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*
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; and
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Studies with transgenic mice expressing model proteins as self Ags have shown that T cells with specificity for self proteins can be demonstrated within the peripheral T cell pool (17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27). Although in many cases this may be due to the absence of thymic expression of the transgene, thereby precluding thymic deletion (28, 29, 30, 31), often potentially autoreactive T cells manage to escape deletion by virtue of their lower avidity for self Ag even when the transgene product is expressed in, or is available to the thymus (19, 21, 24, 25, 27, 32). Thus, as tolerance does not necessarily result in the elimination of all self-reactive T cells, efforts to mobilize those residual cells within the repertoire may provide populations of CTL that are capable of destroying tumor cells expressing self Ags.
Indeed, several recent studies have demonstrated variable success in impeding the growth of certain tumors by immunization with self epitopes that are also tumor-associated Ags (33, 34, 35, 36). Even though T cell responsiveness toward the tumor Ag under investigation was exhibited, no information was available concerning the degree to which self-tolerance may have altered the T cell response repertoire of the host. Thus, to assess the impact of self-tolerance on tumor immunotherapy, it would be useful to compare T cell responses by individuals that express the tumor Ag as self protein with those that do not.
To study the effects of tolerance upon the host’s ability to eliminate tumor cells expressing self epitopes, we have explored the immune response to the influenza virus hemagglutinin (HA)3 expressed both as a tumor Ag in renal carcinoma cells, and as a tissue-specific self Ag in Ins-HA transgenic mice that express HA on pancreatic islet ß cells. As demonstrated previously, these mice are tolerant of the ß cell-expressed HA, even after immunization with influenza virus (37). In this current study, we examine the impact of such tolerance upon the growth in these mice of the HA-expressing renal carcinoma cell line.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c mice were purchased from the breeding colony of The Scripps Research Institute (TSRI, La Jolla, CA). Ins-HA transgenic mice (37) and Clone-4 TCR transgenic mice (38) were generated and characterized as previously described. Each line was back-crossed for at least eight generations with BALB/c mice. All mice were bred and maintained under specific pathogen-free conditions in TSRI vivarium. All experimental procedures were conducted according to the guidelines laid out in National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Cells
The renal carcinoma cell line Renca (39) was originally provided by Dr. Robert Wiltrout (National Cancer Institute, Frederick, MD). Renca-HA was generated by calcium phosphate-mediated plasmid transfection with the construct pIHA, which encodes the HA molecule of the influenza virus A/PR/8/34 (H1N1). Transfection was performed using a Stratagene kit (Stratagene, La Jolla, CA), according to the manufacturer’s instructions. Transfectants were selected in 400 mg/ml of the neomycin analogue, G418 (Life Technologies, Gaithersburg, MD). Drug-resistant cells were sorted for HA expression by staining with the mAb H18, and collecting >105 HA-bright cells per sort to maintain polyclonality. Sorted cells were expanded and resorted a total of five times. Both Renca and Renca-HA cells were maintained in our laboratory by weekly passage in RPMI 1640 medium containing 10% v/v FCS, 25 mM HEPES, 2 mM glutamine, 5 x 10-5 M ß-mercaptoethanol, and 50 mg/ml gentamicin (complete RPMI). Renca-HA cells were grown in complete RPMI supplemented with 200 mg/ml of G418. The SV40-transformed H-2d cell line, B10.D2, was used as a target cell in 51Cr release assays. It was obtained from Dr. Barbara Knowles, University of Pennsylvania (Philadelphia).
Viruses
Influenza virus A/PR/8/34/(H1N1) was grown in the allantoic cavity of 10- to 11-day-old hen’s eggs. Upon isolation, the allantoic fluid was titered for hemagglutination using chick RBC and stored in 1-ml aliquots at -70°C. Wild-type vaccinia virus (Vacc-WT), and the recombinant vaccinia viruses expressing either the whole HA protein (Vacc-HA), or the H-2Kd-restricted HA peptide, IYSTVASSL, (HA(M518–526)-Vacc-KdHA, were kindly provided by Drs. Jack R. Bennink and Jonathan Yewdell from National Institutes of Health.
Peptide
Influenza virus A/PR/8/34 (H1N1) HA peptide (518–526) (sequence: IYSTVASSL) (40) and nucleoprotein (NP) peptide (sequence: TYQRTRALV) were synthesized by TSRI core facility using a 430A peptide synthesizer (Applied Biosystems, Foster City, CA).
Immunization
Six- to eight-week-old mice were injected i.p. with virus. Mice were given 1200 HA units of influenza virus A/PR/8 in the form of allantoic fluid, or 108 plaque-forming units of Vacc-KdHA in PBS.
