The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Romieu, R.
Right arrow Articles by Viguier, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Romieu, R.
Right arrow Articles by Viguier, M.
The Journal of Immunology, 1998, 161: 5133-5137.
Copyright © 1998 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Passive But Not Active CD8+ T Cell-Based Immunotherapy Interferes with Liver Tumor Progression in a Transgenic Mouse Model1

Raphaëlle Romieu2,*, Myriam Baratin*, Michèle Kayibanda*, Valérie Lacabanne*, Marianne Ziol{dagger}, Jean-Gérard Guillet* and Mireille Viguier*

* Laboratoire des Pathologies Infectieuses et Tumorales, Institut National de la Santé et de la Recherche Médicale U445, Institut Cochin de Génétique Moléculaire, Université René Descartes, Paris, France; and {dagger} Service d’Anatomie Pathologique, Hôpital Jean Verdier, Bondy, France


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
To evaluate tumor immunotherapies, we used transgenic mice that harbor a progressive liver tumor associated with the expression of the SV40 large tumor T oncoprotein (SV40-T). To induce "self" tumor Ag-specific CD8+ T cells, mice were injected with an immunodominant SV40-T CTL epitope mixed with a heterologous helper peptide. Despite repeated injections, this vaccine failed to raise a tumor-specific CD8+ T cell response that was efficient enough to counteract tumors. Although coimmunization with SV40-T CTL epitope and heterologous helper peptide efficiently recruited the respective Th cells, only low-avidity SV40-T-specific CD8+ T cells were activated. Furthermore, major alterations in SV40-T-specific B and Th cell responses were characterized. In contrast, transfers of higher-avidity CTLs specific for the same SV40-T epitope were effective in counteracting tumors. These results suggest that passive therapies targeted to self tumor Ag may be more suitable than active immunization in the treatment of spontaneous tumors.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
The identification of antigenic peptides from processed tumor Ag (1) has led to new insights in T cell cancer therapy by active immunization or adoptive CTL transfer (2, 3, 4). The design of tumor vaccines may be hampered by the difficult task of reversing immune unresponsiveness toward tumor Ag, which is most commonly self Ag in human tumors (5).

In the present study, we took advantage of a transgene-encoded viral oncoprotein which is also a "self" tumor Ag that accumulates in tumor cells. Transgenic mice of the antitrobin III-SV40T (ASV-B)3 lineage develop a progressive hepatocellular carcinoma (HCC)3 that is related to the hepatocyte-restricted expression of SV40 large tumor T oncogene (SV40-T) (6). The expression of SV40-T is placed under the control of the antithrombin III liver-specific promoter, which is a differentiation-like tumor Ag such as tyrosinase, Melan/MART-1, or gp100 in human melanomas (1). This transgenic model is probably more representative of spontaneous tumorigenesis than tumor transplantation. In the present study, we explored the effectiveness of CD8+ T cell-based immunotherapies on tumor progression by comparing peptide immunization and adoptive transfers of CTLs.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Mice

Transgenic (C57BL/6 x DBA/2) ASV-B mice carried the SV40 early genes controlled by the antithrombin III liver-specific promoter on the Y chromosome and succumbed to HCC before 36 wk of age (6, 7). These mice were backcrossed with C57BL/6 mice (>25 generations).

Peptides, Ab reagents, and cell lines

SV40-T205–215, SV40-T223–231, SV40-T404–411, and SV40-T488–497 CTL epitopes of SV40-T Ag, Gag390–398 CTL epitope of the HIV gag protein, nucleoprotein 366–374 (NP366–374) of the influenza virus nucleoprotein CTL epitope, and hepatitis B virus core protein (HBVc) 128–140 helper epitope peptides were obtained from Neosystem (Strasbourg, France). The anti-mouse IFN-{gamma} (clones R4-6A2 and XMG1.2) Abs were obtained from PharMingen (San Diego, CA). The SV40-T-specific PAb419 Ab was provided by Dr. E. May (Commissariat à l’Energie Atomique, Fontenay-aux-Roses, France). EL4 is a C57BL/6 T cell lymphoma. The culture medium used was RPMI 1640 medium (Life Technologies, Gaithersburg, MD), 10% FCS, 20 mM HEPES, 2 mM glutamine, antibiotics, and 5 x 10-5 M 2-ME (Sigma, St. Louis, MO).

