule, as F(ab')2 treatments were ineffective in suppressing the reaction. Investigations of the mechanism of the anti-CRI-induced suppression of ABA DTH revealed that the observed suppression is a result of the activation of suppressor cells. Spleen cells taken from animals which received anti-CRI antibodies were able to adoptively transfer suppression to naive recipients. This suppression was shown to be mediated by T cells, as anti-Thy1.2 plus complement completely abrogated the transfer of suppression. In addition, animals pretreated with low doses of cyclophosphamide were not suppressed by the administration of anti-CRI antibodies. The genetic restriction of anti-CRI-induced suppression was demonstrated. Antibodies to the major cross-reactive idiotype, (CRI) associated with anti-ABA antibodies in A/J mice were unable to suppress the development of DTH to ABA in BALB/c mice (H-2d, Igh-1a). Such antibodies were, however, fully active in suppressing ABA DTH in the allotype-congenic C.AL-20 strain which has an allotype (Igh-1d) similar to that of A/J (Igh-1e) on a BALB/c background, and which produces humoral antibodies with the CRI.

Animals↗
PubMed1979

Antigen- and receptor-driven regulatory mechanisms. II. Induction of suppressor T cells with idiotype-coupled syngeneic spleen cells.

Anti-p-azobenzenearsonate (ABA) antibodies, coupled covalently to normal syngeneic spleen cells and then given intravenously to normal animals, were found to be potent tolerogens for delayed-type hypersensitivity (DTH) to ABA. The ability of the antibody-coupled cells to induce tolerance was determined to be a result of the cross-reactive idiotype (CRI+) fraction of the antibodies, because anti-ABA antibodies lacking the CRI+ components when coupled to spleen cells were unable to cause any significant inhibition. Furthermore, genetic analysis revealed that the ability of CRI-coupled cells to inhibit ABA-specific DTH is linked to Igh-1 heavy chain allotype, in as much animals which possess heavy chain allotypes similar to that of A/J were sensitive to this inhibition. Adoptive transfer experiments provided evidence that CRI-coupled cells induce suppressor cells, and spleen cells or thymocytes from animals received CRI-coupled cells were able to transfer suppression to naive recipients. In addition, treatment with anti-Thy1.2 serum plus complement completely abrogated their ability to transfer suppression. Thus, this active suppression is a T-cell-dependent phenomenon. In investigating the specificity of these suppressor T cells, it was found that they functioned in an antigen-specific manner and were unable to suppress the development of DTH to an unrelated hapten 2,4-dinitro-1-fluorobenzene.

Animals↗
PubMed1979

Suppression of idiotype and generation of suppressor T cells with idiotype-conjugated thymocytes.

Inoculation of A/J mice with syngeneic thymocytes conjugated with specifically purified A/J anti-phenylarsonate (anti-Ar) antibodies, selectively suppressed the subsequent synthesis of those anti-Ar antibodies which carry the major cross-reactive idiotype. High titers of anti-Ar antibodies were produced upon subsequent immunization but in most mice the idiotype was undetectable. Suppression similarly occurred in F1(A/J X BALB/c) and in C.AL-20 mice. Although some mice were suppressed when unconjugated antibody was injected, the suppressive effect was much more pronounced, particularly in the F1 and C.AL-20 recipients, when the antibody was coupled to thymocytes. The state of suppression could be adoptively transferred with T cells to mildly irradiated syngeneic recipients. A population enriched for B cells had little if any suppressive effect. There was no requirement for antigen in the generation of suppressors. Thymocytes conjugated with antibody did not induce idiotype-specific suppression in mice that had been recently challenged with antigen. Thymocytes from BALB/c and C57BL/10 mice were effective carriers for the anti-Ar antibodies, i.e., there was no evidence for H-2 restriction. The experiments demonstrate the feasibility of suppressing idiotype production and generating idiotype-specific suppressor T cells without the use of anti-idiotypic antibody or antigen.

Animals↗
PubMed1979

Mechanisms of regulation of cell-mediated immunity. IV. Azobenzenearsonate-specific suppressor factor(s) bear cross-reactive idiotypic determinants the expression of which is linked to the heavy-chain allotype linkage group of genes.

