Negative and positive selection by HLA-DR3(DRw17) molecules in transgenic mice

Strauß, Gudrun; Vignali, Dario A.A.; Schönrich, Günther; Hämmerling, G. J.

doi:10.1007/bf00188172

Cited by 45 publications

(45 citation statements)

References 38 publications

(18 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Murine CD4 is apparently incapable of productively interacting with HLA molecules (20). This suggests an interaction of mouse CD4 with mouse MHC II ␤-chains, which can form interspecies heterodimers with human MHC II ␣-chains in HLA-DR-transgenic mice (19). The inactivation of mouse CD4 in the CD4/DR3 mice used in this study precludes such exceptional activation pathways, and is therefore an important prerequisite for the realistic assessment of tolerance induction by anti-human CD4.…”

Section: Discussionmentioning

confidence: 89%

“…These mice were bred at Institute for Laboratory Animal Science, Medical School Hanover, as previously reported (18). Briefly, TgN(HLADR17a/b)1Dkfz (19) and TgN(hCD4)1Lit-cd4 tm1Lit mice (20) served as founders to establish a strain with transgenic CD4 and HLA-DR3 and inactivated mouse CD4. Animals bearing the desired mutations were identified by PCR or FACS, and were used for further inbreeding (21).…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Anti-Human CD4 Induces Peripheral Tolerance in a Human CD4+, Murine CD4−, HLA-DR+ Advanced Transgenic Mouse Model

Laub

Brecht

Dorsch³

et al. 2002

The Journal of Immunology

View full text Add to dashboard Cite

Selection in vivo of potent mAbs to human CD4 useful for immunotherapy, e.g., for the induction of immunological tolerance, is restricted for ethical reasons. We therefore used multiple transgenic mice that lack murine CD4, but express human CD4 specifically on Th cells, and HLA-DR3 as its natural counterligand (CD4/DR3 mice). The injection of CD4/DR3 mice with anti-human CD4 (mAb Max.16H5) before immunization with tetanus toxoid (TT, day 0) totally blocked the formation of specific Abs. This state of unresponsiveness persisted a subsequent boost again performed in the presence of anti-human CD4. When these mice were left untreated for at least 40 days, and were then re-exposed with TT, but in the absence of anti-human CD4, they consistently failed to induce specific Abs (long-term unresponsiveness). Exposure to second party Ags (hen egg lysozyme, human acetylcholine receptor) induced specific Abs comparable with control mice, demonstrating that the anti-CD4-induced unresponsiveness was Ag specific (immunological tolerance). Importantly, the concurrent injection of TT and anti-human CD4 at day 0, followed by another two anti-CD4 treatments, also led to tolerant animals, indicating that tolerance was inducible at the same day as the Ag exposure is provided. We finally demonstrate a limited ability of spleen cells to respond to TT in vitro, indicating that T cells are essentially involved in the maintenance of TT-specific tolerance. These data show for the first time that the human CD4 coreceptor mediates tolerance-inducing signals when triggered by an appropriate ligand in vivo.

show abstract

Section: Discussionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Anti-Human CD4 Induces Peripheral Tolerance in a Human CD4+, Murine CD4−, HLA-DR+ Advanced Transgenic Mouse Model

Laub

Brecht

Dorsch³

et al. 2002

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Mice-Mice transgenic for DRB1*0301 were originally generated by G. J. Hämmerling and co-workers as previously described (25). Briefly, the DR3 (DRA1*0101/DRB1*0301) transgenes were inserted into (C57BL/6 X DBA/2) F1 embryos and the progeny were back-crossed to B10.Q mice.…”