Peptide immunization with CTL epitopes and in vitro induction of CTL lines

Mice were s.c. injected in the tail with 50 µg of CTL epitope mixed with 140 µg of HBVc128–140 helper epitope peptides (8) in IFA. After 11 days, draining lymph node cell responses were tested ex vivo by IFN-{gamma} enzyme-linked immunospot (ELISPOT). To induce CTL lines, these cells were stimulated for 6 days with irradiated syngeneic LPS/dextran sulfate-activated lymphoblasts that had been pulsed with 10-5 M peptide (9) and were maintained weekly with peptide-pulsed C57BL/6 irradiated splenocytes. Human rIL-2 (10 U/ml, Boehringer Mannheim, Mannheim, Germany) was added every 3 days. Murine rIL-7 (10 ng/ml, Biosource International, Camarillo, CA) was added for the first stimulation.

ELISPOT assay for single-cell IFN-{gamma} secretion

The ELISPOT assay for detecting epitope-specific IFN-{gamma}-secreting T cells was adapted from Miyahira et al. (10). Nitrocellulose microplates (Millipore, Bedford, MA) were coated with 3.5 µg/ml anti-mouse IFN-{gamma} (R4-6A2). A total of 5 x 105-1.8 x 104 lymph node cells were tested in the presence of 30 U/ml human rIL-2. CD8+ T cells were stimulated with 105 irradiated MHC class II-negative EL4 cells pulsed (or not) with 10-5 M peptide. Th cells were activated by the addition of 30 µg/ml HBVc128–140 peptide. After 24 h, the plates were washed, incubated with 3.5 µg/ml biotinylated anti-mouse IFN-{gamma} (XMG1.2), and subsequently incubated with alkaline phosphatase-labeled extravidin. After adding chromogenic alkaline phosphatase conjugate substrate (Bio-Rad, Hercules, CA), IFN-{gamma} spot-forming cells (SFC) were counted using a stereomicroscope.

Immunization with recombinant SV40-T (rSV40-T) for analysis of Th cell responses

Mice were initially injected s.c. in the tail and footpads with 10 µg of rSV40-T (Molecular Biology Resources, Milwaukee, WI) in CFA; after 2 wk, these animals were injected with 5 µg of rSV40-T in IFA. After 10 days, spleen cells (5 x 105/well) were incubated with 0.1–10 µg/ml rSV40-T or 2.5 µg/ml Con A in culture medium containing 1% normal mouse serum and 2% FCS. After 24 and 48 h, supernatant was removed to test effector-released IL-2 and IL-4 with the CTL-L2 and CT4-S bioassays.

