Differences and similarities in the A2.1‐restricted cytotoxic T cell repertoire in humans and human leukocyte antigen‐transgenic mice

Wentworth, Peggy; Vitiello, Antonella; Sidney, John; Keogh, Elissa; Chesnut, Robert W.; Grey, Howard M.; Sette, Alessandro

doi:10.1002/eji.1830260115

Cited by 109 publications

(82 citation statements)

References 24 publications

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“…Peptides were given a net score integrating these data [iTopia iScore; supporting information (SI) Transgenic Mice. We used HLA class I transgenic mice to screen for high-affinity cdr2-specific CTLs, because such mice have been used to study immune responses to human tumor antigens (13,15). Immunizing AAD HLA-A2.1 transgenic mice with recombinant adenovirus-expressing full-length human cdr2 (Ad-hcdr2) yielded robust ex vivo CD8 ϩ T cell responses (frequency Ͼ0.3%) specific for cdr2 (290); weaker responses were seen to six other peptides, and these were not pursued further.…”

Section: Identification Of Cdr2mentioning

confidence: 99%

“…We screened a complete cdr2 peptide library for HLA-A2.1 binding and evaluated immunogenicity and natural processing using HLA-A2.1 transgenic mice previously used to evaluate human tumor-associated antigens (13)(14)(15). Immunization of these mice with adenovirus expressing human cdr2 allowed us to isolate a high-avidity CD8-independent cdr2-specific CTL clone and the genes encoding its T cell receptor (TCR) ␣-and ␤-chains.…”

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confidence: 99%

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A T cell receptor associated with naturally occurring human tumor immunity

Santomasso

Roberts

Thomas

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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The onconeural antigens appear to serve as tumor rejection antigens in the paraneoplastic neurologic disorders. Here, we used an unbiased peptide binding screen, followed by studies in HLA-A2.1 transgenic mice to identify naturally processed HLA-A2.1 restricted epitopes of the paraneoplastic cerebellar degeneration breast/ ovarian cancer antigen cdr2. These mice were used to clone high-avidity cdr2-specific CD8 ؉ T cells that recognize human tumor cells presenting endogenously loaded MHC class I-cdr2 peptide. T cells with this specificity were detected in the peripheral blood of two HLA-A2.1 ؉ paraneoplastic cerebellar degeneration patients. We cloned T cell receptor (TCR) ␣ and ␤ genes from cdr2-specific T cells; electroporation of RNA encoding this TCR turned nonreactive donor T cells into efficient killers of human cdr2-expressing tumor cells. Cloned cdr2-specific TCR genes provide a clinically relevant means for immunologic targeting of human gynecologic cancers.gene therapy ͉ gynecologic cancer ͉ paraneoplastic cerebellar degeneration A new strategy for treating cancer patients has emerged from efforts to stimulate CD8 ϩ cytotoxic T lymphocytes (CTL) through vaccination or adoptive T cell transfer (1-3). This effort has relied on a growing list of human tumor antigens recognized by CTL. However, few of these tumor antigens are associated with naturally robust immune responses and spontaneous tumor rejection, and their clinical utility is unclear. The paraneoplastic neurologic disorders (PNDs), perhaps the best-known examples of naturally occurring tumor immunity (4-7), offer a different approach to this problem. For example, patients with paraneoplastic cerebellar degeneration (PCD) develop an antigen-specific and clinically robust antitumor immune response directed against their breast and ovarian carcinomas (5,8). In one series, two-thirds of PCD patients (34 of 52) presented with neurologic symptoms before the diagnosis of cancer, 87% (45 of 52) had limited oncologic disease when diagnosed, and tumor could only be found by exploratory surgery in 4 of 52; by comparison, only 50-60% of unselected breast cancer patients and 25% of ovarian cancer patients present with limited-stage disease (9).Expression of the PCD antigen, cdr2, is believed to be largely restricted to cerebellar Purkinje neurons (10). The immune system is thought to initiate PCD when cdr2 is abnormally made in breast or ovarian tumors, triggering an antitumor immune response that can break immune tolerance in the brain. Interestingly, cdr2 is expressed by a large proportion of breast (25%) and ovarian (60%) tumors from individuals who do not develop neurological disease (11). Taken together with observations of immune responses made in other PNDs (5-7), cdr2 expression, and perhaps immune responses to it, may develop independently of autoimmune responses. These observations suggest the possibility that some gynecologic cancer patients might benefit from cdr2-directed immunotherapy. In addition, the unique expression of cdr2 in tumor cells (...