Flow cytometry
Single cell suspension of Renca and Renca-HA cells was prepared, and 1 x 106 cells were incubated for 20 min on ice with the mouse anti-HA Ab 37/38. Cells were washed three times in PBS containing 1% w/v BSA (Sigma Chemical Co., St. Louis, MO) and 0.02% w/v sodium azide. Cells were then incubated for 20 min on ice with FITC-conjugated goat anti-mouse IgG (Jackson ImmunoResearch Laboratories, Avondale, PA). All cells were analyzed with a FACScan and CELLQuest software (Becton Dickinson, Mountain View, CA).
Production of effector CTL
Mice immunized with either influenza virus A/PR/8 or Vacc-KdHA were killed after 3 wk, and splenocytes were seeded into 24-well tissue culture plates at 6 x 106 cells/well in 1 ml complete RPMI. APCs were prepared as follows: splenocytes from BALB/c mice were irradiated with 3000 rad and then pulsed for 1 h with either 5 µg/ml of KdHA peptide or 1200 HA units of influenza virus A/PR/8 in 1 ml complete RPMI without FCS. After washing three times in complete RPMI to remove unbound virus/peptide, 1 ml containing 6 x 106 cells was added to the responder Clone-4 TCR splenocytes and cultured for 6 days at 37°C in a humidified incubator with 5% v/v CO2. Clone-4 TCR transgenic effector CTL were prepared as follows: 2 x 106 splenocytes from Clone-4 TCR transgenic mice were seeded into 24-well tissue culture plates containing 6 x 106 cells/well KdHA peptide-pulsed irradiated APCs and cultured for 5 days, as described above.
Cytotoxicity assay
Cells to be used as targets were prepared by incubating at
37°C with 200 µCi of sodium 51chromate for 1
h in the presence or absence of various concentrations of
KdHA peptide, as indicated, or 1200 HA units of influenza
virus A/PR/8. Cells were incubated with Vacc-WT or recombinant vaccinia
viruses Vacc-HA or Vacc-KdHA at an MOI of 10 plaque-forming
units/cell. Target cells were washed three times, resuspended in
complete RPMI, and seeded into 96-well plates at 1 x
104 cells/well in 100 µl of complete RPMI. Effector CTL
were harvested and washed three times in complete RPMI and seeded into
duplicate wells containing the appropriate target cells at various E:T
cell ratios, making a final volume of 200 µl. Plates were incubated
at 37°C in a humidified incubator with 5% v/v CO2 for
6 h. Plates were centrifuged, and 100 µl of supernatant was
removed from each well to assess isotope release using a
-irradiation counter. The percent specific lysis was determined by
the formula: percent specific lysis = (sample release -
spontaneous release/maximum release - spontaneous release) x
100. All cytolytic analyses described in this work were performed at
least three times.
Inoculation and growth of Renca tumor cells
Mice were inoculated s.c. into the left shoulder with 1 x 106 tumor cells in 100 µl of PBS. The size of tumors was determined using the following formula (a2 x b/2), in which a = horizontal diameter, and b = vertical diameter of the tumor mass, as determined using calipers. Tumor cell suspensions from solid tumors to be used as target cells for recognition by KdHA-specific CTL were prepared as follows: mice were killed and the tumor was excised and cut into small pieces approximately 1 to 2 mm3. These were placed into 5 ml of RPMI medium containing only 2.5 U/ml of collagenase A (Boehringer Mannheim Corp., La Jolla, CA) and agitated at 37°C for 45 min. The supernatant containing dispersed tumor cells was removed and the cells were washed three times in complete RPMI before culturing in complete RPMI.