Immunotherapy by peptide immunizations or CTL transfers

ASV-B transgenic mice (7–8-wk-old) received three monthly peptide immunizations of SV40-T223–231 mixed with HBVc128–140 epitope peptides and were sacrificed 2 wk later. Negative controls were immunized with the irrelevant Db-restricted CTL epitopes Gag390–398 or NP366–374. Alternatively, ASV-B transgenic mice (15–23 wk-old) were injected i.v. three times (days 1, 7, and 14) with 2 x 106 CTL line cells specific for SV40-T223–231 or NP366–374 (irrelevant epitope) and were sacrificed 7 days later. The CTL lines were from peptide-immunized nontransgenic C57BL/6 males and were injected just before the weekly restimulation of the CTL lines. Effector CTL functions were tested for specific lytic activity and IFN-{gamma} and TNF secretion. In treated mice, the modulation of tumor weight was calculated relative to nontreated, age-matched ASV-B transgenic mice. Liver histology was analyzed on hematoxylin and eosin-stained frozen sections. The SV40-T expression level was assessed by Western blot. Two independent liver samples for each mouse were treated for total protein extraction. Proteins (100 µg) were separated by SDS-PAGE on 10% acrylamide gels and transferred onto nitrocellulose membranes. Blots were revealed using SV40-T-specific mAb PAb419 of the IgG2b isotype and rabbit anti-mouse IgG2b (PharMingen).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
We tested the efficiency of CD8+ T cell-based therapies that are specific for self tumor Ag epitopes. Four H-2b-restricted SV40-T CTL epitopes have been described previously in C57BL/6 mice (11, 12, 13). SV40-T205–215, SV40-T223–231, and SV40-T404–411 are codominant epitopes (12, 13), whereas SV40-T488–497 is a subdominant epitope (13). Active therapy was targeted to a Db-restricted CTL-dominant epitope mapping to the SV40-T223–231 sequence. In our model, some of the four SV40-T CTL epitopes were found to be endogenously presented by three HCC cell lines derived from transgenic mice; SV40-T223–231 was the most efficiently presented epitope by the HCC cell lines (14). Transgenic mice were immunized with SV40-T223–231 by three monthly injections that began before the macroscopic tumor growth phase. The I-Ab-restricted helper peptide HBVc128–140 was included in the immunizing formulation as described previously (8, 9). We observed neither reduction in liver tumor size (Fig. 1Go) nor major modifications of HCC histology in immunized mice (data not shown). Analysis of their liver SV40-T expression failed to demonstrate an alteration of tumor Ag expression (data not shown). Thus, repeated injections of an SV40-T CTL epitope peptide, even when supplemented with a potent helper peptide, failed to interfere with tumor progression in ASV-B transgenic mice.



View larger version (20K):
[in this window]
[in a new window]
  		FIGURE 1. Absence of tumor weight reduction in peptide-immunized ASV-B transgenic mice. Transgenic mice were treated with three consecutive monthly injections of SV40-T223–231 (n = 5) mixed with HBVc128–140 helper peptide, of irrelevant CTL epitopes NP366–374 (n = 2), or of Gag390–398 (n = 1). Mice were 22 or 23 wk old when sacrificed. Actual values of liver weights were 6.4, 6.6, and 6.7 g (immunization with irrelevant CTL epitopes); 6.6, 6.9, 7.1, 7.2, and 7.6 g (immunization with SV40-T223–231); or 7.3 ± 0.37 g (nontreated, age-related transgenic mice, n = 7).

 
To assess active immunization failure, we analyzed the induction of SV40-T-specific CD8+ T cells in transgenic mice immunized with a mixture of the four SV40-T CTL epitope peptides. Vaccination with CTL epitope peptides in IFA has been reported to be protective against viral infections (15, 16) or tumor transplantations (3). However, in this progressive tumor, such an immunization protocol failed to induce detectable SV40-T-specific CD8+ T cell responses (data not shown). In an attempt to amplify in vivo CD8+ T cell responses, mice were coimmunized with a potent helper peptide, HBVc128–140 (8, 9). Specific CD8+ T cells were quantified ex vivo by an IFN-{gamma} ELISPOT conducted on uncultured lymph node cells. The number of SV40-T223–231- and SV40-T404–411-specific CD8+ T cells was dramatically reduced in 8-wk-old immunized transgenic mice compared with nontransgenic control littermate mice (Fig. 2Go, A and B). It is noteworthy that these responses were further reduced in >20-wk-old transgenic mice (terminal phases of HCC; data not shown). Nevertheless, the presence of SV40-T205–215- and SV40-T488–497-specific CD8+ T cells could be detected in half of the transgenic mice (Fig. 2Go, C and D). Therefore, transgenic mice displayed various degrees of alteration of the SV40-T-specific CD8+ T cell repertoire affecting mainly the dominant SV40-T CTL epitopes, previously defined in C57BL/6 mice (12, 13). Indeed, two of the three codominant SV40-T CTL epitopes were profoundly tolerogenic, whereas the subdominant epitope was partially tolerogenic. Of note, we observed no clear correlation between the induction of tolerance and the hierarchy of the CTL epitopes previously defined for their presentation by HCC tumor cell lines, since only one (SV40-T223–231) of the two tolerogenic dominant epitopes (SV40-T223–231 and SV40-T404–411) was found to be presented in vitro (14).



