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Biomedical subjects

L Adorini

Publications and source records attributed to L Adorini.

At least 127 records · Page 7Linked to original sources
PubMed1990

Co-dominant restriction by a mixed-haplotype I-A molecule (alpha k beta b) for the lysozyme peptide 52-61 in H-2k x H-2b F1 mice.

Helper (CD4+) T lymphocytes recognize protein Ag as peptides associated to MHC class II molecules. The polymorphism of class II alpha- and beta-chains has a major influence on the nature of the peptides presented to CD4+ T lymphocytes. For instance, T cell responses in H-2k and H-2b mice are directed at different epitopes of the hen egg lysozyme (HEL) molecule. The current studies were undertaken with the aim of defining the role of mixed haplotype I-A (alpha k beta b and alpha b beta k) molecules in T cell responses to HEL in (H-2k x H-2b)F1 mice, as well as the nature of the immunogenic peptides of HEL recognized in the context of I-A alpha k beta b and I-A alpha b beta k. A series of HEL-reactive T cell lines and hybridomas derived from MHC class II heterozygous (C57BL/6 x C3H F1) mice were established. Their responsiveness to HEL and synthetic HEL peptides was analyzed with the use of L cells transfected with either I-A alpha k beta b or I-A alpha b beta k as APC. Out of 28 clonal T cell hybridomas tested, 13 (46%) only responded to HEL presented by I-A alpha k beta b, 11 (40%) by I-A alpha b beta k (and to a minor extent I-A alpha k beta k), only 4 (14%) were primarily restricted by I-Ak, and none by I-Ab. All the I-A alpha k beta b-restricted T cell hybridomas responded to the HEL peptide 46-61 and to its shorter fragment 52-61, even at concentrations as low as 0.3 nM. As this determinant has been previously defined as immunodominant for I-Ak but not for I-Ab mice, these results suggest a role for the I-A alpha k chain in the selection and immunodominance of HEL 52-61 in H-2k mice. The fine specificity of I-A alpha k beta b-restricted T cell hybridomas for a series of different HEL peptides around the sequence 52 to 61 suggests that peptide 52-61 binds to I-A alpha k beta b with higher affinity than to I-A alpha k beta k. The peptides recognized in the context of I-A alpha b beta k and I-A alpha k beta k were not identified.

Animals↗
PubMed1990

Structural requirements for the interaction between class II MHC molecules and peptide antigens.

Previous work from our and other laboratories indicates that T cells recognize a complex between the MHC restriction element and peptide antigen fragments. This paper reviews the structural characteristics of the formation of such a complex. By analyzing in detail the interactions between purified IA(d) and IE(d) molecules and their peptide ligands, we found that some structural characteristics apply to both antigen-MHC interactions. In particular, we found: 1) each MHC molecule is capable of binding many unrelated peptides through the same peptide-binding site; 2) despite this permissiveness of binding, it is possible to define certain structural features of peptides that are associated with the capacity to bind to a particular MHC specificity (IA(d) or IE(d)); 3) IA(d) and IE(d) molecules recognize different and independent structures on the antigen molecule; 4) only about 10% of the single amino acid substitutions tested on two IA(d)- and IE(d)-binding peptides had significant effect on their MHC-binding capacities, while over 80% of these substitutions significantly impaired T cell recognition of the Ia-peptide complex; 5) based on the segregation between residues that are crucial for T cell activation and Ia binding, the easiest model for the antigen-Ia-T-cell-receptor complex pictures the antigen molecule sandwiched in a planar conformation between the MHC and the T cell.

Amino Acid Sequence↗
PubMed1990

Antigen presentation and self-nonself discrimination.

Self-nonself discrimination is primarily carried out by T cells. Since the ligand recognized by T cells is a complex formed by antigenic peptides bound to MHC molecules, positive and negative selection of T lymphocytes must be based on the recognition of complexes formed by self-peptides bound to MHC molecules. This requires that self-antigens are continuously processed, bound by MHC molecules, and presented to T cells under conditions inducing both positive selection of T cells potentially able to recognize foreign antigens and negative selection, either by physical deletion or functional inactivation, of potentially autoreactive T cells. Self-nonself discrimination is not confined to intrathymic development of T lymphocytes, but it is a continuing process among peripheral T cells. Accordingly, autoimmunity is induced when self-antigens, or foreign antigens cross-reactive with self antigens, bound to MHC molecules, are presented under conditions able to activate self-reactive T cells. Based on these premises, a way of interfering with the induction of autoimmune diseases could rely on blocking the MHC binding site presenting the autoantigen.