T-cell derived suppressor factor(s) (SF) specific for azobenzenearsonate (ABA) were prepared by the mechanical disruption of suppressor cells. Such suppressor factors were adsorbed to and recovered from immunoadsorbents prepared from the F(ab')2 fragments of rabbit immunoglobulin directed against the cross-reactive idiotype of A/J anti-ABA antibodies. These ABA-suppressor factors were not retained on Sepharose 4B immunoadsorbent columns which had been coupled with F(ab')2 fragments or normal rabbit immunoglobulins prepared from prebleeds of rabbits used to make anti-idiotypic antiserum. The specificity of the F(ab')2 rabbit anti-idiotypic serum was established by direct idiotypic-binding assays and by affinity purification over an immunoadsorbent consisting of CRI+ anti-ABA immunoglobulin from A/J mice. ABA-suppressor factors were shown to be specifically absorbed and eluted from F(ab')2 anti-idiotypic columns. Futhermore, the eluted suppressor factor can be specifically reabsorbed and recovered from a second anti-idiotypic immunoadsorbent. The concordance between antigen-binding specificity and the presence of idiotypic determinants was demonstrated by adsorbing ABA SF to antigen columns and then fractionating the ABA-specific factor on anti-idiotypic immunoadsorbents. ABA-suppressor factors were shown to be specifically retained on immunoadsorbents directed against major histocompatibility complex (MHC) determinants. Factor eluted from anti-MHC columns could then be specifically adsorbed to anti-idiotypic immunoadsorbents. This suggests that the same molecular complex that is recognized by the H-2 alloantiserum is specifically adsorbed to an anti-idiotypic immunoadsorbent. Genetic analysis of the expression of CRI+ suppressor factor was performed using the C.AL-20 mouse strain which has the AL/N allotype and produces CRI+ anti-ABA immunoglobulins. The implication of these findings to the nature of T-cell-derived regulatory molecules is discussed.

Animals↗
PubMed1979

Structural studies on induced antibodies with defined idiotypic specificities. VII. The complete amino acid sequence of the heavy chain variable region of anti-p-azophenylarsenate antibodies from A/J mice bearing a cross-reactive idiotype.

This paper reports the complete amino acid sequence of the variable region of heavy chains derived from A/J anti-p-azophenylarsenate antibodies bearing a cross-reactive idiotype. The structure of this induced idiotypically defined antibody is homogeneous and provides the first direct evidence that heritable idiotypes are defined chemical entities. There are certain similarities between the structure of this murine antibody and the human myeloma protein Eu as well as guinea pig anti-p-azophenylarsonate antibodies. The amino acid sequence of approximately 15% of the constant region of this IgG1 molecule is also described. Combined with our studies of the variable region of the light chains of these molecules, this study represents the first complete V domain structure of an induced idiotypically defined antibody with heritable characteristics.

Amino Acid Sequence↗
PubMed1978

Effect of idiotype-specific suppressor T cells on primary and secondary responses.

Previous reports have shown that suppression of idiotype can be adoptively transferred by T cells, or by rosettes containing T cells with anti-idiotypic receptors, from an idiotypically suppressed, syngeneic mouse. The present data indicate that secondary B cells are highly resistant to such suppression. Priming recipients to the relevant hapten, p-azophenylarsonate, 6 days or 4 mo before the adoptive transfer prevented suppression. This was independent of the carrier used for the hapten group during priming or subsequent immunization, suggesting that resistance to suppression is attributable to secondary cells with specificity for the hapten. The effect of suppressor T cells could also be overcome by mixing them with specifically purified B cells having receptors for the hapten group before the adoptive transfer. Adoptive transfer of the suppressed state by specifically purified B cells from suppressed, hyperimmunized animals confirmed our previous finding that the suppression of idiotype can also be caused by B cells lacking idiotypic receptors, evidently through a mechanism involving clonal dominance. Possible mechanisms of idiotypic suppression by T cells are discussed.

Animals↗
PubMed1978

Analysis of the cellular basis of idiotype-specific suppression.