View larger version (30K):
[in this window]
[in a new window]
  		FIGURE 2. Analysis of SV40-T-specific CD8+ T cell repertoire in ASV-B transgenic (•) and control ({circ}) mice. Transgenic (n = 7) or control (nontransgenic ASV-B female mice, n = 4) mice were immunized with the pool of SV40-T CTL epitopes (SV40-T205–215, SV40-T223–231, SV40-T404–411, and SV40-T488–497) mixed with HBVc128–140 helper peptide. Epitope-specific CD8+ T cell responses were assayed ex vivo by IFN-{gamma} ELISPOT. Uncultured lymph node cells were exposed for 24 h to EL4 cells pulsed with individual SV40-T CTL epitopes. Results are expressed as numbers of IFN-{gamma} SFC per 106 cells; the SD between replicates was <10%. The background values (always <10) obtained in the absence of peptide were subtracted from the values obtained with Ag stimulation.

 
We subsequently wondered whether the altered SV40-T-specific CD8+ T cell response was linked to a multispecific immunosuppression of Th or CD8+ T cell responses that could have been exerted by tumor cells. Both transgenic and control mice also responded to HBVc128–140 by specific T cell proliferation and IFN-{gamma} and IL-2 secretion but not by IL-4 secretion (data not shown), suggesting that these mice could mount equivalent Th1 cell responses to nonself HBVc128–140 helper peptide.

In addition, no IL-4- or TNF-secreting SV40-T223–231-specific CD8+ T cells were detected ex vivo in transgenic mice immunized with SV40-T223–231 mixed with HBVc128–140 (data not shown). We subsequently assessed the avidity of SV40-T223–231-specific CD8+ T cells by ex vivo IFN-{gamma} ELISPOT using stimulation with a range of Ag concentrations (Fig. 3GoA). Control mice still had a significant proportion of CD8+ T cells that were activated with 10-9 M SV40-T223–231. Strikingly, SV40-T223–231-specific CD8+ T cells from transgenic mice required 105-fold more peptide to reach detectable activation levels. On the contrary, control and transgenic mice immunized with the heterologous NP366–374 influenza epitope mounted CD8+ T cell responses that were comparable in both number and avidity (Fig. 3GoB). Altogether, these results suggest that alterations in high-avidity CD8+ T cells are specific for SV40-T223–231 and are linked to self tumor Ag-specific deletion or anergy rather than to immune deviation. In vitro, it was nevertheless possible to expand the reduced number of specific CD8+ T cells from immunized transgenic mice. In most instances, one round of restimulation was sufficient to induce SV40-T223–231-specific transgenic CTL lines displaying lymphokine production and lytic activities comparable with control CTL lines (data not shown). These observations support the relevance of an ex vivo analysis of the T cell repertoire, as reported in other studies (17).



View larger version (21K):
[in this window]
[in a new window]
  		FIGURE 3. Comparison of CD8+ T responses in 8-wk-old ASV-B transgenic (•) and control ({circ}) mice. A,Transgenic or control mice (n = three per group) were immunized with SV40-T223–231 and HBVc128–140. B, Transgenic (n = four per group) or control mice (n = three per group) were immunized with NP366–374 and HBVc128–140. Epitope-specific T cell responses were assayed ex vivo by IFN-{gamma} ELISPOT. Uncultured lymph node cells were exposed for 24 h to EL4 cells pulsed with SV40-T223–231 (10-9–10-3 M) (A) or to EL4 cells pulsed with NP366–374 (10-11–10-4 M) (B). Results are expressed as described in Fig. 2Go.

