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Biomedical subjects

Z A Nagy

Publications and source records attributed to Z A Nagy.

At least 37 records · Page 2Linked to original sources
PubMed1991

Graft-versus-host resistance induced by class II major histocompatibility complex-specific T cell clones.

Possible mechanisms of graft-vs.-host (GVH) resistance have been studied using a panel of seven class II major histocompatibility complex-specific T cell clones for elicitation and challenge. One clone recognized I-Ak,d,f, and expressed V beta 8.3 together with J beta 1.5. The remaining six clones were I-Ek specific and expressed V beta 15 rearranged to J beta 1.1 or J beta 1.3. The I-Ek-specific clones were also homologous to each other and different from the I-A-reactive one in the D and N regions. Four of the seven clones exhibited I-Ek-specific cytolytic activity. Each clone, when injected in sublethal numbers into appropriate recipients, could induce resistance to a subsequent lethal dose of any other clone in the panel. The resistance did not require sharing of either T cell receptor beta chains or antigen specificity, or MHC molecules by the eliciting and challenging clone. Cytolytic and noncytolytic clones were equally efficient in inducing GVH resistance. A prerequisite of resistance induction was the activation of eliciting clone subsequent to recognition of class II molecules in the host. Clones preactivated with high concentrations of recombinant interleukin 2, in vitro, could induce GVH resistance also in syngeneic hosts, suggesting that resistance induction was associated with the activated state of clone, rather than antigen recognition per se. In all instances of resistance, the challenging clones failed to induce vascular leakage, which was the cause of death in susceptible recipients (Lehmann, P. V., G. Schumm, D. Moon, U. Hurtenbach, F. Falcioni, S. Muller, and Z. A. Nagy. 1990. J. Exp. Med. 171:1485). Lipopolysaccharide (LPS) induced resistance to vascular leakage did not provide crossresistance to GVH and vice versa, suggesting that interleukin 1 alpha and tumor necrosis factor alpha implicated in LPS resistance are not involved in GVH resistance. Although the mechanism remains unclear, the most likely explanation for GVH resistance in this system is either the downregulation of permeability increasing effect in the challenging clone, or an induced refractoriness of blood vessels to this effect.

Amino Acid Sequence↗
PubMed1990

Selective in vivo inhibition of T cell activation by class II MHC-binding peptides administered in soluble form.

A synthetic peptide corresponding to residues 53-61 of hen egg white lysozyme, as well as its N-succinyl C-amide, inhibit in vivo priming for T cell responses when administered in soluble form, in osmotic minipumps implanted s.c., 1 day before immunization. The inhibition exhibits MHC selectivity that corresponds to the binding specificity of these peptides for class II MHC molecules in vitro. Approximately fourfold higher doses of soluble competitor are required than of competitor in CFA-depot, in order to achieve comparable levels of inhibition. The inhibition of priming to a nonimmunodominant T cell determinant requires lower doses of soluble competitor than the suppression of priming to a dominant T cell determinant. The soluble competitors do not appear to induce class II MHC-restricted T cell response against themselves.

Animals↗
PubMed1990

Induction of graft versus host-associated immunodeficiency by CD4+ T cell clones.

Previous studies have shown that the injection of parental T cells into MHC class II mismatched F1 recipient mice can lead to graft-vs-host (GvH) reaction that manifests itself by multiple symptoms. The objective of our study was to analyze GvH reactivity induced by a single T cell clone specific for host I-A or I-E alloantigen. The T cell clones tested for GvH potential were CD4+, with or without cytolytic activity in vitro and with a lymphokine pattern that classifies them as Th1 cells. The inoculation of a single T cell clone induced a severe, but transient immunodeficiency in the host that was independent of its cytolytic activity, as demonstrated by the failure to generate a CTL response to third party allogeneic cells in vitro. Induction of immunodeficiency in the recipients required preactivation of the clones in vitro by rIl-2 and the presence of the stimulator class II alloantigen in the host. Spleen cells from these mice lacked suppressor cells, they were deficient in Il-2 secretion and exhibited a decrease in the number of CD4+ T cells. In addition, I-E expression was reduced, however, without any changes in the macrophage population and an increase in surface Ig and the B cell marker B220. Simultaneous to the immunodeficiency, the clone-injected mice produced elevated antibody titers to ssDNA.

