HLA transgenic mice as humanized mouse models of disease and immunity.

Taneja, Veena; David, Chella S.

doi:10.1172/jci2860

Cited by 65 publications

(41 citation statements)

References 39 publications

(24 reference statements)

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“…Transgenic mice expressing human class II molecules (in the absence of endogenous mouse class II) have been used to study other autoimmune disorders, including rheumatoid arthritis and multiple sclerosis (15)(16)(17)(18). We have studied the effect of gluten in double transgenic mice expressing HLA-DQ and human CD4 genes in the absence of endogenous class II and CD4 genes.…”

Section: Hla-dq Determines the Response To Exogenous Wheatmentioning

confidence: 99%

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

Black¹,

Murray

David³

2002

The Journal of Immunology

136

107

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We have investigated the genetic basis of the immune response to dietary gluten in HCD4/DQ8 and HCD4/DQ6 double transgenic mice. Mice were immunized with gluten i.p. or individual peptides s.c. and spleen or draining lymph node T cells were challenged in vitro. Strong proliferative responses to gluten were seen in the HCD4/DQ8 mice, whereas the HCD4/DQ6 mice responded to gluten poorly. A series of overlapping peptides spanning gliadin were synthesized. The HCD4/DQ8 mice reacted to many of the individual peptides of gliadin, while the HCD4/DQ6 mice were relatively unresponsive. T cells isolated from HCD4/DQ8 mice also responded well to modified (deamidated) versions of the gliadin peptides, whereas HCD4DQ6 mice did not. The T cell response to gluten was CD4 dependent and DQ restricted and led to the production of cytokines IL-6, TGF-β, and IL-10. Finally, intestinal lymphocytes isolated from gluten-fed HCD4/DQ8 mice displayed an activated phenotype. These data suggest that this HLA class II transgenic murine model of gluten sensitivity may provide insight into the initiation of the MHC class II-restricted gluten sensitivity in celiac disease.

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Section: Hla-dq Determines the Response To Exogenous Wheatmentioning

confidence: 99%

HLA-DQ Determines the Response to Exogenous Wheat Proteins: A Model of Gluten Sensitivity in Transgenic Knockout Mice

Black¹,

Murray

David³

2002

The Journal of Immunology

136

107

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“…T ransgenic (Tg) 3 mice expressing HLA class II molecules have provided a precise testing ground for screening disease-associated T cell determinants (1,2). HLA-DR4-restricted T cell responses, and in some cases clinical signs of autoimmune disease, were demonstrated after immunization with type II collagen (3)(4)(5), human cartilage Ag gp39 (6), glutamic acid decarboxylase 65 (7,8), insulin (9), and myelin oligodendrocyte glycoprotein (MOG)-91-108 peptide (10).…”

mentioning

confidence: 99%

Recombinant TCR Ligand Induces Tolerance to Myelin Oligodendrocyte Glycoprotein 35-55 Peptide and Reverses Clinical and Histological Signs of Chronic Experimental Autoimmune Encephalomyelitis in HLA-DR2 Transgenic Mice

Vandenbark

Rich

Mooney

et al. 2003

The Journal of Immunology

103

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In a previous study, we demonstrated that myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide could induce severe chronic experimental autoimmune encephalomyelitis (EAE) in HLA-DR2+ transgenic mice lacking all mouse MHC class II genes. We used this model to evaluate clinical efficacy and mechanism of action of a novel recombinant TCR ligand (RTL) comprised of the α1 and β1 domains of DR2 (DRB1*1501) covalently linked to the encephalitogenic MOG-35-55 peptide (VG312). We found that the MOG/DR2 VG312 RTL could induce long-term tolerance to MOG-35-55 peptide and reverse clinical and histological signs of EAE in a dose- and peptide-dependent manner. Some mice treated with lower doses of VG312 relapsed after cessation of daily treatment, but the mice could be successfully re-treated with a higher dose of VG312. Treatment with VG312 strongly reduced secretion of Th1 cytokines (TNF-α and IFN-γ) produced in response to MOG-35-55 peptide, and to a lesser degree purified protein derivative and Con A, but had no inhibitory effect on serum Ab levels to MOG-35-55 peptide. Abs specific for both the peptide and MHC moieties of the RTLs were also present after treatment with EAE, but these Abs had only a minor enhancing effect on T cell activation in vitro. These data demonstrate the powerful tolerance-inducing therapeutic effects of VG312 on MOG peptide-induced EAE in transgenic DR2 mice and support the potential of this approach to inhibit myelin Ag-specific responses in multiple sclerosis patients.

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“…The use of outbred strains might better overcome immunological restrictions of the major histocompatibility complex. Moreover, when thinking of the development of a T. gondii vaccine for human use, genetically engineered mice expressing human rather than mouse H2 (Taneja & David 1998) might be helpful in order to draw conclusions of vaccine efficacy in humans. Despite the high number of vaccine studies in mice, only a few have addressed protection against congenital infection.…”

Section: Discussionmentioning

confidence: 99%