 
To further explore self tumor Ag-specific tolerance in transgenic mice, B and Th cell responses were assayed in mice immunized with rSV40-T protein. In control mice, the activation of spleen cells by rSV40-T was demonstrated by the specific production of IL-2 and IL-4 (Table IGo) in the absence of significant cell proliferation (data not shown). Immunized transgenic mice (8 and 18 wk old) did not show detectable SV40-T-specific Th cell responses (Table IGo), although they did display normal responses to Con A (data not shown). The addition of IL-1{alpha}, a costimulator of Th2 cell proliferation (18), to cell culture could not revert this unresponsiveness (data not shown). There were major concomitant qualitative and quantitative reductions in SV40-T-specific B cell responses in transgenic mice (data not shown). Thus, SV40-T Ag is most probably presented in vivo, leading to early tolerance of SV40-T-specific immune cells. Various mechanisms may account for self-tolerance (19); in particular, the expression of SV40-T Ag during perinatal life (6) might shape the transgenic immune repertoire (19). However, we found that a number of tumor-specific CD8+ T cells escape tolerance, most probably due to their lower avidity. Interestingly, such regulations may affect the specific repertoire for self tumor Ag (20).


View this table:
[in this window]
[in a new window]
  		Table I. SV40-T-specific Th cell responses by spleen cells from ASV-B transgenic or control mice

 
It has been reported recently that the activation of low-avidity CD8+ T cells specific for a self tumor Ag epitope can protect against tumor cell challenge in mice (21). In our study, the activation of low-avidity CD8+ T cells upon peptide immunization failed to counteract tumor progression. This finding could be due to defects in either effector T cells or in tumor cell sensitivity to immune effectors. To test the second possibility, we treated transgenic mice that had already fully developed HCC by adoptive CTL transfers. SV40-T223–231- or control NP366–374-specific CTL lines that had been established from nontransgenic syngenic C57BL/6 male mice were checked for specific lytic activity and IFN-{gamma} or TNF secretion before transfers (data not shown). Transfers of SV40-T223–231-specific CTLs reduced tumor weight by 23–58% (Fig. 4GoA). There was also a major reduction of the SV40-T liver expression level of the mouse displaying a 58% reduction in tumor weight; massive liver necrosis was observed (Fig. 4GoB). In the mouse having a 23% reduction in tumor weight, necrosis was limited to small areas, whereas no significant reduction in SV40-T expression was detected (Fig. 4GoB). In contrast, transgenic mice treated with NP366–374-specific CTLs did not show any of these modifications (data not shown). We could not transfer SV40-T223–231-specific CTL lines established from immunized transgenic mice because of their reduced ability to proliferate in vitro (data not shown). Nevertheless, the results obtained attested to both the antigenicity and sensitivity of liver tumor cells in vivo to SV40-T223–231-specific effector CTLs.



View larger version (56K):
[in this window]
[in a new window]
  		FIGURE 4. Reduction of tumor weight in ASV-B transgenic mice treated by CTL adoptive transfers. A, Transgenic mice received three consecutive weekly transfers of CTL line cells specific for SV40-T223–231 (n = 4) or for the irrelevant epitope NP366–374 (n = 4). Mice were aged 20, 25, or 27 wk when sacrificed. Actual values of liver weights were 6.6 and 6.4 g (20 wk), 7.0 g (25 wk), or 7.7 g (27 wk) for mice treated by transfers of irrelevant CTLs; 4.2 and 4.8 g (20 wk) or 3.3 and 6.0 g (27 wk) for mice treated by transfers of SV40-T223–231-specific CTLs; and 6.8 ± 0.2 g (20 wk, n = 6), 7.4 ± 0.5 g (25 wk, n = 8), or 7.9 ± 0.6 g (27 wk, n = 8) for nontreated, age-related transgenic mice. B, Liver SV40-T expression level and histology of the two transgenic mice displaying a 58% and 23% reduction, respectively, of tumor weight upon transfers of SV40-T223–231-specific CTLs. SV40-T expression was assessed on protein extracts from two independent liver samples. Positive controls were from nontreated, age-matched transgenic mice; negative controls were from nontransgenic ASV-B female mice. A histologic examination (x40) of hematoxylin and eosin-stained frozen liver sections showed large foci of necrosis. Controls were nontreated, age-matched transgenic mice.

