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S Trembleau

Publications and source records attributed to S Trembleau.

18 recordsLinked to original sources
PubMed1997

A peptide-binding motif for I-A(g7), the class II major histocompatibility complex (MHC) molecule of NOD and Biozzi AB/H mice.

The class II major histocompatibility complex molecule I-A(g7) is strongly linked to the development of spontaneous insulin-dependent diabetes mellitus (IDDM) in non obese diabetic mice and to the induction of experimental allergic encephalomyelitis in Biozzi AB/H mice. Structurally, it resembles the HLA-DQ molecules associated with human IDDM, in having a non-Asp residue at position 57 in its beta chain. To identify the requirements for peptide binding to I-A(g7) and thereby potentially pathogenic T cell epitopes, we analyzed a known I-A(g7)-restricted T cell epitope, hen egg white lysozyme (HEL) amino acids 9-27. NH2- and COOH-terminal truncations demonstrated that the minimal epitope for activation of the T cell hybridoma 2D12.1 was M12-R21 and the minimum sequence for direct binding to purified I-A(g7) M12-Y20/K13-R21. Alanine (A) scanning revealed two primary anchors for binding at relative positions (p) 6 (L) and 9 (Y) in the HEL epitope. The critical role of both anchors was demonstrated by incorporating L and Y in poly(A) backbones at the same relative positions as in the HEL epitope. Well-tolerated, weakly tolerated, and nontolerated residues were identified by analyzing the binding of peptides containing multiple substitutions at individual positions. Optimally, p6 was a large, hydrophobic residue (L, I, V, M), whereas p9 was aromatic and hydrophobic (Y or F) or positively charged (K, R). Specific residues were not tolerated at these and some other positions. A motif for binding to I-A(g7) deduced from analysis of the model HEL epitope was present in 27/30 (90%) of peptides reported to be I-A(g7)-restricted T cell epitopes or eluted from I-A(g7). Scanning a set of overlapping peptides encompassing human proinsulin revealed the motif in 6/6 good binders (sensitivity = 100%) and 4/13 weak or non-binders (specificity = 70%). This motif should facilitate identification of autoantigenic epitopes relevant to the pathogenesis and immunotherapy of IDDM.

Amino Acid Sequence↗
PubMed1997

Deviation of pancreas-infiltrating cells to Th2 by interleukin-12 antagonist administration inhibits autoimmune diabetes.

Nonobese diabetic (NOD) mice develop spontaneous insulin-dependent diabetes mellitus (IDDM), and the pancreas-infiltrating T cells invariably show a Th1 phenotype. We demonstrated here that the interleukin (IL)-12 antagonist (p40)2 can deviate the default Th1 development of naive T cell receptor (TCR)-transgenic CD4+ cells to the Th2 pathway in vitro. Although (p40)2 does not modify the cytokine profile of polarized Th1 cells, it prevents further recruitment of CD4- cells into the Th1 subset. To study the involvement of Th1 and Th2 cells in the initiation and progression of IDDM, we targeted endogenous IL-12 by administration of (p40)2 in NOD mice. (p40)2 administration to NOD mice inhibits interferon-gamma but not IL-10 production in response to lipopolysaccharide (LPS) or to the putative autoantigen IA-2. Serum immunoglobulin isotypes determined after (p40)2 treatment indicate an increase in Th2 and a decrease in Th1 helper activity. Administration of (p40)2 from 3 weeks of age onwards, before the onset of insulitis, results in the deviation of pancreas-infiltrating CD4+ but not CD8+ cells to the Th2 phenotype as well as in the reduction of spontaneous and cyclophosphamide-accelerated IDDM. After treating NOD mice with (p40)2 from 9 weeks of age, when insulitis is well established, few Th2 and a reduced percentage of Th1 cells are found in the pancreas. This is associated with a slightly decreased incidence of spontaneous IDDM, but no protection from cyclophosphamide-accelerated IDDM. In conclusion, deviation of pancreas-infiltrating CD4+ cells to Th2 is associated with protection from IDDM. However, targeting IL-12 after the onset of insulitis, when the pancreas contains polarized Th1 cells, is not sufficient to induce an effective immune deviation able to significantly modify the course of disease.

Animals↗
PubMed1996

Manipulation of the Th1/Th2 cell balance: an approach to treat human autoimmune diseases?

Differentiated T cells produce a restricted set of lymphokines, allowing their subdivision into two major subsets: Th1 and Th2 cells. This has lead to a new paradigm for immunoregulation based on the Th1/Th2 dichotomy. A strict compartmentalization of T cells into Th1 and Th2 is clearly an oversimplification: regulatory and effector mechanisms in the immune system encompass much more than Th1 and Th2 cells. This oversimplification is nevertheless useful to carry out experiments designed to test the paradigm. Based on results obtained in different experimental models of autoimmune diseases, the subdivision of T cells into Th1 and Th2 subsets has been extended to suggest that Th1 cells contribute to the pathogenesis of several organ-specific autoimmune diseases, whereas Th2 cells may inhibit disease development. Although more slowly and maybe less clearly, a similar dichotomy is starting to emerge in human autoimmune diseases. It will soon be possible to formally test immunointervention based on Th1/Th2 cell manipulation in clinical situations: the tools and a conceptual frame are already available. In this review we will examine two key factors affecting the Th1/Th2 balance: antigen and the role of cytokines influencing the development of Th1 and Th2 cells. The rational manipulation of these two variables may ultimately lead to an effective control of Th1 and Th2 cells potentially able to alter the natural course of human autoimmune diseases.