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Section: Identification Of Cdr2mentioning

confidence: 99%

mentioning

confidence: 99%

A T cell receptor associated with naturally occurring human tumor immunity

Santomasso

Roberts

Thomas

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…12 We have recently employed HLA-A2 (AAD) transgenic mice to characterize immune responses to E7 DNA vaccines. 13 As HLA-A2 transgenic mice also express murine MHC class I molecules (H-2D b and K b ), when HLA-A2 transgenic mice were vaccinated with DNA encoding CRT linked to wild-type E7, the vaccinated mice generated predominantly H-2D b -restricted E7-specific CD8…”

Section: Combination Of Hpv E6 and E7 Dna Vaccines S Peng Et Almentioning

confidence: 99%

“…We observed that the presence of the E7 49-57 aa sequence within the E7 gene of the CRT/E7 DNA vaccine suppresses the efficient activation of HLA-A2 restricted E7 (aa [11][12][13][14][15][16][17][18][19][20] peptide-specific CD8 + T cell-mediated immune responses 13 in HLA-A2 transgenic mice. In order to avoid this situation and accurately characterize the HLA-A2-restricted E7-specific CD8 + T-cell immune response in HLA-A2 transgenic mice, we generated pcDNA3-CRT/ mtE7(del aa49-57), a DNA vaccine that deletes aa49-57 from the E7 gene.…”

Section: Combination Of Hpv E6 and E7 Dna Vaccines S Peng Et Almentioning

confidence: 99%

A combination of DNA vaccines targeting human papillomavirus type 16 E6 and E7 generates potent antitumor effects

et al. 2005

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Human papillomavirus (HPV) infects large numbers of women worldwide and is present in more than 99% of all cervical cancers. HPV E6 and E7 are two viral oncoproteins that are consistently expressed in HPV infections and HPVassociated malignancies. We have previously developed DNA vaccines encoding calreticulin (CRT) linked either to HPV type 16 (HPV-16) E6 or to HPV-16 E7, both of which generated significant antitumor effects against E6-and E7-expressing tumors. In this study, we demonstrate that simultaneous vaccination of C57BL/6 mice or HLA-A2 transgenic mice with both CRT/E6 and CRT/E7 DNA vaccines generates significant E6-and E7-specific T-cell immune responses in vaccinated mice. Furthermore, combined vaccination with both CRT/E6 and CRT/E7 DNA generates significantly better therapeutic antitumor effects against HPV E6-and E7-expressing tumors than vaccination with either CRT/E6 DNA or CRT/E7 DNA alone. Our data suggest that it may be desirable to combine DNA vaccines targeting E6 with DNA vaccines targeting E7 to develop effective immunotherapeutic strategies for control of HPV infection and HPV-associated lesions in a clinical setting.

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“…Thus, the HLA-A2 transgenic mice may potentially be useful for evaluating HLA-A2-restricted CD8 responses with specificities correlating with those observed in humans. 4 We have acquired HLA-A2.1(AAD) transgenic mice that express a chimeric HLA class I molecule, comprising the a-1 and a-2 domains from human HLA-A*0201 and the a-3 transmembrane/cytoplasmic domain from mouse H-2D d . 5 These transgenic mice have been used by other researchers to characterize the immunogenicity and vaccine effects of several HLA-A2-restricted CTL epitopes from viral antigens.…”

Section: Introductionmentioning

confidence: 99%

Characterization of HLA-A2-restricted HPV-16 E7-specific CD8+ T-cell immune responses induced by DNA vaccines in HLA-A2 transgenic mice

Peng

Trimble

et al. 2005

Gene Ther

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We have recently demonstrated that linkage of DNAencoding calreticulin to DNA-encoding human papillomavirus-16 E7 antigen strongly enhances the efficacy of DNA vaccines against E7-expressing tumors in animal models. In this study, as a prelude to clinical translation, we characterized the ability of DNA-encoding calreticulin linked to DNAencoding E7 antigen to generate HLA-A2-restricted E7-specific CD8 + T-cell responses in HLA-A2 (AAD) transgenic mice, as well as antitumor effects against an E7 + HLA-A2 + tumor cell line, TC-1/A2. Our results show that while vaccination with CRT/E7 DNA generates strong H-2D brestricted E7 (amino acid (aa)49-57)-specific CD8 + T-cell immune responses in both C57BL/6 and HLA-A2 (AAD) transgenic mice, no such responses were generated to HLA-A2-restricted epitopes in either type of mouse. In contrast, vaccination with DNA-encoding calreticulin linked to DNA encoding a mutant version of E7 with a deleted aa49-57 epitope leads to the generation of an HLA-A2-restricted E7 (aa11-20)-specific CTL response in HLA-A2 (AAD) transgenic mice. More importantly, vaccination with CRT/ mtE7 (del aa49-57) DNA protects against a lethal challenge with TC-1/A2 tumor cells in HLA-A2 (AAD) transgenic mice. Furthermore, our in vitro studies demonstrate that the presence of the E7 (aa49-57) epitope does not suppress presentation of the HLA-A2-restricted E7 (aa11-20) epitope through MHC class I molecules. Thus, the predominant E7 aa49-57-specific CD8+ T-cell immune response in HLA-A2 transgenic mice vaccinated with CRT/E7 is likely due to preferred expansion of E7 aa49-57-specific CD8 + T cells in vaccinated mice. These results highlight the importance of epitope immunodominance in the evaluation of immune responses in HLA-A2 (AAD) transgenic mice.

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Differences and similarities in the A2.1‐restricted cytotoxic T cell repertoire in humans and human leukocyte antigen‐transgenic mice

Cited by 109 publications

References 24 publications

A T cell receptor associated with naturally occurring human tumor immunity

A T cell receptor associated with naturally occurring human tumor immunity

A combination of DNA vaccines targeting human papillomavirus type 16 E6 and E7 generates potent antitumor effects

Characterization of HLA-A2-restricted HPV-16 E7-specific CD8+ T-cell immune responses induced by DNA vaccines in HLA-A2 transgenic mice

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