 
Both intrinsic selection of the immune repertoire and effects of tumors may constitute drawbacks to immunotherapies targeted at tumor Ag. Using a transgenic model, we found that adoptive transfer of self tumor Ag-specific CTLs was more suited to interfering with tumor development than active peptide immunization. This difference could be linked to major alterations in the tumor-specific immune repertoire that are likely to occur in a similar fashion in spontaneous tumors (1, 20). Thus, a selection of autologous CD8+ T cells appears necessary to elicit optimal tumor Ag-specific effector functions for adoptive transfer in patients. This selection could be assessed during the necessary phase of in vitro expansion or directly in vivo by adjuvant treatments (22).


   Acknowledgments
 
We thank Drs. P. Briand and L. Rénia for helpful discussions. We also thank Noah Hardy for editing the English text.


   Footnotes
 
1 This work was supported by grants from the Association pour la Recherche contre le Cancer, the Ligue Nationale contre le Cancer, and the Comité de Paris of the Ligue Nationale contre le Cancer (axe Immunologie des Tumeurs). Back

2 Address correspondence and reprint requests to Raphaëlle Romieu, Institut National de la Santé et de la Recherche Médicale U445, Institut Cochin de Génétique Moléculaire, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France. E-mail address: Back

3 Abbreviations used in this paper: ASV-B, antitrombin III-SV40T; HCC, hepatocellular carcinoma; SV40-T, SV40 large tumor T oncogene; NP, nucleoprotein; HBVc, hepatitis B virus core protein; ELISPOT, enzyme-linked immunospot; SFC, spot-forming cells. Back

