Derivation of HLA-B*0702 transgenic mice: functional CTL repertoire and recognition of human B*0702-restricted CTL epitopes

Alexander, Jeff; Oseroff, Carla; Sidney, John; Sette, Alessandro

doi:10.1016/s0198-8859(02)00786-3

Cited by 47 publications

(83 citation statements)

References 46 publications

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“…17,[30][31][32][33][34][35][36] Moreover, our results confirm that the murine antigen processing machinery correctly generates the same tumorderived epitopes, which are processed in humans-both in ABabDII mice (gp100 epitope, Figure 3C) and in murine NIH/3T3 fibroblasts (Melan-A/MART-1 epitope, Figure 4C). However, we wanted to confirm that the TEL-AML1 epitope could not be processed by human proteasomes.…”

Section: The Tel-aml1 Peptide Is Not Processed By Human Proteasomes Isupporting

confidence: 67%

The only proposed T-cell epitope derived from the TEL-AML1 translocation is not naturally processed

Popović

Kloetzel

et al. 2011

Blood

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Adoptive therapy with T-cell receptor (TCR)-engineered T cells is a promising approach in cancer treatment. While usage of T cells specific for tumor-associated antigens (TAAs) can lead to serious side effects because of autoimmunity, targeting true tumor-specific mutations, such as the products of translocations in leukemias, should reduce such a risk. A potentially ideal target might be the chimeric protein TEL-AML1, which results from the chromosomal translocation 12;21 and represents the most common fusion gene in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Within the fusion region of TEL-AML1, a single epitope has been described by reverse immunology as immunogenic in HLA-A*0201 restriction settings. As a potential source of TCRs specific for this TEL-AML1 epitope, we have used mice expressing a human TCR-␣␤ repertoire and human MHC class I. Surprisingly, we have found that, although a specific functional CD8 ؉ T-cell response against this peptide could be evoked, the described epitope was in fact not endogenously processed. Analyses done with a potent antigen-presenting cell line, as well as with purified human proteasomes, support the conclusion that this peptide cannot be proposed as a potential target in immunotherapy of ALL in HLA-A*0201-restricted fashion. (Blood. 2011; 118(4):946-954) IntroductionImmunotherapy of cancer through adoptive transfer of genemodified T cells is a promising approach 1-3 ; however, the choice of target antigen is decisive for its success. 4 Although targeting tumor-associated self-antigens is an approach applicable to a variety of tumors, serious side effects are occasionally seen. Adoptive transfer of autologous peripheral lymphocytes genetically engineered to express TCRs specific for melanocyte differentiation antigens Melan-A/MART-1 and gp100 in melanoma patients led to a partial clinical response, accompanied by autoimmune attack against skin, retina, and inner ear. 5 Targeting ERBB2, which is overexpressed in a variety of tumors, through chimeric antigen receptor (CAR)-transduced lymphocytes in a colon cancer patient resulted in a serious adverse event, because of recognition of low levels of ERBB2 on normal lung cells. 6 Targeting true tumor specific mutations, such as the products of translocations in leukemias, should reduce such a risk of autoimmunity. The chimeric protein TEL-AML1, resulting from the chromosomal translocation 12;21 represents the most common fusion gene in childhood BCP-ALL, 7 which places it among principal target candidates. Furthermore, because the TEL-AML1 fusion protein is an important transforming factor in leukemogenesis, 8,9 selection of antigen-loss variants is less likely to occur.A nonamer peptide derived from the TEL-AML1 fusion region has been described as immunogenic in HLA-A*0201 restriction settings. 10 Using reverse immunology approach, 11 a peptide which binds to HLA-A*0201 was identified. The peptide was used to induce cytotoxic T-cell (CTL) lines, which recognized autologous leukemic cells and the leukemi...

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Section: The Tel-aml1 Peptide Is Not Processed By Human Proteasomes Isupporting

confidence: 67%

The only proposed T-cell epitope derived from the TEL-AML1 translocation is not naturally processed

Popović

Kloetzel

et al. 2011

Blood

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“…Poor immunogenicity can be a legitimate concern when epitopes are identified using only computer-based motif scans because many motif-positive peptides will not bind to HLA molecules with high affinity. The affinity of HLA-peptide binding has proven to be highly predictive of immunogenicity for several viral pathogens (33,80,81), including HIV-1 (53). Thus, HLA-peptide-binding measurements are considered a critical component of the overall process.…”

