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PubMed1992

Role of hapten-anchoring peptides in defining hapten-epitopes for MHC-restricted cytotoxic T cells. Cross-reactive TNP-determinants on different peptides.

Synthetic hapten-peptide conjugates selectively modify cell-bound MHC class I molecules in a haplotype-specific way. We investigated the contribution of the carrier peptides to the structural specificity of T cell-antigenic TNP epitopes, using different H-2Kb-binding TNP-peptides and a collection of TNP/Kb-specific CTL clones. Adjustment of peptide sequences to the proposed Kb-specific "motif" (octamers with F or Y and L in positions 5 and 8, respectively) enhanced Kb-binding and antigenicity by many orders of magnitude. Moreover, several clones reacted to peptides, containing the "motif" and TNP-lysine in position 4 but were otherwise unrelated by sequence. TNP in other positions was not recognized by these cells, but other CTL reacted to TNP in position 7. This points to the positioning of hapten determinants within the MHC binding groove as a major role of the anchoring peptide. However, determination of the limiting amounts of TNP peptides that elicit antigenicity or inhibit other Kb-restricted CTL reactions revealed that TCR also recognize variations in the sequences of carrier peptides. This contribution is low for TNP in position 4 but high in position 7, indicating lysine in position 4 as a particularly dominant and cross-reactive hapten-anchoring site in Kb-associated peptides. This implies that cell modification with lysine-reactive TNP reagents results in immunodominant, highly repetitive TNP epitopes, which may explain the strong antigenicity and the allergenic properties of TNP, as well as the restricted TCR repertoire directed against this hapten. Our data further recommend hapten peptides for general studies of TCR-Ag interactions because in contrast to pure protein Ag, hapten epitopes tolerate substantial structural variations in the MHC-anchoring peptide, and can be located by hapten-specific antibodies.

Amino Acid Sequence↗
PubMed1975

Carrier and hapten functions in immune deviation. II. Role of hapten and carrier on the helper functions of the T cells.

The kinetics of haemagglutinating and haemolytic antibody synthesis to the hapten and to the carrier determinants were studied in guinea-pigs injected intravenously with large doses of the carrier, or of the hapten conjugated to an homogous or heterologous protein carrier and subsquently immunized with the hapten-carrier conjugate in Freund's complete adjuvant. The animals treated with the heterologous conjugates exhibited enhanced reactions to the hapten and supressed reactions to the carrier, whereas the animals injected with the homologous conjugate showed depressed reactions to the hapten but unaffected reactions to the carrier. Pretreatment with the carrier alone-seemed to have no effect. These experiments confirm that the hapten determinant must act at the T-cell level but do not exclude the possibility that it could also act at the B-cell level. On the other hand, they allow the dissociation of the different components of the immune response directed against the hapten and carrier determinants of the antigen molecule in immune deviation.

Animals↗
PubMed1978

Hapten-specific tolerance induced by hapten conjugates of D-glutamic acid, D-lysine (D-Gl) or isologous gamma-globulin: evidence for central B cell tolerance in the presence of carrier-primed helper T cells.

A comparison has been made of the well known hapten-specific tolerance systems induced, respectively, by hapten-D-GL or hapten-isologous gamma-globulin conjugates. The principal question addressed in this study concerned the comparative maintenance of B cell tolerance, induced by one or the other method, after adoptive transfer into carrier-primed, irradiated recipient animals and, in addition, what role, if any, might be played by T lymphocytes in the tolerant donor cell population in maintaining such tolerance. The results clearly show that insofar as the hapten-specific B cell is concerned, no obvious difference exists in the capacity to maintain tolerance adoptive transfer between the hapten-D-GL and hapten-isologous gamma-globulin systems; such cells remained tolerant even in the presence of excess helper T cell activity. Moreover, under the conditions employed, depletion of T lymphocytes from the tolerant donor cell population did not affect the maintenance of hapten-specific B cell tolerance after adoptive transfer to irradiated recipients.

Animals↗
PubMed1986

Suppression of the anti-hapten IgE antibody response with hapten-modified spleen cells.

Spleen cells of BALB/c mice were chemically modified with phosphorylcholine or benzylpenicilloyl hapten. The i.v. administration of such cells into syngeneic animals suppressed the formation of specific IgE antibodies against the respective hapten. The IgE antibody response against ovalbumin, which was used as an immunogenic carrier for the haptens, was not affected and the anti-hapten IgG or IgG1 response remained at the levels of the controls. The suppression could be transferred into X-irradiated mice by T cells from tolerized animals. Moreover, it was demonstrated that not only the induction of IgE, but also an established anti-hapten IgE antibody response is accessible to suppression by treatment with hapten-modified spleen cells from syngeneic animals. The results indicate that the i.v. administration of antigen coupled to syngeneic spleen cells induces T cells which suppress the formation of specific IgE antibodies in the primary and the secondary response without significantly affecting the formation of IgG antibodies.

