Tolerance induced by physiological levels of secreted proteins in transgenic mice expressing human insulin.

Whiteley, Phyllis Jonas; Lake, Jeffrey P.; Selden, Richard F.; Kapp, Judith A.

doi:10.1172/jci114331

Cited by 14 publications

(10 citation statements)

References 21 publications

(14 reference statements)

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“…Our observation that the Fl-generation after a cross between two non-responder mice (H-2b • H-2 k) do not develop insulin antibodies after immunization with human insulin (Fig. 2) seems to be in contrast with the results by Whiteley et al [27], who state that H-2 k/b mice respond to human insulin. Both results are in accordance with observations by Keck [4], who showed that immunization with porcine insulin to the F1 generation of mice with the same H-2 haplotype (H-2k/b), but derived from different strains of non-responder mice, resulted in an antibody response, if one of the strains had C3H (H-2 k) background, as the strain used by Whiteley et al, while no antibody response was seen if (C57BL/10 x B10.BR)F1 mice, that also have the H-2 k/b haplotype, were used.…”

Section: Discussioncontrasting

confidence: 99%

“…The results obtained with different mouse strains and Fl-hybrids immunized with human insulin confirm the observations by Whiteley et al [27] and extend the knowledge of how various inbred strains of mice respond to human insulin. Our observation that the Fl-generation after a cross between two non-responder mice (H-2b • H-2 k) do not develop insulin antibodies after immunization with human insulin (Fig.…”

Section: Discussionsupporting

confidence: 88%

“…In order to verify that the non-transgenic control mice were responders (positive control), i. e. produce antibodies against human insulin, different mouse strains and Fl-hybrids were immunized with human insulin. It has been shown that normal H-2 d, H-2 d/k and H-2 k/b mice respond to human insulin, whereas H-2 b and H-2 k mice do not [27]. Our results (Fig.…”

Section: Resultssupporting

confidence: 53%

“…Antibodies induced by various insulins are extremely cross-reactive [27,44]. Antibodies developed against all the analogues used in this study have cross-reactivity against human insulin.…”

Section: Discussionmentioning

confidence: 92%

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The potential immunogenicity of human insulin and insulin analogues evaluated in a transgenic mouse model

et al. 1994

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Summary Transgenic mice with tissue-specific expression of the human insulin gene in the beta cells of the pancreas do not produce insulin-specific antibodies when injected with human insulin. Tolerant transgenic mice injected with human or porcine insulin reflect the clinical situation. When injected with bovine insulin the transgenic mice produce antibodies. The potential immunogenicity of 12 recombinant human insulin analogues has been tested in this transgenic model. The analogues were designed either to prevent hexamer formation or to improve chemical stability or both. The analogues have amino acid substitutions or deletions at residue 8, 10 and 21 in the A-chain and residue 3, 9, 27 and 28 in the B-chain. The results show that substitution of single amino acids in the A-chain loop of human insulin for the corresponding amino acids in bovine insulin at residues A8 or A10 is sufficient to elicit an antibody response in responder mice. Only human insulin analogues with substitutions at residues 8 or 10 in the Achain elicit antibody formation in the transgenic mice, whereas non-transgenic control groups respond to insulin and all analogues. Antibodies developed against the human insulin analogues are cross reactive with recombinant human insulin. Antibodies developed against an immunogenic analogue could therefore neutralize both the analogue and the native insulin and thereby aggravate the patient's condition. This transgenic mouse immunogenicity model should be useful as an in vivo model to map immunogenic areas of recombinant proteins. [Diabetologia (1994[Diabetologia ( ) 37: 1178[Diabetologia ( -1185

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 88%

Section: Resultssupporting

confidence: 53%

“…Antibodies induced by various insulins are extremely cross-reactive [27,44]. Antibodies developed against all the analogues used in this study have cross-reactivity against human insulin.…”

Section: Discussionmentioning

confidence: 92%

See 2 more Smart Citations

The potential immunogenicity of human insulin and insulin analogues evaluated in a transgenic mouse model

et al. 1994

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“…However, in certain instances it may be necessary to have the transgene in a defined genetic background when inbred and hybrid strains are preferred. This is especially true for research in immunology where a transgene often needs to be placed in a specific H-2 background, (Kaye et al, 1989;Whiteley et al, 1989;Goverman et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

TrackingH-2 alleles in transgenic mice by RFLP and heteroduplex analysis

Shanmugam

Haines

Lake

et al. 1996

Transgenic Research

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Transgenic mice provide valuable tools for biological research including many areas of immunology. In studies involving the major histocompatibility complex (MHC), it is often necessary to place the desired transgene in a specific H-2 (the murine MHC) environment. In this regard, the strains commonly used for the production of transgenic mice also carry well characterized H-2 alleles and provide an appropriate genetic background for MHC related experiments. In this study, a highly polymorphic microsatellite of tetranucleotide repeats from the second intron of the class II Eb gene within the H-2 complex was used in order to identify the corresponding alleles. The relevant H-2 allele(s) along with the transgene were then tracked throughout the production of a chicken ovalbumin-specific transgenic strain. The technique involved PCR-amplification of a DNA sequence encompassing the H-2 specific microsatellite followed by RFLP and heteroduplex analyses. This approach is likely to find wide application in the background checking of transgenic mice, especially in immunological research requiring a defined H-2 background.

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Human insulin as both antigen and protector in type 1 diabetes

Amdare,

Shultz,

Greiner

et al. 2024

Eur J Immunol

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Type 1 diabetes (T1D) is characterized by T‐cell responses to islet antigens. Investigations in humans and the nonobese diabetic (NOD) mouse model of T1D have revealed that T‐cell reactivity to insulin plays a central role in the autoimmune response. As there is no convenient NOD‐based model to study human insulin (hIns) or its T‐cell epitopes in the context of spontaneous T1D, we developed a NOD mouse strain transgenically expressing hIns in islets under the control of the human regulatory region. Female NOD.hIns mice developed T1D at approximately the same rate and overall incidence as NOD mice. Islet‐infiltrating T cells from NOD.hIns mice recognized hIns peptides; both CD8 and CD4 T‐cell epitopes were identified. We also demonstrate that islet‐infiltrating T cells from HLA‐transgenic NOD.hIns mice can be used to identify potentially patient‐relevant hIns T‐cell epitopes. Besides serving as an antigen, hIns was expressed in the thymus of NOD.hIns mice and could serve as a protector against T1D under certain circumstances, as previously suggested by genetic studies in humans. NOD.hIns mice and related strains facilitate human‐relevant epitope discovery efforts and the investigation of fundamental questions that cannot be readily addressed in humans.

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Tolerance induced by physiological levels of secreted proteins in transgenic mice expressing human insulin.

Cited by 14 publications

References 21 publications

The potential immunogenicity of human insulin and insulin analogues evaluated in a transgenic mouse model

The potential immunogenicity of human insulin and insulin analogues evaluated in a transgenic mouse model

TrackingH-2 alleles in transgenic mice by RFLP and heteroduplex analysis

Human insulin as both antigen and protector in type 1 diabetes

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