Immunohistochemistry
Pancreata were excised and one-half was embedded in O.C.T. compound (Miles, Elkhart, IN) and frozen at -70°C. The other half was fixed in 10% v/v Formalin solution (Sigma Chemical Co.) and processed for paraffin embedding. Frozen tissues were cut using a cryomicrotome, and paraffin-embedded tissue was cut using a regular microtome. All sections were placed onto saline-coated Superfrost slides for processing (Fisher Scientific, Pittsburgh, PA). Frozen sections were fixed for 20 min in 1% w/v paraformaldehyde (Sigma Chemical Co.) in PBS, and washed for 5 min in PBS. Nonspecific binding sites were blocked using an avidin-biotin blocking kit (Vector Labs, Burlingame, CA). Sections were incubated for 1 h with affinity-purified rat Abs against mouse CD8 (PharMingen, La Jolla, CA). After washing for 10 min with PBS, sections were incubated with secondary biotinylated affinity-purified F(ab')2 mouse anti-rat IgG Abs for 1 h, and then detected using streptavidin-conjugated horseradish peroxidase (Jackson ImmunoResearch Laboratories), together with diaminobenzidine (DAB) chromagen. Paraffin sections were deparaffinized in xylene and rehydrated in graded ethanol to distilled water. Nonspecific binding sites were blocked by incubating with 10% v/v goat serum in PBS. Sections were incubated for 1 h with guinea pig Abs against mouse insulin (Dako Corp., Carpenteria, CA). After washing for 10 min in PBS, sections were incubated with secondary biotinylated F(ab')2 goat anti-guinea pig IgG (Vector Labs), and detected as described above. Separate serial sections of paraffin-embedded tissue were also stained with eosin (Sigma Chemical Co.), and all slides were counterstained with Mayer’s hematoxylin (Sigma Chemical Co.).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies from our laboratory demonstrated that transgenic
mice expressing the influenza virus HA under the control of the rat
insulin promoter (Ins-HA mice) were tolerant of HA expressed by the
pancreatic ß cells, and did not develop autoimmune diabetes, even
after immunization with influenza A/PR/8/34 (PR8) (37). However, the
presence of KdHA-specific CD8+ T cells,
obtained from either influenza virus-primed nontransgenic mice, or from
Clone-4 TCR transgenic mice that express a TCR specific for a
Kd-restricted peptide epitope of HA, results in autoimmune
destruction of the pancreatic islet ß cells in Ins-HA mice and the
onset of diabetes (37, 38). To address the effect of self-tolerance
upon the recognition of tumor cells expressing self epitope, the BALB/c
renal carcinoma cell line (Renca) was transfected with the HA gene from
PR8 (Renca-HA). Expression of the HA gene was confirmed by the presence
of HA protein on the cell surface, as determined by FACS analysis using
anti-HA Abs (Fig. 1
A). Lysis of Renca-HA
cells was observed using CTL obtained from Clone-4 TCR transgenic mice
(38) (Fig. 1B). CD8+ T cells obtained
from Clone-4 TCR mice have specificity for the dominant epitope of the
HA molecule, the IYSTVASSL peptide, that is presented in association
with H-2Kd (40).
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, A and B).
Renca-HA cells did not grow in conventional BALB/c mice (Fig. 2C), but did grow in Ins-HA mice (Fig. 2D). On day 35, a small tumor appeared in two of the
BALB/c recipients. However, target cells prepared from the excised
tumor were not lysed by KdHA-specific Clone-4 CTL,
indicating that these tumor cells had lost expression of HA (data not
shown). In contrast, target cells prepared from tumor excised from
Ins-HA recipients on day 17 following transfer were lysed by Clone-4
CTL (data not shown). These results suggested that HA expression by the
tumor resulted in generation of an immune response capable of
eliminating Renca HA cells in the BALB/c mouse, but not in the Ins-HA
mouse.
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Recent studies in which tumor-associated self Ags have been used
as a basis for tumor vaccines suggest that it may be possible to obtain
effective tumor-specific immunity while maintaining self-tolerance (5, 33, 36). To determine whether the HA molecule could function as a tumor
Ag in tolerant mice, we compared the growth of the Renca-HA tumor cells
in unprimed Ins-HA mice and mice previously immunized with the
influenza virus. Three weeks before the introduction of Renca-HA tumor
cells, Ins-HA mice were primed with PR8 virus. Fifteen days after
injection of the Renca-HA cells, solid tumors appeared in the unprimed
Ins-HA mice (Fig. 3A);
however, none of the Ins-HA mice immunized with PR8 developed tumors
(Fig. 3B). Significantly, all mice remained
euglycemic throughout the experiment (data not shown). However, the
fact that none of these mice was diabetic did not rule out the
possibility that as a consequence of tumor rejection, some degree of
ß cell destruction may have occurred. Thus, a histologic examination
of pancreata obtained from these mice was performed. Sections of
pancreatic tissue taken from unprimed Ins-HA mice showed no signs of
any lymphocytic infiltration of the islets or surrounding parenchyma
(Fig. 4, A and
B). Islet cell clusters appeared intact and expressed
high levels of insulin (Fig. 4C). Following
immunization of Ins-HA mice with PR8, the vast majority of pancratic
islets remained free of any cellular infiltration, although an
extremely small number, fewer than 10%, demonstrated a peripheral
localization of CD8+ T cells. However, such peri-insulitis
was not associated with ß cell destruction, as analyses of serial
sections of pancreatic tissue demonstrated uniform insulin expression
by these islets. Rejection of Renca-HA cells by PR8-primed Ins-HA mice
did not result in an increase in either the total number of islets
demonstrating peri-insulitis, or the amount of cellularity exibited by
such islets. Sections of islets that exibit the most cellularity within
the pancreatic tissue are demonstrated (Fig. 4D–F). CD8+ T cells were
present at the periphery of the islets (Fig. 4D, arrows);
however, examination of insulin expression, in serial sections of
infiltrated islets, gave no evidence of any associated ß cell
destruction (Fig. 4, E and F). Together,
these observations indicated that successful rejection of Renca-HA
tumor cells by Ins-HA mice could occur while maintaining tolerance to
ß cells expressing HA.