Animals↗
PubMed1995

Oral tolerance to haptens: intestinal epithelial cells from 2,4-dinitrochlorobenzene-fed mice inhibit hapten-specific T cell activation in vitro.

The mechanisms underlying the induction of immunological tolerance after feeding soluble exogenous antigens, including proteins and haptens, are still unclear. Using a model of oral tolerance to the contact-sensitizing hapten 2,4-dinitrochlorobenzene (DNCB), we have compared the ability-of intestinal epithelial cells and of Peyer's patch APC to present DNCB in vitro or ex vivo after oral feeding, to specific peripheral lymph node T cells from DNCB-sensitized mice. In contrast to Peyer's patch APC, which induce efficient hapten-specific T cell activation upon exposure to the hapten either in vitro or in vivo, mature MHC class-II-positive intestinal epithelial cells were unable to induce T cell activation in either case. Interestingly, enterocytes from DNCB-fed mice exerted a dramatic inhibitory effect on the proliferative response of hapten-primed T cells in response to dinitrobenzene sulfonate presented by syngeneic spleen cells. This inhibitory effect, which was also observed with supernatant of intestinal epithelial cells from DNCB-fed mice, could be reversed by neutralizing anti-transforming growth factor (TGF)-beta antibodies. In addition, pre-incubation of hapten-sensitized T cells with enterocytes from DNCB-fed mice induced T cell anergy, which could be reversed by exogenous interleukin-2 or interleukin-4. These data demonstrate that intestinal epithelial cells activated in vivo by oral administration of DNCB are able to block proliferation of activated T cells through secretion of immunosuppressive cytokines such as TGF-beta. It is proposed that intestinal epithelial cells may play a significant role in oral tolerance by limiting T cell-mediated hypersensitivity responses.

Administration, Oral↗
PubMed1984

Inhibition of plaque-forming cells with anti-idiotope or hapten: variation due to hapten density on indicator red cells.

Phosphorylcholine (PC)-specific antibody plaque-forming cells (PFC) were enumerated in the spleen of BALB/c mice immunized with S. pneumoniae R36a bacterial vaccine. Two indicator red blood cells were compared: RBC coupled with the hapten, PC-RBC, and cells coupled with PC-bearing polysaccharide from the pneumococcus, PnC-RBC. Equal numbers of direct (IgM) PFC were detected with both types of indicator cells. However, a significant difference appeared in the attempt to inhibit the respective PFC either with hapten (monovalent PC chloride, PCCl) or with monoclonal antibodies against T15 idiotopes (anti-Id). At optimal coupling concentrations, inhibition of anti-PnC-RBC plaques required a 10-fold higher concentration of the hapten when compared to anti-PC-SRBC plaques. Also, the inhibition of anti-PnC-SRBC plaques with anti-Id required much higher concentration of the antibody. The phenomenon may be explained by a higher epitope density on PnC-RBC than on PC-RBC. Heavily coupled PC-RBC were more difficult to inhibit (much like the PnC-RBC) by either the hapten or the anti-Id than lightly coupled PC-RBC. A mathematical analysis of the experimental curves supports the notion that under the assay conditions used, inhibition by either the hapten or the anti-Id is influenced primarily by antibody secretion rate and epitope density on indicator cells. If the 2 variables are too high, a significant inhibition of PFC with a low affinity anti-Id may not be possible. The theory also predicted that addition of a small amount of hapten into the assay would be roughly equivalent to secretion rate reduction and would facilitate the plaque inhibition by anti-Id. Indeed, we show a synergism between a minute (non-inhibitory) amount of PCCl and anti-Id in the inhibition of PC-specific PFC. These results point out that the detection of an idiotype-bearing PFC by plaque-inhibition assay is greatly influenced by technical variation in the assay, in particular, the preparation of the indicator red cells.

Animals↗
PubMed2005

T cell receptor (TCR) interaction with haptens: metal ions as non-classical haptens.