Animals↗
PubMed1990

Acute lethal graft-versus-host reaction induced by major histocompatibility complex class II-reactive T helper cell clones.

T cell clones isolated from class II MHC-disparate MLR combinations, and specific for I-Ak and I-Ek molecules, respectively, are shown to induce acute lethal graft-vs-host disease in unirradiated recipients. Cytolytic and noncytolytic clones are equally efficient in this respect. The lethal disease is dependent on recognition of the stimulatory class II molecules in the host. The clones home to lungs and liver, and become activated in these organs as demonstrated by an in vivo thymidine incorporation assay. After activation, a severe vascular leak syndrome develops causing death of the recipients within 5 d after the injection of 5 x 10(6) to 10(7) cloned cells. The disease develops without the participation of secondary host-derived inflammatory mechanisms, such as mast cell degranulation, complement activation, and the release of prostaglandins, oxygen radicals, or proteolytic enzymes. The results raise the possibility that Th cells can directly influence vascular permeability, and control, thereby, the acute inflammatory reaction of blood vessels.

Alleles↗
PubMed1990

Flexibility of the T cell repertoire. Self tolerance causes a shift of T cell receptor gene usage in response to insulin.

Bovine insulin(BI)-specific I-Ab-restricted T cell clones have been characterized for fine specificity and TCR gene usage. We have demonstrated that mouse strains carrying H-2b on three different genetic backgrounds (C57BL, BALB, and 129) rearrange and express the V beta 6 gene in a large proportion (36%) of insulin-specific clones. In these strains, the non-MHC background did not seem to influence TCR gene usage in response to BI. The V beta 6+ clones appeared to be selected by the antigen. In contrast, no V beta 6+ clones could be isolated from (B6 x DBA/2)F1 mice, where V beta 6+ (and V beta 8.1+) T cells are deleted by self tolerance to Mls-1a. Thus, although a small proportion of residual V beta 6+ cells had been demonstrated in Mls-1a mice, these cells could not be retrieved in a response that uses V beta 6 predominantly. In functional terms, therefore, the deletion of V beta 6 by self tolerance appears to be complete. Instead of V beta 6, the majority (up to 60%) of I-Ab- as well as I-Ad-restricted insulin-specific clones from the (B6 x DBA/2)F1 mice expressed V beta 8.2 and V beta 8.3. This shift of gene usage was not accompanied by any detectable change in the fine specificity pattern of response. Thus, in the insulin-specific response, the flexibility of T cell repertoire fully compensates for deletions caused by self tolerance.

Animals↗
PubMed1990

Peptide competition for antigen presentation.

Since each major histocompatibility complex (MHC) molecule can bind many different peptides, it might be predicted that competition for the same MHC-binding site takes place between peptides with unrelated sequences. As Luciano Adorini and Zoltan Nagy report here, this does indeed occur, both in vitro and in vivo. In-vivo competition between peptides for antigen presentation to T lymphocytes is an important influence on the immunodominance of T-cell determinants. In addition, it is possible to modulate T-cell activation by interfering with the binding of antigenic peptides to MHC class II molecules. This could represent a suitable approach to a rational treatment of autoimmune diseases and, possibly, of allograft rejection.

Animals↗
PubMed1989

Competition for antigen presentation in living cells involves exchange of peptides bound by class II MHC molecules.

T cells recognize foreign proteins as peptides bound to self molecules encoded by the major histocompatibility complex (MHC). The kinetics of interaction between purified class II MHC molecules and peptides is unusual, in that the rate of association is very slow, but once formed, the complexes are extremely stable. This raises the question of how the antigen-presenting cell provides a sufficient number of free MHC binding sites to ensure T cell immunity. We present results suggesting that an exchange of peptide in MHC binding sites may take place under physiological conditions.