Received for publication July 9, 1998. Accepted for publication September 10, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Van den Eynde, B., P. van der Bruggen. 1997. T cell-defined tumor antigens. Curr. Opin. Immunol. 9:684.[Medline]
  2. Rosenberg, S. A.. 1997. Cancer vaccines based on the identification of genes encoding cancer regression antigens. Immunol. Today 18:175.[Medline]
  3. Feltkamp, M. C., H. L. Smits, M. P. Vierboom, R. P. Minnaar, B. M. de Jongh, J. W. Drijhout, J. ter Schegget, C. J. Melief, W. M. Kast. 1993. Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by human papillomavirus type 16-transformed cells. Eur. J. Immunol. 23:2242.[Medline]
  4. Marchand, M., P. Weynants, E. Rankin, F. Arienti, F. Belli, G. Parmiani, N. Cascinelli, A. Bourlond, R. Vanwijck, Y. Humblet, et al 1995. Tumor regression responses in melanoma patients treated with a peptide encoded by gene MAGE-3. Int. J. Cancer 63:883.[Medline]
  5. Parmiani, G.. 1993. Tumor immunity as autoimmunity: tumor antigens include normal self proteins which stimulate anergic peripheral T cells. Immunol. Today 14:536.[Medline]
  6. Dubois, N., M. Bennoun, I. Allemand, T. Molina, G. Grimber, M. Daudet-Monsac, R. Abelanet, P. Briand. 1991. Time-course development of differentiated hepatocarcinoma and lung metastasis in transgenic mice. J. Hepatol. 13:227.[Medline]
  7. Romieu, R., V. Lacabanne, M. Kayibanda, B. Antoine, M. Bennoun, S. Chouaib, J.-G. Guillet, M. Viguier. 1997. Critical stages of tumor growth regulation in transgenic mice harboring a hepatocellular carcinoma revealed by distinct patterns of tumor necrosis factor-{alpha} and transforming growth factor-ß mRNA production. Int. Immunol. 9:1405.[Abstract/Free Full Text]
  8. Milich, D. R., J. L. Hughes, A. McLachlan, G. B. Thornton, A. Moriarty. 1988. Hepatitis B synthetic immunogen comprised of nucleocapsid T-cell sites and a envelope B-cell epitope. Proc. Natl. Acad. Sci. USA 85:1610.[Abstract/Free Full Text]
  9. Sette, A., A. Vitiello, B. Reherman, P. Fowler, R. Nayersina, W. M. Kast, C. J. Melief, C. Oseroff, L. Yuan, J. Ruppert, et al 1994. The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. J. Immunol. 153:5586.[Abstract]
  10. Miyahira, Y., K. Murata, D. Rodriguez, J. R. Rodriguez, M. Esteban, M. M. Rodrigues, F. Zavala. 1995. Quantification of antigen-specific CD8+ T cells using an ELISPOT assay. J. Immunol. Methods 181:45.[Medline]
  11. Deckhut, A. M., J. D. Lippolis, S. S. Tevethia. 1992. Comparative analysis of core amino acid residues of H-2Db-restricted cytotoxic T-lymphocyte recognition epitopes in simian virus 40 T antigen. J. Virol. 66:440.[Abstract/Free Full Text]
  12. Mylin, L. M., A. M. Deckhut, R. H. Bonneau, T. D. Kierstead, M. J. Tevethia, D. T. Simmons, S. S. Tevethia. 1995. Cytotoxic T lymphocyte escape variants, induced mutations, and synthetic peptides define a dominant H-2Kb-restricted determinant in simian virus 40 tumor antigen. Virology 208:159.[Medline]
  13. Mylin, L. M., R. H. Bonneau, J. D. Lippolis, S. S. Tevethia. 1995. Hierarchy among multiple H-2b-restricted cytotoxic T lymphocyte epitopes within simian virus 40 T antigen. J. Virol. 69:6665.[Abstract]
  14. Lacabanne, V., M. Viguier, R. Romieu, M. Kayibanda, F. Connan, S. Sermet, B. Antoine, J.-G. Guillet, J. Choppin. 1998. Differential presentation of endogenously processed CTL epitopes by mouse hepatocarcinoma cell lines induced by SV40 large T antigen. Int. Immunol. 10:463.[Abstract/Free Full Text]
  15. Schulz, M., R. M. Zinkernagel, H. Hengartner. 1991. Peptide-induced antiviral protection by cytotoxic T cells. Proc. Natl. Acad. Sci. USA 88:991.[Abstract/Free Full Text]
  16. Kast, W. M., L. Roux, J. Curren, H. J. Blom, A. C. Voordouw, R. H. Meloen, D. Kolakofsky, C. J. Melief. 1991. Protection against lethal Sendai virus infection by in vivo priming of virus-specific T lymphocytes with a free synthetic peptide. Proc. Natl. Acad. Sci. USA 88:2283.[Abstract/Free Full Text]
  17. Lalvani, A., R. Brookes, S. Hambleton, W. J. Britton, A. V. Hill, A. J. McMichael. 1997. Rapid effector function in CD8+ memory T cells. J. Exp. Med. 186:859.[Abstract/Free Full Text]
  18. Kurt-Jones, E. A., S. Hamberg, J. Ohara, W. E. Paul, A. K. Abbas. 1987. Heterogeneity of helper/inducer T lymphocytes: lymphokine production and lymphokine responsiveness. J. Exp. Med. 166:1774.[Abstract/Free Full Text]
  19. Miller, J. F., R. A. Flavell. 1994. T-cell tolerance and autoimmunity in transgenic models of central and peripheral tolerance. Curr. Opin. Immunol. 6:892.[Medline]
  20. Theobald, M., J. Biggs, J. Hernandez, J. Lustgarten, C. Labadie, L. A. Sherman. 1997. Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes. J. Exp. Med. 185:833.[Abstract/Free Full Text]
  21. Morgan, D. T., H. T. Keuwel, S. Fleck, H. I. Levitsky, D. M. Pardoll, L. A. Sherman. 1998. Activation of low-avidity CTL specific for a self epitope results in tumor rejection but not autoimmunity. J. Immunol. 160:643.[Abstract/Free Full Text]
  22. Yee, C., S. R. Riddell, P. D. Greenberg. 1997. Prospects for adoptive T cell therapy. Curr. Opin. Immunol. 9:702.[Medline]