Haptens are classified as low molecular chemicals with an intrinsic potential to covalently modify proteins, and many of them are strong inducers of contact hypersensitivity (CHS). CHS is T cell mediated, and hapten-specific T cells have been shown to interact with hapten-modified, MHC-associated peptides. However, the most common contact sensitizer in the industrialized world is nickel. In contrast to classical haptens, nickel ions do not form covalent bonds to proteins, but rather become caught in reversible coordination complexes. We here review work demonstrating that some T cells, indeed, may react to such Ni complexes on the MHC/peptide-surface absolutely comparable to other haptens. In other cases, Ni ions unlike classical haptens, may activate T cells by crosslinking their receptors to MHC molecules, independent of the nature of the associated peptide. Moreover, Ni-interacting proteins appear to make use of the reversibility of Ni-binding, and to mediate the transfer of Ni-ions to the receptor-MHC interphase. We have demonstrated such properties for human serum albumin (HSA) as well as for transferrin and identified numerous new Ni-binding proteins in human B-cell lines or dendritic cells by affinity purification and mass spectroscopy. These proteins include a notable number of known heat shock proteins and chaperones, implying that Ni may functionally interfere with these stress proteins.

Animals↗
PubMed1998

An improved method for the production of antibodies to lipophilic carboxylic hapten using small amount of hapten-carrier conjugate.

A rapid, simple and low cost procedure for preparing minute amount of hapten-protein conjugates was developed using 4-acetyl benzoic acid (ABA) and two other closely related small chromophoric haptens. The amide bond-generating mixed anhydride method of Erlanger was modified to promote conjugation to various proteins (bovine serum albumin, ovalbumin, casein and hemocyanin) or to a synthetic homopolymer (Poly-DL-lysine). The key process in this synthesis is the use of a reversed micellar medium allowing strong carrier haptenization as determined by spectrophotometric measurement at characteristic hapten absorption peaks. This coupling procedure is applicable to as little hapten material as 0.2 micromol and is disclosed to be most valuable for other rare lipid haptens which pose analytical problem in biological fluids and matrices. Specific mice polyclonal antibodies were produced following multiple intraperitoneal injections of (ABA)23-BSA conjugate as revealed by indirect and competitive ELISA. Calculated KD for the interaction of the antibodies with free ABA was found to be 5 X 10(-5)M.

Animals↗
PubMedDate not supplied

Characterization of protein-hapten conjugates. 2. Electrospray mass spectrometry of bovine serum albumin-hapten conjugates.

Fifteen hapten-bovine serum albumin (BSA) conjugates were prepared from five commercially available activated haptens. Each hapten was coupled to BSA at three different ratios. The conjugates were characterized by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and two mass spectrometry (MS) methods: matrix-assisted laser desorption ionization (MALDI) and liquid chromatography-electrospray ionization (LC-ESI). SDS-PAGE was useful in detecting protein cross-linking, but not assessing hapten density. MALDI-MS and LC-ESI-MS gave comparable qualitative results, but LC-ESI-MS provided a clearer representation of the distribution of hapten-protein species present in the conjugates. Conjugate species substitute with up to 25 haptens per BSA were recorded by LC-ESI-MS.

Animals↗
PubMed1962

Delayed hypersensitivity to hapten-protein conjugates. I. The effect of carrier protein and site of attachment to hapten.

Further data have been presented showing that the specificity of the delayed hypersensitivity reaction in the guinea pig to hapten-protein conjugates involves to a considerable degree a contribution by the protein carrier. The carrier contribution is such that sensitization to guinea pig albumin-m-azobenzenesulfonate, for example, does not result in cross-reaction with conjugates of the same hapten with unrelated proteins such as ovalbumin or human gamma globulin, nor were cross-reactions observed between conjugates prepared with the same hapten, coupled to the same protein, but by two different chemical routes, such that the point of attachment of the hapten to the protein differed. It thus appears that in this system both hapten and carrier protein are necessary, but that neither alone is in general sufficient to stimulate the delayed sensitive cell. Desensitization experiments with cross-reacting hapten-protein conjugates have suggested the presence of a multiplicity of antigenic determinants participating in the elicitation of the delayed lesion, and of a concomitant development of a heterogeneity of specificities in the population of delayed sensitive cells in the sensitized animal. The data are discussed in terms of the apparent requirement of the delayed sensitivity mechanism for a larger functional antigenic determinant than that required for interaction with circulating antibodies. Some possible explanations for this difference, and some of its consequences, are discussed.

Animals↗
PubMed1970

Hapten-carrier relationships of isoantigens. A model for immunological maturation based on the conversion of haptens of carriers by antibody.