Ammonium Chloride↗
PubMed1989

Structural requirements for the interaction between peptide antigens and I-Ed molecules.

We have analyzed the structural characteristics of the interaction between I-Ed molecules and their peptide ligands. It was found that unrelated good I-Ed binders share structurally similar "core" regions that were experimentally demonstrated to be crucial for binding to I-Ed molecules. Single amino acid substitution analogues of one good I-Ed binder, hen egg lysozyme 107-116, were analyzed for their capacity to bind to I-Ed molecules and to activate two different I-Ed-restricted T cell hybridomas. The results illustrate the great permissiveness of I-Ed-peptide interaction and the great specificity of T cell recognition. It was concluded from these analyses that basic residues on the peptide molecule play a crucial role in binding to I-Ed. This contrasts with the structural requirements for binding to the other Iad isotype, I-Ad, the crucial hydrophobic residues. Thus, different class II molecules of the same MHC haplotype may have rather distinct peptide binding specificities, thereby expanding the repertoire of possible immunogenic peptides presented for T cell recognition.

Amino Acid Sequence↗
PubMed1989

Inhibition of T cell response with peptides is influenced by both peptide-binding specificity of major histocompatibility complex molecules and susceptibility of T cells to blocking.

Synthetic peptides corresponding to sequences 46-62 and 51-62 of mouse lysozyme and 46-61 of hen egg-white lysozyme (HEL) were used as competitors in a variety of T cell responses. The competitors, according to their binding specificity for major histocompatibility complex (MHC) were expected to inhibit T cell responses restricted to I-Ak, but not those restricted to I-Ad, I-Ek molecules. In competition experiments with T cell hybridomas, the poor binder I-Ed molecule required 10- to 15-fold higher competitor concentrations than the good binder I-Ak molecule to achieve 50% inhibition of antigen presentation. Similarly, the nonresponder state of H-2d mice to HEL peptide 46-61 could be overcome by increasing the immunizing dose, and proliferative T cell responses to different antigens in association with a variety of class II MHC molecules could be blocked by the mouse lysozyme and HEL peptides. Thus, the capability of some and failure of other MHC molecules to bind certain peptides appeared quantitative, rather than of an all or none nature, in these experimental systems. The susceptibility of uncloned T cell lines to peptide competitors was found to decrease with time. Lines maintained by repeated restimulation with antigen and APC, but without exogenous interleukin 2, acquired resistance within weeks. In contrast, T cell clones retained their susceptibility to peptide competitors over a long period of time. The latter data raise the possibility that a competition between ubiquitous (self) peptides and foreign antigen may result in the selection of T cells that have high avidity for the activating antigen-MHC complex, and are thus relatively resistant to competition at the level of antigen presentation.

Amino Acid Sequence↗
PubMed1989

Why peptides? Their possible role in the evolution of MHC-restricted T-cell recognition.

The peptide-presenting function of major histocompatibility complex (MHC) molecules permits pathogenic microorganisms to evade the host's immune system in two different ways: first, by escape of pathogen-derived antigenic peptides from presentation, and second, by molecular mimicry, that is resemblance between MHC-bound self and foreign peptides. These two mechanisms could have served as selective pressures in the evolution of the MHC. In this article, Zoltan Nagy and colleagues propose that escape from presentation selects for one or a few MHC molecules with the capacity to bind a broad range of different peptides. In contrast, molecular mimicry is considered to be the driving force for MHC diversification, that is it increases the number (polymorphism) and selectivity of peptide-binding sites.

Animals↗
PubMed1988

Mechanisms influencing the immunodominance of T cell determinants.