We have investigated the ability of B and T lymphocyte subclasses from donor mice that produce high levels of anti-Ar antibody but have been suppressed for one idiotypic component (CRI) to induce and maintain idiotypespecific suppression. Our studies indicate: 1) Memory B cells from such mice can preempt virgin CRI+ B cells present in the host from contributing to the anti-Ar response. 2) T cells can also adoptively transfer idiotypespecific suppression. 3) B and T cells do not act synergistically in this transfer of idiotype-specific suppression. 4) Extremely small numbers of Ly23 cells transfer suppression of idiotype and most probably represent true Ts cells. 5) Ly1 cells from hyperimmune idiotypically suppressed donors can induce idiotype-specific suppression. This latter result most likely reflects the induction of idiotype-specific suppressor cells in the host.

Animals↗
PubMed1978

Structural studies on induced antibodies with defined idiotypic specificities. VI. Amino terminal sequences of the heavy and light chain variable regions of anti-p-azophenylarsonate antibodies from A/J mice suppressed for a cross-reactive idiotype.

Previous studies in this series have been directed toward the elucidation of the heavy and light chain variable region structures of antibodies raised in A/J mice to the p-azophenylarsonate (Ar) hapten, certain of which bear a cross-reacting idiotype. The present study concerns an analysis of anti-Ar antibodies that arise in A/J mice suppresed for a cross-reacting idiotype. The results indicate that when an idiotype is suppressed and the animal subsequently hyperimmunized, the resultant antibodies are "deviated" into different V-region subgroups, both in the heavy and light polypeptide chains. The study presents the first primary structural analysis of a humoral immune response that has been manipulated by an idiotypic reagent.

Amino Acid Sequence↗
PubMed1977

Complete inhibition of the expression of an idiotype by a mechanism of B-cell dominance.

Mice of the C.AL-20 strain, which express genes controlling CH regions of the AL/N strain on a BALB/c background, normally synthesize antibodies to the p-azophenylarsonate group (anti-Ar antibodies) with an idiotype characteristic of the A strain. The synthesis of the idiotype, as quantitated by a sensitive assay, can be completely inhibited by the transfer of leukocytes from BALB/c mice producing anti-Ar antibodies, which lack the idiotype. A number of control experiments show that the inhibition is not attributable to suppressor T cells and that the synergistic action of such cells is not required. The results indicate that B-cell dominance, mediated by secondary cells, can completely prevent the expression of unprimed cells with receptors of the same specificity. It is uncertain whether this effect is due entirely to selective capture of antigen by the secondary cells, or whether some type of active suppression by B cells is involved.

Animals↗
PubMed1977

Presence on idiotype-specific suppressor T cells of receptors that interact with molecules bearing the idiotype.

All A/J mice produce anti-p-azophenylarsonate (anti-Ar) antibodies, some of which share a cross-reactive idiotype. The idiotype can be suppressed by treatment with anti-idiotypic antiserum before immunization, although normal concentrations of anti-Ar antibodies are synthesized. We have previously reported that such suppressed mice, if hyperimmunized and then allowed to rest, contain up to 10% of splenic T cells which form rosettes with autologous RBC coated with Fab fragments of anti-Ar antibodies bearing the idiotype. Our present results indicate that the rosette-forming T cells include the idiotype-specific suppressor T-cell population. The suppressive activity is largely depleted by removal of the rosette-forming lymphocytes, and the rosettes themselves are highly suppressive. The data do not establish whether all of the idiotype-specific rosette-forming cells are suppressor cells. The system may provide a source of large numbers of suppressor cells for further study, and facilitate investigation of the mechanism of generation of idiotype-specific suppressor cells.

Animals↗
PubMed1977

Frequency of occurrence of idiotypes associated with anti-p-azophenylarsonate antibodies arising in mice immunologically suppressed with respect to a cross-reactive idiotype.