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

Capacity of intact proteins to bind to MHC class II molecules.

Here we have demonstrated that denatured, but not native protein antigens can interact with Ia molecules. Thus, the failure of native antigens to be recognized as such by T cells appears to be at least in part due to a deficient antigen/Ia interaction. These results also support previous observations that some T cells can recognize denatured antigens without a further processing requirement. Moreover, a striking correlation was observed between the in vitro binding pattern of denatured proteins and the pattern of restriction of T cell responses elicited by immunization with the native antigen, raising the possibility that an unfolding step may actually occur early during in vivo processing and influence the final outcome of Ia-restricted T cell responses.

Animals↗
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

An Apple IIE microcomputer program for multiple non-independent comparisons by the Scheffe's test.

When more than two groups of observations from the same set of experimental data are compared and pairwise tested for equality of their means, appropriate statistical treatment of the data is required. The overall variation in the set of data must be considered, and also the statistical non-independence of each pairwise comparison must be taken into account. We describe a simple Apple IIE microcomputer program that applies the Scheffe's test for multiple comparisons. A numerical example and a sample output of this program are also included. The listing of the program is reported in the Appendix.

Analysis of Variance↗
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↗
PubMed1989

Vaccine T-cell epitope selection by a peptide competition assay.

The binding of several peptides derived from the Plasmodium falciparum circumsporozoite protein (CS protein) to the human major histocompatibility complex class II proteins HLA-DR5 and -DRw6 was examined in a competition assay. Fixed antigen-presenting cells (APCs) were incubated with various concentrations of each peptide and suboptimal concentrations of stimulator peptides. The binding of the CS peptides to DR5 or DRw6 proteins was then determined in a proliferation assay using two established DR5 or DRw6-restricted T-cell clones with specificity for the stimulator peptides as responder cells. One of five CS peptides, comprising together about 50% of the CS protein sequence, was found to compete with the binding of the stimulator peptides to DR5 and DRw6. The CS peptide CS-(378-398), binding to DR5 and DRw6, was then shown to be able to induce primary in vitro responses of T cells from donors with DR5 and DRw6 haplotypes. CS-(378-398)-induced T-cell clones responded not only to the homologous peptide but also to the native CS protein in the presence of appropriate APCs. The strategy we have applied is of considerable general interest for the engineering of vaccines against any pathogen, since it greatly facilitates the selection of appropriate T-cell epitopes to be incorporated in the vaccine.

Amino Acid Sequence↗
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 restoration of T cell functions by human IL-1 beta or its 163-171 nonapeptide in immunodepressed mice.

The immunorestorative capacities of human (hu) IL-1 beta or its synthetic fragment 163-171 (VQGEESNDK) were assessed in vivo in mice immunodepressed by aging, sublethal irradiation, or both. Subcutaneous administration of hu rIL-1 beta into immunodepressed animals immediately after carrier (horse red blood cells, HRBC) priming could restore to normal levels Th cell activity. This was measured as the ability of spleen cells from HRBC-primed mice to induce a hapten-specific antibody response in spleen cells from nonimmune mice in vitro stimulated with the hapten-carrier conjugate TNP-HRBC. In parallel, the ability of spleen cells from hu rIL-1 beta-treated immunodepressed animals to produce T cell growth factor activity upon in vitro mitogen stimulation was also increased significantly as compared to that of untreated mice and approached that of immunocompetent controls. The immunorestorative activity of hu rIL-1 beta on Th cell activity and T cell growth factor production could be mimicked by the synthetic nonapeptide 163-171 which, at the doses used, produced in most instances even greater effects than the whole protein. Although the optimal immunorestorative doses of the 163-171 peptide were several orders of magnitude higher than those of hu rIL-1 beta, the complete lack of IL-1-like inflammatory and toxic effects suggests that the synthetic hu IL-1 beta fragment may be successfully used as immunomodulating agent in the therapy of T cell immunodeficiencies.

Adjuvants, Immunologic↗
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↗