Section: Discussionmentioning

confidence: 99%

“…The derivation and characterization of the HLA-A*0201/K b , HLA-A*1101/K b , and HLA-B*0702/K b transgenic mice were described previously (33,50,51). These animals express a chimeric class I molecule composed of the ␣1 and ␣2 domain of HLA class I and the ␣3 domain of murine class I Ags.…”

Section: Hla Transgenic Mice and Cell Linesmentioning

confidence: 99%

Development of a DNA Vaccine Designed to Induce Cytotoxic T Lymphocyte Responses to Multiple Conserved Epitopes in HIV-1

Wilson

McKinney²,

Anders

et al. 2003

The Journal of Immunology

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Epitope-based vaccines designed to induce CTL responses specific for HIV-1 are being developed as a means for addressing vaccine potency and viral heterogeneity. We identified a set of 21 HLA-A2, HLA-A3, and HLA-B7 restricted supertype epitopes from conserved regions of HIV-1 to develop such a vaccine. Based on peptide-binding studies and phenotypic frequencies of HLA-A2, HLA-A3, and HLA-B7 allelic variants, these epitopes are predicted to be immunogenic in greater than 85% of individuals. Immunological recognition of all but one of the vaccine candidate epitopes was demonstrated by IFN-γ ELISPOT assays in PBMC from HIV-1-infected subjects. The HLA supertypes of the subjects was a very strong predictor of epitope-specific responses, but some subjects responded to epitopes outside of the predicted HLA type. A DNA plasmid vaccine, EP HIV-1090, was designed to express the 21 CTL epitopes as a single Ag and tested for immunogenicity using HLA transgenic mice. Immunization of HLA transgenic mice with this vaccine was sufficient to induce CTL responses to multiple HIV-1 epitopes, comparable in magnitude to those induced by immunization with peptides. The CTL induced by the vaccine recognized target cells pulsed with peptide or cells transfected with HIV-1 env or gag genes. There was no indication of immunodominance, as the vaccine induced CTL responses specific for multiple epitopes in individual mice. These data indicate that the EP HIV-1090 DNA vaccine may be suitable for inducing relevant HIV-1-specific CTL responses in humans.

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“…HLA-A*0201/K b and HLA-A*1101/K b transgenic mice were used in these studies as representative for the HLA-A2 and HLA-A3 HLA supertypes, respectively (46,47). Target cells, or APC, for the CTL assays were generated by the transfection of Jurkat (HLA-A*0201/K b ) or 721.221 (HLA-A*1101/K b ) cells with same genes used to produce the HLA transgenic mice (47,48).…”

Section: Immunogenicity Studies Using Hla Transgenic Micementioning

confidence: 99%

Recognition of Variant HIV-1 Epitopes from Diverse Viral Subtypes by Vaccine-Induced CTL

McKinney¹,

Skvoretz²,

Livingston³

et al. 2004

The Journal of Immunology

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Recognition by CD8+ T lymphocytes (CTL) of epitopes that are derived from conserved gene products, such as Gag and Pol, is well documented and conceptually supports the development of epitope-based vaccines for use against diverse HIV-1 subtypes. However, many CTL epitopes from highly conserved regions within the HIV-1 genome are highly variable, when assessed by comparison of amino acid sequences. The TCR is somewhat promiscuous with respect to peptide binding, and, as such, CTL can often recognize related epitopes. In these studies, we evaluated CTL recognition of five sets of variant HIV-1 epitopes restricted to HLA-A*0201 and HLA-A*1101 using HLA transgenic mice. We found that numerous different amino acid substitutions can be introduced into epitopes without abrogating their recognition by CTL. Based on our findings, we constructed an algorithm to predict those CTL epitopes capable of inducing responses in the HLA transgenic mice to the greatest numbers of variant epitopes. Similarity of CTL specificity for variant epitopes was demonstrated for humans using PBMC from HIV-1-infected individuals and CTL lines produced in vitro using PBMC from HIV-1-uninfected donors. We believe the ability to predict CTL epitope immunogenicity and recognition patterns of variant epitopes can be useful for designing vaccines against multiple subtypes and circulating recombinant forms of HIV-1.

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Derivation of HLA-B0702 transgenic mice: functional CTL repertoire and recognition of human B0702-restricted CTL epitopes

Cited by 47 publications

References 46 publications

The only proposed T-cell epitope derived from the TEL-AML1 translocation is not naturally processed

The only proposed T-cell epitope derived from the TEL-AML1 translocation is not naturally processed

Development of a DNA Vaccine Designed to Induce Cytotoxic T Lymphocyte Responses to Multiple Conserved Epitopes in HIV-1

Recognition of Variant HIV-1 Epitopes from Diverse Viral Subtypes by Vaccine-Induced CTL

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