The preferential recognition of certain amino acid sequences from foreign protein antigens by T cells is referred to as T cell epitope immunodominance. To determine the mechanisms underlying this phenomenon, we have studied the correlation between the interaction of a series of synthetic peptides encompassing the entire hen egg-white lysozyme (HEL) sequence with class II molecules of the H-2k haplotype, and T cell responsiveness to these peptides. After HEL priming, three immunodominant T cell epitopes were found: two, included in the HEL sequences 51-61 and 112-129, were recognized in association with I-Ak molecules, and one, included in sequence 1-18, in association with I-Ek molecules. Accordingly, these peptides bound to the appropriate class II molecule, as demonstrated by competition for antigen presentation. Several other HEL peptides, although capable of associating with class II molecules, were not immunodominant. The absence of immunodominance has been shown to arise by three different mechanisms: (a) competition by an immunodominant peptide for presentation in vivo, (b) failure to generate the peptide during antigen processing, and (c) an inherently poor capacity of the T cell repertoire to respond to a particular peptide-MHC complex.

Animals↗
PubMed1988

In vivo competition between self peptides and foreign antigens in T-cell activation.

Cytotoxic and helper T lymphocytes recognize foreign antigen in the form of short peptides associated with class I and class II major histocompatibility complex (MHC) molecules, respectively. A recent study of the three-dimensional structure of a class I MHC molecule revealed a cleft formed by the amino-terminal half of the protein, which could serve as the binding site for these peptides. Because an individual possesses only a limited set of different MHC molecules, each molecule of this set must have the ability to bind a large number of different peptides in order to ensure full immunocompetence. Thus, it can be anticipated that peptides with unrelated sequences compete for binding to the same MHC molecule, and, indeed, this has been shown to occur in vitro. We therefore decided to see whether such competition could also regulate the cell responses in vivo. We have found that a synthetic peptide corresponding to residues 46-62 of mouse lysozyme, although not immunogenic itself, effectively inhibits the priming for T-cell responses when injected into mice together with foreign protein or peptide antigens. The inhibition observed strictly correlates with the capacity of the competitor to bind to the particular MHC molecule presenting the foreign antigen, and its extent depends on the molar ratio between antigen and competitor.

Animals↗
PubMed1988

Interaction of an immunodominant epitope with Ia molecules in T-cell activation.

The amino acid sequence corresponding to residues 107-116 of hen egg-white lysozyme (HEL) has been identified as containing an immunodominant T-cell epitope recognized in association with the I-Ed molecule. The immunodominance of this epitope in HEL-primed H-2d mice was demonstrated by analysis of the T-cell proliferative response induced by synthetic peptides covering almost the entire HEL sequence. All the T-cell hybridomas from H-2d mice analyzed recognize the HEL sequence 107-116 in association with the I-Ed molecule. Correlating with the restriction of T-cell recognition, HEL-(105-120)-peptide binds to I-Ed but not to I-Ad molecules. Conservative or semiconservative substitutions at positions 113 (Asn----Lys), 114 (Arg----His), or 115 (Cys----Ala) abrogate the ability of HEL-(105-120) to activate T cells. Substitutions at residues 113 and 115 affect T-cell recognition but not the binding to I-Ed molecules, whereas, as shown by binding data and competition experiments, an Arg----His substitution at position 114 profoundly impairs the capacity of the peptide to interact with I-Ed molecules. In agreement with these results, [Lys113]HEL-(105-120)-peptide but not [His114]HEL-(105-120)-peptide was found to be immunogenic in H-2d mice. Thus, a single semiconservative substitution drastically reduces binding capacity and abolishes immunogenicity, suggesting that a strict correlation exists between binding of a peptide to Ia molecules and its immunogenicity.

Amino Acid Sequence↗
PubMed1988

Lack of influence of cyclosporine on antigen presentation to lysozyme-specific T cell hybridomas.

Cyclosporine (CsA) was tested for its ability to inhibit antigen presentation by spleen cells or the B lymphoma line A20 to T cell hybridomas specific for hen egg-white lysozyme (HEL). Antigen-presenting cells (APC) were treated with CsA or nonimmunosuppressive derivatives thereof during or prior to encounter with antigen. The APC were then washed extensively and incubated in CsA-free medium for 6 hr before the T hybridoma cells were added. Under these conditions, CsA had no effect on antigen presentation up to the cytostatic regimen (1 microgram/ml). Omission of the 6-hr interval between CsA treatment of APC and the addition of T hybridoma resulted in inhibition of interleukin 2 production, although the CsA concentrations required were 10-75-fold higher than the ones inhibiting T cells directly (IC50: 100-150 ng/ml vs. 2-10 ng/ml). The responses to both HEL and a synthetic peptide of HEL sequence 105-120 were inhibited, indicating that the step influenced by the drug was not antigen-processing. The nonimmunosuppressive derivatives remained ineffective under these conditions. The results illustrate that the carryover of CsA from APC to T cells can mimic a drug effect on antigen presentation. Therefore, the demonstration of a CsA effect on antigen presentation can only be considered as conclusive when the readout of APC function is not a T cell response.

