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S Trembleau

Publications and source records attributed to S Trembleau.

At least 19 recordsLinked to original sources
PubMed2001

IL-12 administration reveals diabetogenic T cells in genetically resistant I-Ealpha-transgenic nonobese diabetic mice: resistance to autoimmune diabetes is associated with binding of Ealpha-derived peptides to the I-A(g7) molecule.

Nonobese diabetic (NOD) and NOD-DRalpha transgenic (tg) mice, expressing Aalpha(d):Abeta(g7) and Aalpha(d):Abeta(g7) plus DRalpha:Ebeta(g7) class II molecules, respectively, both develop insulin-dependent diabetes mellitus (IDDM), whereas NOD-Ealpha tg mice expressing Aalpha(d):Abeta(g7) plus Ealpha:Ebeta(g7) are protected. We show that IL-12 administration induces rapid IDDM onset in NOD-DRalpha but fails to provoke insulitis and diabetes in NOD-Ealpha tg mice. Nevertheless, T cells from IL-12-treated NOD-Ealpha tg mice secrete IFN-gamma and transfer IDDM to NOD-SCID and NOD-Ealpha-SCID recipients, demonstrating the presence of peripheral diabetogenic Th1 cells in the protected mice. Surprisingly, regulatory cells were undetectable. Moreover, Ealpha:Ebeta(g7) could substitute for DRalpha:Ebeta(g7) in Ag presentation, arguing against mechanisms of protection involving capture of diabetogenic I-A(g7)-restricted epitopes by Ealpha:Ebeta(g7)molecules. Interestingly, the expression of naturally processed epitopes derived from DRalpha- and Ealpha-chains bound to I-A(g7) is different in the two strains of tg mice, and the difference is enhanced by IL-12 administration. I-A(g7) molecules from both NOD-DRalpha and NOD-Ealpha tg mice present the conserved DRalpha/Ealpha 52-68 sequence, at high and low levels, respectively. In addition, only IDDM-resistant NOD-Ealpha tg mice possess APCs bearing Ealpha65-77/I-A(g7) complexes, which tolerize the specific T cells. This is associated with the selective inhibition of the response to insulinoma-associated protein 2 (IA-2), an autoantigen in IDDM. Our results support protective mechanisms based on I-A(g7) blockade by peptides unique to the Ealpha-chain, such as Ealpha65-77 and/or tolerance of diabetogenic T cells cross-reactive with Ealpha-peptide/I-A(g7) complexes.

Animals↗
PubMed2000

Early Th1 response in unprimed nonobese diabetic mice to the tyrosine phosphatase-like insulinoma-associated protein 2, an autoantigen in type 1 diabetes.

The insulinoma-associated protein 2 (IA-2) is a phosphatase-like autoantigen inducing T and B cell responses associated with human insulin-dependent diabetes mellitus (IDDM). We now report that T cell responses to IA-2 can also be detected in the nonobese diabetic (NOD) mouse, a model of human IDDM. Cytokine secretion in response to purified mouse rIA-2, characterized by high IFN-gamma and relatively low IL-10 and IL-6 secretion, was elicited in spleen cells from unprimed NOD mice. Conversely, no response to IA-2 was induced in spleen cells from BALB/c, C57BL/6, or Biozzi AB/H mice that express, like NOD, the I-A(g7) class II molecule, but are not susceptible to spontaneous IDDM. The IA-2-induced IFN-gamma response in NOD spleen cells could already be detected at 3 wk and peaked at 8 wk of age, whereas the IL-10 secretion was maximal at 4 wk of age and then waned. IA-2-dependent IFN-gamma secretion was induced in CD4(+) cells from spleen as well as pancreatic and mesenteric lymph nodes. It required Ag presentation by I-A(g7) molecules and engagement of the CD4 coreceptor. Interestingly, cytokines were produced in the absence of cell proliferation and IL-2 secretion. The biological relevance of the response to IA-2 is indicated by the enhanced IDDM following a single injection of the recombinant protein emulsified in IFA into 18-day-old NOD mice. In addition, IFN-gamma production in response to IA-2 and IDDM acceleration could be induced by IL-12 administration to 12-day-old NOD mice. These results identify IA-2 as an early T cell-inducing autoantigen in the NOD mouse and indicate a role for the IA-2-induced Th1 cell response in IDDM pathogenesis.