Autoimmune Diseases↗
PubMed1995

Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice.

T cells play a major role in the development of insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic (NOD) mice. Administration of interleukin 12 (IL-12), a key cytokine which guides the development of T helper type 1 (Th1) CD4+ T cells, induces rapid onset of IDDM in NOD, but not in BALB/c mice. Histologically, IL-12 administration induces massive infiltration of lymphoid cells, mostly T cells, in the pancreatic islets of NOD mice. CD4+ pancreas-infiltrating T cells, after activation by insolubilized anti T cell receptor antibody, secrete high levels of interferon gamma and low levels of IL-4. Therefore, IL-12 administration accelerates IDDM development in genetically susceptible NOD mice, and this correlates with increased Th1 cytokine production by islet-infiltrating cells. These results hold implications for the pathogenesis, and possibly for the therapy of IDDM and of other Th1 cell-mediated autoimmune diseases.

Animals↗
PubMed1995

Efficient immune responses in mice lacking N-region diversity.

Mice with a null mutation in the terminal deoxynucleotidyl transferase (TdT) gene harbor immunoglobulin and T cell receptor repertoires essentially devoid of N-region diversity. Consequently, the CDR3 loops important for antigen recognition are shorter and considerably less diverse than those of wild-type controls. We find surprisingly normal immune responses in TdT0 mice, as regards both efficiency and specificity. This provokes a reconsideration of the assumption that N-region diversity is required for an effective T and B cell repertoire.

Amino Acid Sequence↗
PubMed1995

The role of IL-12 in the induction of organ-specific autoimmune diseases.

The concept that T cells are subdivided into T helper 1 (Th1) and Th2 subsets was recently extended to suggest that Th1 cells contribute to the pathogenesis of several organ-specific autoimmune diseases, whereas Th2 cells inhibit disease development. Here, Sylvie Trembleau and colleagues examine the role of interleukin 12 (IL-12), a key cytokine guiding the development of Th1 cells, in the induction of autoimmune diseases, and discuss potential immunointervention strategies based on administration of IL-12 antagonists.

Animals↗
PubMed1995

DR alpha: E beta heterodimers in DRA transgenic mice hinder expression of E alpha: E beta molecules and are more efficient in antigen presentation.

HLA-DRA transgenic (tg) mice on H-2d background were constructed to study assembly, expression and function of DR alpha: E beta class II heterodimers when an alternate E alpha chain is available. Cytofluorimetric analysis and immunoprecipitation studies demonstrate that the majority (90%) of E beta d molecules on class II-positive splenocytes from DRA-tg mice are associated with DR alpha rather than E alpha chains. To characterize the functional role of the interspecies as compared with the wild-type I-E molecules, MHC restriction and T cell epitope immunodominance of synthetic peptides spanning the entire sequence of 65 kDa heat shock protein (hsp) from Mycobacterium tuberculosis were determined in hsp-primed DRA-tg and DBA/2 mice. A similar pattern of responsiveness was observed in both strains, but hsp epitopes recalled a higher response in DRA-tg as compared with DBA/2 mice. A panel of T cell hybridomas specific for two hsp peptides or a hen egg white lysozyme peptide presented by both DR alpha: E beta d and E alpha d: E beta d was studied in detail. Surprisingly, DR alpha: E beta d dimers present these peptides more efficiently than E alpha d: E beta d, even when the TCR was selected in mice expressing only E alpha d: E beta d molecules. The higher efficiency of antigen presentation by DR alpha: E beta d dimers does not appear to depend on increased binding affinity for peptides, as demonstrated by competition for antigen presentation, nor on increased efficiency in the interaction with CD4 molecules. Rather, the higher efficiency of antigen presentation could be explained by a more effective ligand-TCR interaction. This is consistent with molecular modeling based on the class II structure, indicating that 16 out of 17 substitutions between the first domain of E alpha d and DR alpha chains ile outside the peptide binding groove and are potentially available for interaction with the TCR.

Amino Acid Sequence↗
PubMed1993

Determinant capture as a possible mechanism of protection afforded by major histocompatibility complex class II molecules in autoimmune disease.

How peptide-major histocompatibility complex (MHC) class II complexes are naturally generated is still unknown, but accumulating evidence suggests that unfolding proteins or long peptides can become bound to class II molecules at the dominant determinant before proteolytic cleavage. We have compared the immunogenicity of hen egg-white lysozyme (HEL) in nonobese diabetic (NOD), (NOD x BALB/c)F1, and E(d) alpha transgenic NOD mice. We find that a response to the subdominant ANOD-restricted determinant disappears upon introduction of an E(d) molecule, and is restored when scission of HEL separates this determinant from its adjoining, competitively dominant, E(d)-restricted determinant. This suggests that the E(d) molecule binds and protects its dominant determinant on a long peptide while captured neighboring determinants are lost during proteolysis. These results provide clear evidence for "determinant capture" as a mechanism of determinant selection during antigen processing and a possible explanation for MHC-protective effects in insulin-dependent diabetes mellitus.