In chickens, erythrocyte isoantigens have hapten-carrier relationships. Specific anticarrier antibody depresses the immune response to the carrier and enhances the immune response to the hapten. Antigenic determinants of "haptenic" isoantigens behave as carriers if they are coated with specific antibody. It is postulated that every humoral antibody response involves the cooperation of a carrier with a hapten and the progressive conversion by antibody of haptens to carriers. Thus a carrier is viewed as an antigenic determinant which is coated with antibody. The antibody-forming cell only synthesizes antibody to the uncoated haptenic determinants. The consequences of this interpretation for the development of immunological maturity and the secondary immune response are discussed.

Animals↗
PubMed1980

T lymphocyte-mediated suppression of myeloma function in vitro. II. Evidence for regulation of hapten-binding myelomas by syngeneic hapten-specific cytolytic T lymphocytes.

BALB/c splenocytes stimulated in vitro with trinitrophenyl (TNP)-modified syngeneic cells inhibit the secretion of antibody by the TNP-binding BALB/c myeloma MOPC 315 in the presence of soluble TNP-Keyhole limpet hemocyanin (KLH). The effector cells are hapten-specific, H-2-restricted, Thy-1.2-bearing, Ly-2-positive T lymphocytes whose precursors are resistant to pretreatment with cyclophosphamide. These phenotypic properties are typical of hapten-specific cytolytic T lymphocytes (CTL). The TNP-reactive CTL that inhibit MOPC 315 cells fail to suppress H-2d myelomas that do not bear TNP-specific surface receptors, and this is not attributable to differences in total binding of TNP-KLH to the different myeloma cells. Moreover, azobenzene arsonate (ABA)-specific CTL inhibit MOPC 315 cells in the presence of the double conjugate TNP-ABA-KLH, but not in the presence of soluble TNP-KLH or ABA-KLH. These results show that H-2-restricted, hapten-specific lymphocytes regulate the function of myeloma cells that bind the hapten only to specific surface receptors, and provide a model for associative recognition of surface H-2 determinants and receptor-bound antigen. The results are discussed with reference to the mechanisms of T lymphocyte-target cell interactions, and the possible physiologic role of hapten-reactive CTL in specifically regulating anti-hapten antibody responses.

Animals↗
PubMed1983

Hapten-reactive inducer T cells. I. Definition of two classes of hapten-specific inducer cells.

Hapten-reactive inducer T cell clones can be divided into two groups based on their activation specificity. The first and largest group is conjugate specific. These clones are activated only by hapten coupled to the same carrier protein used for in vitro selection. The second group, which is quite rare, is hapten specific. Clones of this type are activated by hapten coupled to all foreign and autologus proteins tested. Both types of clones corecognize soluble antigen in association with products of the I-A locus. The hapten-specific cells were used to analyze the molecular basis of I-A vs. I-E gene control. The physiologic significance of hapten- and carrier-specific inducer T cells in the response to foreign antigens and autoantigens is discussed.

Animals↗
PubMedDate not supplied

Reactivity of contact allergenic haptens to amino acid residues in a model carrier peptide, and characterization of formed peptide-hapten adducts.

The type of chemical reaction between hapten and carrier protein in the formation of a complete antigen in vivo giving rise to an allergic contact dermatitis (ACD, type IV allergy) is essentially unknown. About 4000 low-molecular organic compounds are known to have allergenic properties. alpha,beta-Unsaturated carbonyl structures are frequently present among these compounds. Haptens giving rise to antibody formation and type I allergy have been shown to add predominantly to lysine in the carrier protein. In this paper, the reactivity of activated type IV haptens to a model peptide is reported. Essentially all amino acids with nucleophilic properties were present in the model peptide. Investigation of the relative reactivities of the amino acid residues to activated haptens under biomimetic conditions is performed in order to determine the proportions between the adducts of the different amino acid moieties. In all cases, the electrophilic alpha,beta-unsaturated haptens were found to be added to the cysteine residue and no lysine adduct was recorded. Nuclear magnetic resonance (NMR) spectroscopy was used to exclude steric hindrance of any amino acid residue in the addition reaction. The hapten-modified peptides were isolated and characterized by NMR and mass spectrometry.

Amino Acids↗
PubMed1975

Modulation of the immune response by passive antibodies. I. Anti-hapten antibodies enhanced delayed hypersensitivity to the carrier and depressed antibody synthesis to the hapten.

The modulating effects of passive antibodies on both delayed hypersensitivity to the carrier and antibody synthesis to carrier and hapten determinants were studied in guinea pigs. Animals were injected with antibodies directed against either the carrier or the hapten prior to immunization with the hapten-carrier conjugate in Freund's complete adjuvant. Anti-hapten antibodies have been shown to have an enhancing effect on delayed hypersensitivity to the carrier and a suppressive effect on antibody synthesis to the hapten. In this experiment, anti-carrier anti-bodies seemed to have had no effect on delayed hypersensitivity to the carrier and on antibody synthesis to the hapten.