Aging↗
PubMed1999

Pancreas-infiltrating Th1 cells and diabetes develop in IL-12-deficient nonobese diabetic mice.

IL-12 and IL-12 antagonist administration to nonobese diabetic (NOD) mice accelerates and prevents insulin-dependent diabetes mellitus (IDDM), respectively. To further define the role of endogenous IL-12 in the development of diabetogenic Th1 cells, IL-12-deficient NOD mice were generated and analyzed. Th1 responses to exogenous Ags were reduced by approximately 80% in draining lymph nodes of these mice, and addition of IL-12, but not IL-18, restored Th1 development in vitro, indicating a nonredundant role of IL-12. Moreover, spontaneous Th1 responses to a self Ag, the tyrosine phosphatase-like IA-2, were undetectable in lymphoid organs from IL-12-deficient, in contrast to wild-type, NOD mice. Nevertheless, wild-type and IL-12-deficient NOD mice developed similar insulitis and IDDM. Both in wild-type and IL-12-deficient NOD mice, approximately 20% of pancreas-infiltrating CD4+ T cells produced IFN-gamma, whereas very few produced IL-10 or IL-4, indicating that IDDM was associated with a type 1 T cell infiltrate in the target organ. T cell recruitment in the pancreas seemed favored in IL-12-deficient NOD mice, as revealed by increased P-selectin ligand expression on pancreas-infiltrating T cells, and this could, at least in part, compensate for the defective Th1 cell pool recruitable from peripheral lymphoid organs. Residual Th1 cells could also accumulate in the pancreas of IL-12-deficient NOD mice because Th2 cells were not induced, in contrast to wild-type NOD mice treated with an IL-12 antagonist. Thus, a regulatory pathway seems necessary to counteract the pathogenic Th1 cells that develop in the absence of IL-12 in a spontaneous chronic progressive autoimmune disease under polygenic control, such as IDDM.

Animals↗
PubMed1999

A peptide binding motif for I-Eg7, the MHC class II molecule that protects E alpha-transgenic nonobese diabetic mice from autoimmune diabetes.

The nonobese diabetic (NOD) mouse, a model of spontaneous insulin-dependent diabetes mellitus (IDDM), fails to express surface MHC class II I-Eg7 molecules due to a deletion in the E alpha gene promoter. E alpha-transgenic NOD mice express the E alpha E beta g7 dimer and fail to develop either insulitis or IDDM. A number of hypotheses have been proposed to explain the mechanisms of protection, most of which require peptide binding to I-Eg7. To define the requirements for peptide binding to I-Eg7, we first identified an I-Eg7-restricted T cell epitope corresponding to the sequence 4-13 of Mycobacterium tuberculosis 65-kDa heat shock protein (hsp). Single amino acid substitutions at individual positions revealed a motif for peptide binding to I-Eg7 characterized by two primary anchors at relative position (p) 1 and 4, and two secondary anchors at p6 and p9. This motif is present in eight of nine hsp peptides that bind to I-Eg7 with high affinity. The I-Eg7 binding motif displays a unique p4 anchor compared with the other known I-E motifs, and major differences are found between I-Eg7 and I-Ag7 binding motifs. Analysis of peptide binding to I-Eg7 and I-Ag7 molecules as well as proliferative responses of draining lymph node cells from hsp-primed NOD and E alpha-transgenic NOD mice to overlapping hsp peptides revealed that the two MHC molecules bind different peptides. Of 80 hsp peptides tested, none bind with high affinity to both MHC molecules, arguing against some of the mechanisms hypothesized to explain protection from IDDM in E alpha-transgenic NOD mice.

Amino Acid Sequence↗
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↗