Animals↗
PubMed1993

Selective immunosuppression.

Experimental models of autoimmune diseases have demonstrated that such disease can be prevented or treated by selectively interfering with activation of any of these cell types: antigen-presenting cells, autoreactive T cells and regulatory T cells. Luciano Adorini and colleagues discuss these approaches to selective immunosuppression and examine how similar strategies may become applicable to the treatment of human autoimmune diseases.

Animals↗
PubMed1993

Selective immunosuppression.

Experimental models of autoimmune diseases have demonstrated that such disease can be prevented or treated by selectively interfering with activation of any of these cell types: antigen-presenting cells, autoreactive T cells and regulatory T cells. Luciano Adorini and colleagues discuss these approaches to selective immunosuppression and examine how similar strategies may become applicable to the treatment of human autoimmune diseases.

Animals↗
PubMed1992

Absence of T cell tolerance to pancreatic islet cells.

To examine whether the lack of self-tolerance to beta cells is responsible for the development of type I diabetes in nonobese diabetic (NOD) mice, we attempted to induce T cell responses to cells from the islets of Langerhans. The data show that all NOD mice, irrespective of age, sex, and disease progression, possess islet cell-specific CD4+, MHC class II-restricted T cells. Both primary and secondary proliferative responses to islet cells were readily induced. The activation of T cells required presentation of islet cell Ag by APC in the responding lymph node cell population. Cells from other tissues, e.g., salivary gland, adrenal gland, and spleen, failed to activate autologous T lymphocytes. T cells specific for other Ag did not respond to islet cells, indicating that the proliferation is not the result of nonspecific stimulation by islet cell products. The presence of islet cell-reactive T cells is, however, not unique to NOD mice, because similar T cell reactivity was also demonstrated in non-diabetes-prone mouse strains. Hence, self-tolerance to islet cells appears to be absent. The results indicate a normal occurrence of islet cell-reactive T cells in both diabetes-prone as well as non-diabetes-prone mice. Thus, the lack of tolerance cannot be the initial cause of diabetes, but the activation of such autoreactive T cells may be important for the development of the disease.

Animals↗
PubMed1991

Immunoglobulin isotypes of C57BL/6 nu/nu, lpr/lpr mice. Lack of direct intrinsic effect of the lpr gene on B cell hyperactivity.

The absolute concentrations of mouse immunoglobulin (Ig) heavy chain isotypes were determined by specific ELISAs in the serum of C57BL/6 (B6) mice doubly homozygous at the nude (nu) and the lymphoproliferation (lpr) locus (B6 nu, lpr mice), and compared with normal B6 nu mice. The distribution and the absolute concentrations of all Ig isotypes were found to be very similar in B6 nu, lpr and B6 nu mice, for both sexes and with similar increases in titers with ageing. Thus, the major part of the severe autoimmunity and hyperglobulinemia characteristic of the lpr syndrome of euthymic B6 lpr mice, including their elevated titers of thymus-independent IgM and IgG3 isotypes, is abrogated by the nude mutation, an effect of which is the lack of thymus differentiation. Though a postulated intrinsic activity of the lpr gene directly on B cell hyperactivity cannot be discarded, its expression would then require the presence of either the thymus or of T cells or of other cells or factors whose expression is also abrogated by the homozygosity at the nude locus.

Aging↗
PubMed1990

Serum concentrations of IgM, IgG1, IgG2b, IgG3 and IgA in C57BL/6 mice and their congenics at the nu(nude)locus.

The absolute concentrations of IgM, IgG1, IgG2b, IgG3 and IgA were determined in mice of C57BL/6 background, from weaning to one year of age, by quantitative isotype-specific, indirect double sandwich ELISAs. The comparison of 10-40 weeks-old athymic nude C57BL/6 females with age matched females of the wild strain showed a general decrease of the whole serum Ig levels in the athymic mice, which was however contributed quite differently by the different Ig isotypes: a significant decrease (about 3.5 fold) was found for IgG2b only (0.34 mg/ml), whereas 1.5 fold more IgM (0.28 mg/ml) and about 2 fold more IgG3 (0.27 mg/ml) were detected, the IgG1 (0.19 mg/ml) and IgA (0.07 mg/ml) levels remaining within the normal range ! Limited data for IgG2a suggest that that this isotype may also be decreased in nude mice (0.36 mg/ml) in comparison with normal B6 + mice (0.54 mg/ml). Thus, although homozygosity at the nu locus results in a lack of effector T cells, our data show, at the humoral level, a limited degree of thymus dependence of an Ig isotype. It is intriguing that, although thymus dependence of several Ig isotypes looked evident ten years ago in early studies on nude mice, more recent data are very variable and controversial in this respect.

Animals↗