Animals↗
PubMed1986

Two adjacent epitopes on a synthetic dodecapeptide induce lactate dehydrogenase B-specific helper and suppressor T cells.

The outcome of an immune response to the enzyme lactate dehydrogenase B (LDH-B) is determined by the interplay between two types of regulatory T lymphocytes, T helper (Th) and T suppressor (Ts) cells. Most mouse strains are capable of generating Th but not Ts cells, and are therefore high responders to LDH-B in terms of both antibody production and antigen-specific T-cell proliferation. However, in strains expressing the b or k allele at the E beta locus of the major histocompatibility complex (Mhc), Ts cells are induced that partly or totally abrogate the proliferative response of Th cells to LDH-B. As a result, these strains are phenotypically medium (E beta b expressors) or low (E beta k expressors) responders. Because the suppression in the LDH-B system is antigen-specific (i.e. it only affects LDH-B-specific Th cells), it is conceivable that the Th and Ts cells use the antigen itself to communicate with each other. To investigate this possibility, we set out to determine which epitopes of the LDH-B molecule are recognized by Th and Ts cells. On the basis of previous studies, a loop structure extending from residue 211 to residue 224 of pig LDH-B appeared to be preferentially recognized by most Th-type (class II Mhc-restricted, proliferating) clones. By using a synthetic peptide, we demonstrate here that both Th and Ts cells are induced by the 211-222 stretch of LDH-B sequence. The use of two further dodecapeptides, each with a single amino-acid substitution in comparison with the pig 211-222 sequence, has revealed that Th and Ts cells have different fine specificities. Thus the loop appears to have two closely linked, if not overlapping, epitopes, one recognized by Th and the other by Ts cells. This finding is consistent with two possible mechanisms of suppression, namely bridging of Th and Ts cells by antigen and subsequent transmission of a suppressive signal, and competition for antigen between Th and Ts cells.

Animals↗
PubMed1986

Antigen presentation by liposomes: inhibition with antibodies.

The involvement of both antigen and class II major histocompatibility complex (MHC) molecules in T cell activation by liposome-bound antigens was investigated. We used a pigeon cytochrome c (PCC)-specific Ek-restricted T cell hybridoma that can be activated to produce interleukin 2 by liposomes carrying either PCC and Ek molecules, or a high concentration of PCC alone. We demonstrated that the MHC-restricted response of this hybridoma to liposomes is specifically blocked by both anti-MHC and anti-PCC monoclonal antibodies, whereas unrestricted activation is only inhibited by PCC-specific antibody.

Animals↗
PubMed1986

Complementation of class II A alleles in the immune response to (GluLysTyr) polymers.

The proliferative T cell responses to poly(GluLysTyr) (GLT) and poly(GLULysPhe) (GLPhe) are restricted by the E alpha E beta class II MHC molecule (E) in most responded strains. Some nonresponder strains that carry responder E beta, but cannot express cell surface E molecules, can complement with other nonresponder strains that provide the missing E alpha chain needed for the expression of E molecules and for responsiveness to GLT and GLPhe. Here another type of complementation is described between two E-nonexpressor haplotypes, H-2f and H-2s, which result in E-nonexpressor F1 hybrids, which are responders to GLT. The restriction element involved in this response is an Af/As hybrid molecule. The data support the hypothesis that conformational determinants resulting from the free association of alpha and beta chains in heterozygotes can increase the immune potential of the individual.

Animals↗