Section: Methodsmentioning

confidence: 99%

Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis

Menconi

Osman

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

We previously showed that an HLA-DR variant containing arginine at position 74 of the DR␤1 chain (DR␤1-Arg74) is the specific HLA class II variant conferring risk for autoimmune thyroid diseases (AITD). We also identified 5 thyroglobulin (Tg) peptides that bound to DR␤1-Arg74. We hypothesized that blocking the binding of these peptides to DR␤1-Arg74 could block the continuous T-cell activation in thyroiditis needed to maintain the autoimmune response to the thyroid. The aim of the current study was to identify small molecules that can block T-cell activation by Tg peptides presented within DR␤1-Arg74 pockets. We screened a large and diverse library of compounds and identified one compound, cepharanthine that was able to block peptide binding to DR␤1-Arg74. We then showed that Tg.2098 is the dominant peptide when inducing experimental autoimmune thyroiditis (EAT) in NOD mice expressing human DR␤1-Arg74. Furthermore, cepharanthine blocked T-cell activation by thyroglobulin peptides, in particular Tg.2098 in mice that were induced with EAT. For the first time we identified a small molecule that can block Tg peptide binding and presentation to T-cells in autoimmune thyroiditis. If confirmed cepharanthine could potentially have a role in treating human AITD. Autoimmune thyroid diseases (AITD),2 Graves disease (GD), and Hashimoto thyroiditis (HT), are among the most common autoimmune disorders, afflicting up to 5% of the United States population (1). They are characterized by infiltration of the thyroid by lymphocytes reactive to thyroid antigens and production of thyroid-specific antibodies (2). Complex interaction of genetic susceptibility factors, environmental triggers, and epigenetic alterations leads to the breakdown of tolerance, resulting in AITD (3-5). Currently, there is no satisfactory therapy except for hormone replacement therapy in HT or thyroid suppression or ablation in GD (6 -10). To develop new therapies for AITD a better understanding of their etiology is needed. We have been studying the etiology of AITD using a reverse-genetics approach, i.e. dissecting the mechanisms causing disease through unbiased genetic screening studies. These studies led to the identification of a specific HLA-DR pocket sequence that is strongly associated with AITD (11). The presence of arginine at position 74 of the DR␤ chain renders the individual highly susceptible to AITD, whereas glutamine at position 74 is protective (12). These data were confirmed by other groups (13). The presence of DR␤1-Arg74 (from here on we refer to the HLA-DR3 containing arginine at position 74 as HLA-DR␤1-Arg74) results in a more positively charged P4 pocket. With this structural change in the pocket, the selectivity and binding of pathogenic peptides is affected, conferring higher risk for disease (12).Besides the HLA genes, two thyroid-specific genes, the thyroglobulin (Tg) and thyrotropin receptor (TSHR) genes also contribute to the etiology of AITD (2). Thyroglobulin is the most abundant thyroidal protein (14), and it is the precursor to ...

show abstract

“…The A␤ 0 DR2 (DRB1*1502)-and A␤ 0 DR3 (DRB1*0301)-transgenic mice have also been described previously (22)(23)(24)(25). These HLAclass II-transgenic mice have normal phenotypes without evidence of autoantibody production up to 12 mo of age, which covered the period of study.…”

mentioning

confidence: 87%

HLA-DR Modulates Autoantibody Repertoire, But Not Mortality, in a Humanized Mouse Model of Systemic Lupus Erythematosus

Paisansinsup

Vallejo

Luthra

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

To evaluate the disease-modulating role of HLA-DR2 and DR3 molecules, which have been associated with systemic lupus erythematosus, a humanized mouse model was examined. HLA-DR2 (DRB1*1502)- and DR3 (DRB1*0301)-transgenic mice were backcrossed to the New Zealand Mixed 2410 (NZM 2410, H2z) strain. Seventh generation DR2 and DR3 transgene-positive animals along with their transgene-negative littermates and the parental strain NZM2410 were monitored for proteinuria, azotemia, autoantibody production, development of nephritis, and mortality. The results showed no significant differences in proteinuria, azotemia, or mortality between the backcrosses with and without HLA-DR2 or HLA-DR3. However, the genetic analysis of different backcrosses showed that heterozygosity at the endogenous H2-E locus (Ez/Eb) was strongly linked with acceleration of lupus nephritis in both HLA-DR2 and HLA-DR3 transgenics. More importantly, the presence of the HLA-DR2, but not the HLA-DR3, transgene significantly enhanced the production of anti-dsDNA, but not anti-ssDNA, anti-histone-dsDNA complex, or anti-histone, Abs. In contrast, neither HLA-DR2 nor HLA-DR3 influenced the development of glomerulonephritis or the degree of immune complex deposition. Moreover, nephritic kidneys from mice with and without HLA-DR2 or HLA-DR3 transgenes showed similar patterns of cytokine expression. Collectively, these findings provide molecular evidence that the association of HLA-DR2 or HLA-DR3 with lupus susceptibility is related to the type of autoantibody rather than to disease mortality. The use of a humanized mouse model provides a way of dissecting the roles of human MHC genes in systemic lupus erythematosus pathogenesis.

show abstract

Negative and positive selection by HLA-DR3(DRw17) molecules in transgenic mice

Cited by 45 publications

References 38 publications

Anti-Human CD4 Induces Peripheral Tolerance in a Human CD4+, Murine CD4−, HLA-DR+ Advanced Transgenic Mouse Model

Anti-Human CD4 Induces Peripheral Tolerance in a Human CD4+, Murine CD4−, HLA-DR+ Advanced Transgenic Mouse Model

Identifying a Small Molecule Blocking Antigen Presentation in Autoimmune Thyroiditis

HLA-DR Modulates Autoantibody Repertoire, But Not Mortality, in a Humanized Mouse Model of Systemic Lupus Erythematosus

Contact Info

Product

Resources

About