This article has been cited by other articles:


Home page
 BloodHome page
A. Roth, G. M. Baerlocher, M. Schertzer, E. Chavez, U. Duhrsen, and P. M. Lansdorp
Telomere loss, senescence, and genetic instability in CD4+ T lymphocytes overexpressing hTERT
Blood, July 1, 2005; 106(1): 43 - 50.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
E. Belnoue, C. Guettier, M. Kayibanda, S. Le Rond, A.-M. Crain-Denoyelle, C. Marchiol, M. Ziol, D. Fradelizi, L. Renia, and M. Viguier
Regression of Established Liver Tumor Induced by Monoepitopic Peptide-Based Immunotherapy
J. Immunol., October 15, 2004; 173(8): 4882 - 4888.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
J. Li, W. Li, S. Liang, D. Cai, M. P. Kieny, L. Jacob, A. Linnenbach, J. W. Abramczuk, H. Bender, K. Sproesser, et al.
Recombinant CD63/ME491/Neuroglandular/NKI/C-3 Antigen Inhibits Growth of Established Tumors in Transgenic Mice
J. Immunol., September 15, 2003; 171(6): 2922 - 2929.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
X. Zheng, J.-X. Gao, H. Zhang, T. L. Geiger, Y. Liu, and P. Zheng
Clonal Deletion of Simian Virus 40 Large T Antigen-Specific T Cells in the Transgenic Adenocarcinoma of Mouse Prostate Mice: An Important Role for Clonal Deletion in Shaping the Repertoire of T Cells Specific for Antigens Overexpressed in Solid Tumors
J. Immunol., November 1, 2002; 169(9): 4761 - 4769.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
R. Ganss, E. Ryschich, E. Klar, B. Arnold, and G. J. Hammerling
Combination of T-Cell Therapy and Trigger of Inflammation Induces Remodeling of the Vasculature and Tumor Eradication
Cancer Res., March 1, 2002; 62(5): 1462 - 1470.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
H. Nishikawa, K. Tanida, H. Ikeda, M. Sakakura, Y. Miyahara, T. Aota, K. Mukai, M. Watanabe, K. Kuribayashi, L. J. Old, et al.
Role of SEREX-defined immunogenic wild-type cellular molecules in the development of tumor-specific immunity
PNAS, November 20, 2001; (2001) 251547298.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
T. D. Schell, B. B. Knowles, and S. S. Tevethia
Sequential Loss of Cytotoxic T Lymphocyte Responses to Simian Virus 40 Large T Antigen Epitopes in T Antigen Transgenic Mice Developing Osteosarcomas
Cancer Res., June 1, 2000; 60(11): 3002 - 3012.
[Abstract] [Full Text] [PDF]

Home page
 J. Virol.Home page
T. D. Schell, L. M. Mylin, I. Georgoff, A. K. Teresky, A. J. Levine, and S. S. Tevethia
Cytotoxic T-Lymphocyte Epitope Immunodominance in the Control of Choroid Plexus Tumors in Simian Virus 40 Large T Antigen Transgenic Mice
J. Virol., July 1, 1999; 73(7): 5981 - 5993.
[Abstract] [Full Text]

Home page
 Proc. Natl. Acad. Sci. USAHome page
H. Nishikawa, K. Tanida, H. Ikeda, M. Sakakura, Y. Miyahara, T. Aota, K. Mukai, M. Watanabe, K. Kuribayashi, L. J. Old, et al.
Role of SEREX-defined immunogenic wild-type cellular molecules in the development of tumor-specific immunity
PNAS, December 4, 2001; 98(25): 14571 - 14576.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Romieu, R.
Right arrow Articles by Viguier, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Romieu, R.
Right arrow Articles by Viguier, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS