The use of human leucocyte antigen class I transgenic mice to investigate human immune function

Faulkner, Lee; Borysiewicz, Leszek K.; Man, Stephen

doi:10.1016/s0022-1759(98)00162-8

Cited by 11 publications

(2 citation statements)

References 81 publications

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“…Indeed, it is unclear how well various HLA, or even murine H-2 class I, molecules interact with murine tapasin for assembly in murine cells. For example, in transgenic mice expressing HLA class I molecules, inefficient interactions between these molecules and components of the murine Ag presentation machinery (such as tapasin) may modify the spectrum of peptide Ags presented at the cell surface and may contribute to difficulties encountered in generating HLA-restricted CTL (33).…”

Section: Discussionmentioning

confidence: 99%

Distinct Functions of Tapasin Revealed by Polymorphism in MHC Class I Peptide Loading

Peh

Laham

Burrows

et al. 2000

The Journal of Immunology

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Peptide assembly with class I molecules is orchestrated by multiple chaperones including tapasin, which bridges class I molecules with the TAP and is critical for efficient Ag presentation. In this paper, we show that, although constitutive levels of endogenous murine tapasin apparently are sufficient to form stable and long-lived complexes between the human HLA-B*4402 (B*4402) and mouse TAP proteins, this does not result in normal peptide loading and surface expression of B*4402 molecules on mouse APC. However, increased expression of murine tapasin, but not of the human TAP proteins, does restore normal cell surface expression of B*4402 and efficient presentation of viral Ags to CTL. High levels of soluble murine tapasin, which do not bridge TAP and class I molecules, still restore normal surface expression of B*4402 in the tapasin-deficient human cell line 721.220. These findings indicate distinct roles for tapasin in class I peptide loading. First, tapasin-mediated bridging of TAP-class I complexes, which despite being conserved across the human-mouse species barrier, is not necessarily sufficient for peptide loading. Second, tapasin mediates a function which probably involves stabilization of empty class I molecules and which is sensitive to structural compatibility of components within the loading complex. These discrete functions of tapasin predict limitations to the study of HLA molecules across some polymorphic and species barriers.

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Section: Discussionmentioning

confidence: 99%

Distinct Functions of Tapasin Revealed by Polymorphism in MHC Class I Peptide Loading

Peh

Laham

Burrows

et al. 2000

The Journal of Immunology

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“…HLA-A2/K b transgenic mice were used in an attempt to study CTL responses restricted by both murine and human MHC molecules. 31 These studies defined a cross-reactive CD8 1 T-cell epitope that was HLA-A2 restricted and was immunogenic to human T cells. …”

mentioning

confidence: 99%

Definition of an HPV18/45 cross‐reactive human T‐cell epitope after DNA immunisation of HLA‐A2/KB transgenic mice

McCarthy

Youde

Man

2006

Intl Journal of Cancer

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Although human papillomavirus (HPV) types 16 and 18 are the most common types associated with cervical cancer worldwide, other related HPV types such as HPV 35, 45 and 58 have significant prevalence in geographically distinct populations. For development of global prophylactic and therapeutic vaccine strategies, it is important to study immune responses against these viruses and to define the degree of cross-reactivity between related HPV types. To investigate the potential for T cell cross-reactivity after vaccination, HLA-A2/K b transgenic mice were immunised with DNA plasmid constructs containing HPV18 and 45 E6 and E7.Splenocytes from immunised mice were tested in direct ELIspot assays against overlapping pools of HPV 18 peptides. Immunisation with either HPV18 or HPV45 E6 DNA produced dominant T cell responses against an epitope (KCIDFYSRI) that was shared between HPV18 and HPV45. This peptide was shown to bind to HLA-A*0201 but not D b or K b molecules on the cell surface. Furthermore this peptide was shown to be immunogenic in vitro to human T cells from 2 out of 3 HLA-A2 1 healthy donors. Collectively, these results demonstrate that HPV 18 and 45 E6 DNA vaccines are immunogenic in mice and demonstrate that cross-reactive T cell responses against closely related HPV types can be induced in vivo. The use of the HLA-A2/K b transgenic mice allowed definition of an HLA-A*0201 binding peptide epitope that would have been rejected on the basis of predicted major histocompatibility complex binding affinity. ' 2005 Wiley-Liss, Inc.Key words: HPV; CTL; cervical cancer; epitope; cross-reactivity Human papillomavirus (HPV) infection is strongly associated with the development of virtually all cervical cancers, 1 and some head, neck 2 and skin cancers. 3 Cervical cancer is the 2nd leading cause of female cancer mortality worldwide, with an estimated 400,000 new cases every year. 4 The global burden of cervical cancer has lead to much research into prophylactic and therapeutic vaccines. Despite encouraging recent data with prophylactic vaccines, 5 there is still a need to develop therapeutic approaches for cancer and to address the considerable burden of recurrent HPVassociated anogenital neoplasias.Cell-mediated immunity is important in the control of HPV infection, as HPV-associated cervical lesions are more prevalent in immunosuppressed individuals. 6,7 Furthermore, regression of HPV-induced warts is associated with lymphocytic infiltration in man and animal models. 8 CD8 1 cytotoxic T lymphocytes (CTL) are known to protect against persistent viruses, 9 but importantly can also mediate tumour regression in animal models 10,11 and in a limited number of clinical studies in man. 12-14 CD8 1 CTL recognise endogenously processed peptides bound to major histocompatibility complex (MHC) class I molecules on tumour cells. 15 For oncogenic HPV types, the intracellular E6 and E7 proteins provide attractive targets because of their persistent and obligate expression in tumour cells. 16 Therapeutic approaches have largely ta...

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Humanized SCID Mouse Models for Biomedical Research

Pearson

Greiner

Shultz

2008

Current Topics in Microbiology and Immunology

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The use of human leucocyte antigen class I transgenic mice to investigate human immune function

Cited by 11 publications

References 81 publications

Distinct Functions of Tapasin Revealed by Polymorphism in MHC Class I Peptide Loading

Distinct Functions of Tapasin Revealed by Polymorphism in MHC Class I Peptide Loading

Definition of an HPV18/45 cross‐reactive human T‐cell epitope after DNA immunisation of HLA‐A2/KB transgenic mice

Humanized SCID Mouse Models for Biomedical Research

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