Inoculation of rabbit anti-idiotypic (anti-id) antibodies suppresses the subsequent appearance of a cross-reactive idiotype (CRI) associated with the anti-p-azophenylarsonate (anti-Ar) antibodies of A/J mice. Such suppressed mice produce normal concentrations of anti-Ar antibodies which lack the CRI, but against which anti-id antisera can be prepared. The anti-Ar antibodies of an individual, suppressed mouse do not in general share idiotype with anti-Ar antibodies of other A/J mice, either suppressed or nonsuppressed. The present experiments were undertaken to quantitate several "private idiotypes" in a large number of hyperimmunized A/J mice. Anti-Ar antibodies of three mice, suppressed for the CRI, were labeled with 125I and subjected to isoelectric focusing. Four single peaks, that were over 90% reactive with autologous antiid, were randomly selected for use as ligands in a radioimmunoassay, and ascitic fluids containing anti-Ar antibodies from 181 A/J mice were tested as inhibitors. Two of the four idiotypes could not be detected in any mouse other than the donor. The concentration of the idiotype was less than 1 part in 1,250 to less than 1 part in 25,000 of the anti-Ar antibody population; these are minimum values. A third idiotype was detected in 3 of the 181 mice, but at very low concentrations. The fourth idiotype was present in 28% of the mice, again at a low concentration. The data support the existence of a very large repertoire of anti-Ar antibodies in the A/J strain and are consistent with a process of random somatic mutation for generating diversity in hypervariable regions. It is proposed that the cross-reactive idiotype may be controlled by a germ line gene or a gene related to a germ line gene through a small number of somatic mutations; and that the idiotypes that were not detectable in other mice were the products of genes that had undergone extensive mutations, with a low probability of recurrence in other mice.

Animals↗
PubMed1977

Transfer of idiotype suppression and idiotypes by leukocytes from ascitic fluids.

A procedure is described for producing ascites containing both high concentrations of antibodies and immunologically active leukocytes. In mice that were immunologically suppressed with respect to a cross-reactive idiotype, the ascitic cells were found to be very active in adoptively transferring the suppressed state to mildly irradiated, syngeneic recipients and simultaneously transferring the capacity to produce the "private" idiotype characteristic of the donor's anti-p-azophenylarsonate antibodies. The participation of both T and B cells is therefore suggested. As few as 2 x 10(6) cells were sufficient for suppression and for inducing the production of the private idiotype in the recipient, in concentrations comparable to that of the donor mouse. A single donor can thus be used to colonize many recipients with the private idiotype, without sacrifice of the donor. The method should be useful in structural studies of antibodies of a given specificity with different idiotypes, and for investigations of the mechanism of idiotype suppression, as well as other studies in cellular immunology.

Animals↗
PubMed1977

Two str1cturally similar haptens each induce a different inherited idiotype.

When mice of the A/J strain were immunized with azobenzenearsonate (ABA) directly coupled to a protein, they produced antibodies that share an inherited cross-reactive idiotype (CRI). In the antigenic determinant that induces CRI, ABA is very probably coupled to tyrosine, and the structure that protrudes from the polypeptide backbone has two benzene rings and a molecular weight of 419. When this same structure is separated from the polypeptide backbone by a spacer of 99 daltons, it induces a different inherited idiotype (ABA-HOP-e) in the same strain of mice. Our data suggest that antibodies with the idiotype CRI recognize the terminal benzene ring and the azo group, but do not fit closely around the second ring structure. Antibodies with the idiotype ABA-HOP-e have fine specificity for both benzene rings. Both idiotypes are inherited and both are linked to genes controlling constant regions of the heavy chains.

Animals↗
PubMed1977

Production of large amounts of antibodies, complement, and leukocytes in ascitic fluids of guinea pigs.

A method is described for the production in guinea pigs of large amounts of ascitic fluid containing non-specific IgG, antiprotein antibodies, complement, other serum proteins and leukocytes. The method is an adaptation of a procedure previously applied to mice. A major difference is the extended schedule of inoculations required for the induction of ascites in guinea pigs; a requirement for boosting with antigen intradermally while repeatedly inoculating adjuvant intraperitoneally; and the much larger quantities obtained. The average yield of ascitic fluid, when antigen was not used, was 113 ml per animal, and the average yield of IgG was 0.87 g. With antigen (keyhole limpet hemocyanin) the average yields were 143 ml and 1.6 g of antibody per guinea pig. Complement titers were 41 to 74% of those in serum. The number of leukocytes per ml of ascites ranged from 7 X 10(6) to 20 X 10(6). The method should be useful for the production of large amounts of leukocytes, antibodies and other serum proteins from a small colony of laboratory animals. In addition, cells can be obtained without the need to sacrifice the animal.

Animals↗