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P Ivanyi

Publications and source records attributed to P Ivanyi.

At least 37 records · Page 2Linked to original sources
PubMed1992

Immunogenetic basis of the seronegative spondyloarthropathies.

This review discusses recent data relevant to better understanding the HLA-B27 association with seronegative spondyloarthropathies. Although much is known about the B27 molecule, its contribution to the pathogenesis of disease is unclear. It is still unknown whether the B27 molecule is involved directly, and whether this is due to the basic function of the molecule, ie, presentation of allele-specific antigenic peptides to the T-cell receptor. Experiments performed with B27 transgenic mice and rats strongly support the view that some unique or special property of the B27 molecule is involved in pathogenesis. However, the data are of a preliminary nature.

Amino Acid Sequence↗
PubMed1991

A subpopulation of mouse cytotoxic T lymphocytes recognizes allogeneic H-2 class I antigens in the context of other H-2 class I molecules.

Recently, independent lines of evidence strongly suggested that peptides derived from one foreign major histocompatibility complex (MHC) molecule bound to another MHC molecule can give rise to multiple composite MHC complexes that are able to stimulate allo-(xeno)-reactive T cells. In this study, we describe that in vivo immunization of mice with cells mismatched with the recipient for a single class I antigen results in the induction of CD8+ cytotoxic T lymphocytes (CTL) specific for allogeneic class I locus products (Dd, Kd, Dq) in the context of other class I molecules (Ks, Kd, Kk) present on stimulator cells. Evidently, the target antigen for these class I-restricted alloreactive CTL is not the native class I molecule but peptides derived from endogenous processing of allogeneic class I products presented by class I molecules. Using a combination of limiting dilution and split-well analyses, we estimated for Kk-restricted Dq-specific alloreactive CTL a precursor frequency (CTLpf) that was approximately 10 times lower than the CTLpf for "classical" nonrestricted Dq-specific alloreactive CTL. These data suggest that H-2 class I peptides presented by intact H-2 class I molecules are allostimulatory, supporting the concept that the capacity for presentation of MHC peptides by MHC molecules constitutes a part of the allogeneic immune response.

Animals↗
PubMed1991

Frequency analysis of HLA-specific cytotoxic T lymphocyte precursors in humans.

Frequencies of HLA class 1-specific cytotoxic T lymphocyte precursors (CTLp) from 33 responders were determined in 115 responder/stimulator combinations. In each combination there was a single HLA-A or HLA-B antigen mismatch. A wide range of CTLp frequency (CTLpf) values was found for most A and B locus antigens. Some A locus antigens appeared less immunogenic than other A locus antigens. The effect of additional C locus differences was negligible. The relationship between responder and stimulator HLA antigens is of minor importance because HLA-specific CTLpf against crossreactive (CREG) and subtype antigens were not significantly lower than CTLpf against non-CREG antigens. The CTLpf did not correlate with Bw4 or Bw6 mismatches. The existence of a broad range of values for HLA class I-specific CTLpf is of general interest. We have arbitrarily subdivided the CTLpf values into high, medium, low, and very low. In about 20% of the combinations the HLA-specific CTLpf were low or not even detectable in our assay. In contrast, HLA-specific CTLpf in combinations with multiple HLA antigen differences were regularly high. Our results confirm the high values of allospecific CTLpf in general but simultaneously point to unexpected variations. Frequency analysis of HLA-specific CTLp may be considered a new parameter in clinical transplantation for the selection of appropriate donor/recipient pairs.

Cross Reactions↗
PubMed1990

Specificity and frequency of primary anti-HLA cytotoxic T lymphocytes in normal and HLA-B27.2-, HLA-B27.5-, and HLA-Cw3-transgenic mice. A transgenic model for MHC xenoantigen recognition.

Previous studies have shown that the lymphocytes of naive mice produce a strong primary CTL responses in vitro to human MHC class I Ag presented by HLA-transgenic mouse (TGM) cells. A limiting dilution (LD) assay was used to analyze this xenoreactive CTL repertoire in mice. Frequencies of HLA class I-specific CTL precursors (CTLp) were estimated in naive normal and HLA-B27.2-, -B27.5- and HLA-Cw3-double TGM (i.e., mice expressing HLA and human beta 2-microglobulin (hu beta 2m]. The xenoreactive CTLp frequencies were compared to frequencies of CTLp to H-2 alloantigens estimated in naive normal mice. The results showed that the frequencies of HLA class I-specific CTLp are comparable with those of alloreactive CTLp. This overlap in CTLp frequencies suggests that HLA class I xenoantigens are recognized by primary mouse CTL as allelic variants of H-2K and H-2D. This was confirmed in split well analysis by the observation that the xenoreactive response was not restricted by self-MHC of the responding mouse. Thus, primary HLA class I-specific mouse CTL clones recognized their target Ag regardless of whether they were expressed on H-2-mismatched mouse cells or on human cells. The frequencies of HLA class I-specific CTLp in HLA-TGM were comparable to those in normal mice. We propose that MHC allo- and xenoreactive CTL responses are not caused by the activation of CTLp specific for self-MHC plus peptide but to the activation of CTLp recognizing MHC allo- and xenoantigens directly or as peptides presented by their native MHC molecules.

Animals↗
PubMed1990

Abnormal anti-viral immune response in mice is corrected in HLA-B27.2-transgenic mice.

In contrast to the strong Sendai virus-specific cytotoxic T-lymphocyte (CTL) responses in C57BL/6 mice. H-2Kb mutant bm1 mice are nonresponders to Sendai virus. By appropriate crossings between HLA-B27 double-transgenic mice and Kb mutant bm1 mice, and after subsequent selection, H-2bm1 homozygous mice were produced expressing the human HLA-B27.2 and beta 2-microglobulin genes. Here we show that the introduction of a human HLA class I gene into the genome of the H-2bm1 Sendai virus-nonresponder mutant mice resulted in good responsiveness to Sendai virus, and in normal levels of Sendai virus-specific CTL precursors. The CTL response in the HLA-B27.2 double-transgenic H-2bm1 mice against Sendai virus was restricted by the HLA-B27.2 molecule. These results show the direct involvement of HLA class I molecules in regulation of the anti-viral CTL repertoire and represent for the first time a correction of abnormal anti-viral immunity in mice by incorporation of a human MHC class I (HLA-B27.2) gene.

Animals↗
PubMed1990

Variations in the T-cell repertoire against HLA antigens in humans.

Allospecific anti-HLA class I antigen cytotoxic T-lymphocyte precursor frequencies (CTLpf) have been estimated in peripheral blood of healthy blood donors with responder stimulator combinations mismatched for one HLA-A,B antigen. The CTLpf ranged from 1 in 400 to 1 in 10,000, with most frequent values of 1 in 600 to 4000. The following observations were made: (1) CTLpf against the same HLA antigen vary among different responders; (2) CTLpf of one responder against various HLA antigens may be different; (3) "narrow" responders produce cytotoxic T lymphocytes that recognize only the private (stimulator) alloantigen, while "broad" responders produce mainly broadly cross-reactive cytotoxic T lymphocytes with public specificity. Split-well analysis shows that very few cytotoxic T lymphocytes of "broad" responders recognize the private alloantigen only. These individual variations are not dependent on the HLA phenotype, because they also occurred in unrelated HLA-identical responders stimulated against the same mismatched stimulator cells.

Cytotoxicity Tests, Immunologic↗
PubMed1990

Effect of a Tyr-to-His point-mutation at position 59 in the alpha-1 helix of the HLA-B27 class-I molecule on allospecific and virus-specific cytotoxic T-lymphocyte recognition.

HLA-B2703, a mutation of HLA-B2705, is characterized by a Tyr-to-His substitution at position 59 in the alpha 1 domain of the class-I heavy chain. So far, the HLA-B2703 subtype was found only in two Black individuals and it is the first polymorphism at position 59 of MHC class-I molecules. We have examined whether the single amino-acid substitution at position 59 results in an alloantigenic determinant and HLA-restriction element, and whether HLA-B2703 functionally differs from HLA-B2705. In vitro, HLA-B2703-positive lymphocytes were not stimulated by HLA-B2705-positive cells. Nevertheless, HLA-B2703 was recognized as an alloantigen. HLA-B2702-anti-HLA-B2705 CTL lysed HLA-B2703-positive cells less efficiently than HLA-B2705-positive cells. In addition, anti-HLA-B27 antibodies were found that lysed HLA-B2705 but not HLA-B2703 positive cells. Also, CTL clones have been described that can distinguish HLA-B2703 from HLA-B2705 (1). However, the HLA-B2703 subtype did not function as a private virus restriction element. HLA-B2705-restricted influenza virus-specific CTL also recognized HLA-B2703-positive virus-infected cells, and vice versa. Thus, the HLA-B2703 mutation represents an example of a class-I antigen without specific significance for the recognition of viral peptides.

Animals↗
PubMed1990

Dysfunction of HLA-B27.

Every HLA antigen, as defined by the WHO-HLA Nomenclature, is unique. The major function of these molecules is to present antigen-peptides to the T-cell receptor, thereby contributing to the immunological defence mechanism. This function is regulated for each MHC antigen by its unique structure, with the peptide-binding pockets of the three-dimensional groove of the corresponding molecules playing the critical role. However, HLA-B27 is special by virtue of its disease association(s). Various aspects which might provide an explanation for--or at least a clue to an understanding of the specific role of--B27 in its disease associations are reviewed. Since it appears that there are no published experimental data which would support either of the alternative hypothetical possibilities, the bulk of current theories must therefore be purely speculative. The only lead to a better understanding of the function of B27 in disease associations is the postinfectious reactive arthritis. If it is the B27 molecule itself which is involved, further in vivo work on B27 transgenic animals might help solve this problem with its numerous unknown factors.

Animals↗
PubMed1990

HLA class-I-transgenic mice as model system to study MHC-restricted antigen recognition in man.

In order to develop a possible animal model to study HLA linked diseases of man, we established HLA-B27 transgenic mice (TGM). As aberrant and overexpression of MHC molecules can be toxic for cells, we aimed at obtaining a physiological expression of the human antigen and used a genomic 25kb Sal I fragment for embryo injection, coding for the HLA-B* 2705 heavy chain. Five independent founder mice were obtained containing varying copies of the fragment (1 to 10). RNA analysis from different tissues showed an expression pattern similar to endogenous H-2 class I genes. HLA-B27 antigen could be detected on lymphocytes derived from all five founder mice, even in the absence of human beta 2-microglobulin (hu beta 2m). It was found that the presence of hu beta 2m strongly enhances HLA-B27 cell surface expression in mice with few copies of the transgene, but was not necessary for efficient and high cell surface presentation in the 10 copy line. In all HLA-B27 TGM lines, the HLA molecule functions as restriction element in anti-viral responses. In addition, we could show that T lymphocytes of the transgenic animals respond to the same HLA-B27 restricted influenza peptide as is recognized by human influenza-specific, HLA-B27 restricted cytotoxic T cell lines.

Animals↗
PubMed1989

Immunization with syngeneic Sendai virus-infected cells induce no MHC-restricted antibodies but antibodies specific for H-2 class I determinants.

To find out whether immunoglobulins are able to recognize foreign antigens in the context of syngeneic MHC determinants, an effort was made to trigger the production of MHC-restricted antibodies by syngeneic Sendai virus (SV)-infected cells using the spleen-fragment culture technique. Antibodies were found that mimicked MHC-restricted antibodies by recognizing MHC+SV better than MHC alone. However, the binding was not specific for SV and also occurred on mitogen-stimulated (SV-) or influenza virus-infected cells. We describe the production of H-2 class I-specific lymphocytotoxic antibodies by primary B cells responding to syngeneic SV-infected cells. No viral-specific, H-2-restricted antibodies were found.

Animals↗
PubMed1989

Blood lymphocytes from ankylosing spondylitis patients fail to induce disease-specific cytotoxic T lymphocytes.

The intriguing observation made by Geczy et al. (1) showing the possibility of generating specific ankylosing spondylitis--cytotoxic T lymphocytes by presenting HLA-B27+AS+ cells as antigen-specific stimulator cells prompted us (by using Geczy's approach) to identify cytotoxic T lymphocytes specific for this apparent B27+AS+ target structure. Peripheral blood mononuclear cells (PBMC) of 21 healthy B27+ individuals were stimulated in primary and in short-term cultures with PBMC of an HLA-identical sibling suffering from definite AS (n = 12). In addition, PBMC in vitro modified by "Geczy bacterial products" from two healthy B27+ individuals were used to stimulate B27+ AS- lymphocytes (either autologous or from a healthy HLA-identical sibling). Effector cells raised in primary AS- versus AS+ and AS- versus "modified B27" mixed lymphocyte culture combinations showed no proliferative nor cytotoxic activity at all. The scarcely observed cytotoxic reactivity of restimulated mixed lymphocyte culture was not restricted to AS+B27+ cells. These results demonstrate that PBMC from ankylosing spondylitis patients fail to induce disease-specific cytotoxic T lymphocytes and suggest that an ankylosing spondylitis--related "modified B27" structure does not exist, at least in the patient material tested.

Cells, Cultured↗
PubMed1989

Recognition of xeno-(HLA, SLA) major histocompatibility complex antigens by mouse cytotoxic T cells is not H-2 restricted: a study with transgenic mice.

Cytotoxic T lymphocytes (CTLs) recognize antigens in the context of major histocompatibility complex (MHC) class I gene products. The T-cell receptor (TCR) that mediates this MHC-restricted antigen recognition recognizes short peptide fragments rather than the intact antigen. Presentation of peptides to the TCR may thus be a major function of the MHC. An intriguing question emerging from this model is whether peptide presentation also applies to foreign MHC antigens and which of the available MHC molecules can present preferentially the peptides of the foreign MHC molecule. Allo- and xenoreactive CTLs might either recognize native MHC class I molecules or peptides presented by self MHC or by the foreign class I MHC itself. The finding that synthetic peptides corresponding to MHC class I regions are recognized by allo- and xenoreactive CTLs suggests that recognition of foreign MHC by CTLs might involve degraded fragments presented by syngeneic class I molecules. We used MHC transgenic mice as a tool to study these questions. The CTL responses against human (HLA) antigen B27 were analyzed by using HLA-B27 transgenic mice with various H-2 haplotypes. We report here that mouse xeno-MHC-specific (anti-B27) CTLs are perfectly able to kill human and mouse cells expressing the appropriate xenoantigen and that in primary and secondary responses to xeno-MHC, the mouse T-cell repertoire does not use self-H-2 as a restriction element. Absence of H-2 restriction was confirmed by the lack (less than 1/10(6] of H-2-restricted HLA-specific CTL precursors. Therefore, H-2-restricted recognition of xeno-MHC antigens cannot be generalized as part of a classical MHC class I-specific response. These results indicate that xenoreactive CTLs usually recognize intact MHC molecules or MHC peptides preferentially presented by their native MHC molecule. We suggest the latter possibility.

Animals↗
PubMed1989

HLA expression and function in single and double HLA-B27-transgenic mice.

The expression and function of HLA antigens in mice single transgenic for HLA-B27.2 (sTGM-B27.2) or double transgenic (dTGM) for HLA-B27.2 and human beta 2-microglobulin (h beta 2m) were compared. B27.2 could be well detected on the cell membrane of lymphocytes of sTGM. However, the expression in sTGM was much lower than in dTGM mice. Nevertheless, also in sTGM mice, the B27-transgene product possessed all functional properties of a class I HLA molecule. This was shown by the recognition and induction of antibodies and cytotoxic T cells, by the induction of "allo"-immunity, including skin graft rejection, and by the ability to present viral antigens. In dTGM, the expression of B27 on peripheral blood lymphocytes, spleen and lymphnode cells was comparable to H-2. However, on thymocytes, a relatively lower expression of HLA than H-2 was observed. This low expression of B27 on thymocytes is in concert with the observation that B27 is expressed only in the medulla of the thymus and not detectable in the cortex.

Animals↗
PubMed1989

Specificity of anti-H-2 class I antibodies induced by syngeneic immunization with Sendai virus-treated cells is regulated by the mouse MHC and viral antigens. No evidence for MHC-restricted virus-specific antibodies.

In a previous study, we searched for Sendai virus (SV)-specific antibodies that were restricted in their binding by self-major histocompatability complex (MHC) antigens. In C57BL/6 (B6; H-2b) mice, most of the sera obtained after i.p. injections with syngeneic SV-coated (SV+) spleen cells contained auto- and alloreactive lymphocytotoxic antibodies directed against H-2 class I molecules, but no viral-specific, MHC-restricted antibodies. Here we report that syngeneic immunization with SV+ cells regularly induced H-2-specific antibodies in various mouse strains. From a total of 12 strains tested, only the B10.S (H-2s) strain appeared to be a low responder. The immune responses are of two types: (i) mice of some strains produce autoreactive antibodies and a broad variety of alloreactive antibodies; and (ii) mice of some strains produce only narrow or widely alloreactive antibodies. Because most of the strains differ only in the H-2 region, the patterns observed are regulated by the MHC. To locate the genes involved in the induction of H-2-specific antibodies more precisely, two B6 mutant strains, bm1 (Kb mutant) and bm13 (Db mutant), were immunized with syngeneic SV+ cells. The results suggest that the H-2Db region plays an important role in the induction and specificity of the lymphocytotoxic H-2 class I-specific antibodies present in sera of H-2b mice after syngeneic immunization with SV+ cells. The role of SV in the induction of H-2-specific antibodies was studied in B6 mice after injections of syngeneic cells coated with liposomes bearing the F and HN proteins of SV. The results suggest that SV surface glycoproteins as well as internal proteins are directly involved in regulating the specificity of anti-H-2 antibodies present in sera after syngeneic immunization with SV+ cells. This study does not support the concept that antigen-specific, MHC-restricted antibodies are a part of the B-cell repertoire.

Alleles↗
PubMed1988

Differential recognition by human cytotoxic T cell clones of human M1 fibroblasts transfected with an HLA-B7 gene (JY150) suggests the existence of two different HLA-B7 alleles in the cell line JY (HLA-A2,2;B7,7;Cw-,-;DR4,w6).

We have used a panel of human HLA-B7-specific CTL clones to identify an HLA-B7 gene (JY150) transfected into human M1 fibroblasts (M1/B7). Only a subset of the CTL clones recognized the M1/B7 cells, whereas all CTL clones recognized the donor of the B7 gene, the cell line JY (HLA-A2,2;B7,7;Cw-,-;DR4,w6). Analysis of the fine specificity of these CTL clones was performed by testing the reactivity on M1 cells transfected with an HLA-B27K gene and on a panel of cell lines typed for HLA-B7 subtypes (variants). These results, combined with one-dimensional IEF analysis of the M1/B7 cells and the B7 subtypes, indicated that the differential recognition by the CTL clones of the transfected gene was not caused by aberrant expression of the gene itself or due to the absence of critical accessory molecules on the M1 fibroblast cells. Our data suggest that the widely used HLA-B7 reference cell line JY is not homozygous at the HLA-B locus, but contains two different B7 alleles encoding the B7.2 and B7.4 subtypes.

Alleles↗
PubMed1988

H-2-dependent binding of xenogeneic beta 2-microglobulin from culture media.

Sera of C57BL/6 mice contained lymphocytotoxic antibodies after injections with syngeneic lymphoblasts. The antibodies were directed against bovine beta 2-microglobulin, a component of the culture medium, and mimicked H-2-specific antibodies by a preferential recognition of target cells expressing certain H-2 Ag. This "polymorphic" reactivity pattern was due to a variable capacity of H-2 molecules associated with bovine beta 2-microglobulin.

Animals↗