Animals↗
PubMed1976

Hapten concentrations in the circulation of animals actively immunized with hapten-protein conjugates.

Animals immunized with hapten-protein conjugates subsequently circulate high concentrations of hapten bound by antibody. The levels of hapten detected are capable of significantly reducing antibody titer in the sera immunized animals. In the case of steroid-protein conjugates, the main source of increased plasma steroid concentration is the immunizing conjugate, although a contribution from increased host secretion may also occur. The results for rabbits immunized with digoxin-BSA indicate that the appearance of circulating digoxin followed the appearance of circulating antibody to digoxin. Appearance of digoxin in circulation appears to coincide with the operation of the immune response and may be related to macrophage activity. Similar conclusions are drawn from results obtained for circulating morphine in the serum of a sheep immunized with morphine-BSA. Injected hapten-protein antigens are probably processed by macrophage to produce low molecular weight haptenic fragments which are maintained in circulation for prolonged periods in the form of antibody-hapten complexes.

Animals↗
PubMed1982

The specificity of in vivo tolerance to haptens in NZB and normal mice after exposure to hapten-modified syngeneic spleen cells.

We have evaluated hapten-specific hyporesponsiveness induced by in vivo administration of TNP-modified syngeneic spleen cells (TNP-SC). Pretreatment of non-autoimmune mice led to hyporesponsiveness to challenge with either TNP or the closely related hapten DNP coupled to Ficoll. There was also a significant reduction of the direct PFC response after challenge with TNP-HGG. In tolerized mice challenged with TNP-HGG, the IgM portion of the serum response was similarly suppressed; however, the total serum antibody as well as the indirect PFC response was not suppressed. There was no tolerance at all when the mice were challenged with DNP-HGG. Thus, exposure to TNP-SC results in an incomplete form of hapten-specific B cell tolerance. This tolerance is selective for the IgM isotype and does not extend to the cross-reactive hapten DNP on a thymic-dependent carrier, although it does extend to a DNP on a thymic-independent carrier. Autoimmune NZB mice were defective with regard to tolerance after injection of hapten-modified syngeneic spleen cells. They did manifest a reduced direct PFC response to the challenge with TNP-Ficoll, but failed to demonstrate cross-tolerance to DNP-Ficoll challenge. Moreover, they did not have suppression of the hapten-specific IgM response after challenge with TNP on the thymic-dependent carrier. These abnormalities in tolerance induction in NZB mice to modified self may help to explain the loss of self-tolerance that occurs spontaneously and is expressed as autoimmune disease.

Animals↗
PubMed1999

Fidelity in Hapten Design: How Analogous Are Phosphonate Haptens to the Transition States for Alkaline Hydrolyses of Aryl Esters?

Is antibody catalysis of hydrolysis reactions limited by imperfect mimicry of transition states by haptenic analogs? This question was explored by comparison of calculated transition states for the hydrolyses of aryl esters and the haptens intended to mimic them. The addition-elimination reaction of phenyl acetate and hydroxide ion in the gas phase was examined using ab initio calculations at the RHF/6-31+G(d)//RHF/6-31+G(d) and MP2/6-31+G(d)//RHF/6-31+G(d) levels of theory. Although transition states for both addition and elimination were located, the barrier to elimination disappeared when zero point energy or electron correlation was included. The reaction is therefore concerted, and the transition state for addition is the only relevant transition state in the gas phase. When aqueous solvation is considered through PCM and SCI-PCM calculations, the barrier to addition is shown to increase dramatically, and a stepwise addition-elimination pathway is predicted. A single transition state for the analogous reaction with p-nitrophenyl acetate was also located, and this reaction is predicted to be concerted in both the gas phase and in solution. The calculated geometries, CHELPG atomic charges, and electrostatic potential surfaces of stationary points involved in hydrolysis were compared with those of model phosphonate and phosphinate haptens. The haptens are better mimics of the two transition states and the tetrahedral intermediate than of the reactants or products-exactly the situation desired for catalyst generation-yet they are more analogous to the tetrahedral intermediate and the transition state for elimination than to the rate-determining addition transition state. In addition, the hydrogen-bonding pattern and asymmetry of the stationary points are not faithfully reproduced by the haptens. These considerations suggest that catalysis may be improved by hapten redesign or antibody mutagenesis.

Journal Article↗