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The demonstration of CD8+ T cells within the
periphery of some of the islets from PR8-primed Ins-HA mice, as well as
the success in preventing growth of the Renca-HA cells, compelled us to
examine more carefully the HA-specific T cell response in the tolerant
animals. Conventional BALB/c mice respond to immunization with PR8 by
providing H-2Kd-restricted CTL populations that, upon
restimulation in vitro with PR8-infected APCs, demonstrate specificity
for the dominant Kd-restricted epitope of the influenza
virus NP and the HA, whereas only CTL specific for KdNP
were obtained from Ins-HA mice (Table I).
Thus, as reported previously, tolerance to KdHA is observed
both in vivo and in vitro (37).
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). However, the CTL obtained from Ins-HA
mice demonstrated much lower avidity for KdHA peptide as
compared with the BALB/c effector cells, requiring 100-fold more
peptide to achieve comparable lysis. Such low avidity CTL are not
specific for impurities within the peptide preparation, as evidenced by
the fact that there is an absolute requirement for prior immunization
of Ins-HA mice with PR8 to generate these CTL in vitro (data not
shown). Furthermore, target cells infected with a minigene encoding the
KdHA peptide, IYSTVASSL (Vacc-KdHA), were
also lysed by such CTL (Fig. 6).
Therefore, in Ins-HA mice, tolerance of HA was associated with a T cell
repertoire devoid of high avidity KdHA-specific CTL. Only
targets presenting high densities of the KdHA peptide are
lysed by these low avidity CTL.
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shows that following injection with
Renca-HA tumor cells, BALB/c mice were able to generate CTL having high
avidity for KdHA peptide-pulsed target cells, whereas
KdHA-specific CTL could not be obtained from Ins-HA mice
even after cells were cultured with APCs that had been pulsed with a
high concentration of KdHA peptide.
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These data demonstrated that prior immunization of Ins-HA mice
with PR8 could prevent the growth of Renca-HA cells. However, as such
immunization could also lead to stimulation of Ab and/or T cells with
specificity for portions of the HA other than the IYSTVASSL
peptide, it was of interest to determine whether the priming of CTL
specific for this particular epitope was actually sufficient for tumor
rejection. To this end, Ins-HA mice were infected with
Vacc-KdHA, before receiving Renca-HA cells. As was
observed following immunization with PR8, in vitro restimulation of
splenocytes obtained from Vacc-KdHA-primed Ins-HA mice with
KdHA peptide-pulsed APCs resulted in a population of
CTL that demonstrated low avidity for KdHA (Fig. 5
). As
described in Figure 8, Renca-HA cells
grew in Ins-HA mice previously immunized with Vacc-WT, whereas
tumor cells were rejected following transfer into Ins-HA mice that
received the Vacc-KdHA. Thus, vaccination of Ins-HA mice
with the dominant KdHA peptide was sufficient to prevent
the growth of Renca-HA tumor cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first compared conventional BALB/c mice and Ins-HA mice with respect to their ability to support the growth of tumor cells that express HA. Although the untransfected parental cells (Renca) grew progressively in both mouse lines, Renca-HA cells were rejected by BALB/c mice. This, together with the fact that KdHA-specific CTL were detectable in BALB/c mice, indicated that the anti-HA immune response in BALB/c mice is successful in eliminating tumor cells expressing a high concentration of this foreign protein. It is not yet clear as to the identity of the APCs involved in presentation of Ag to KdHA-specific CTLp. Studies in other tumor models have concluded that tumor cells generally do not directly stimulate T cells, and that the Ags must first be processed by professional APCs that are better able to provide both Ag and costimulatory molecules required for T cell stimulation (41, 42). HA expression by the tumor may provide abundant Ag for APC processing through the cross-priming pathway (43, 44). However, the dependence of T cells on costimulation is inversely related to the amount of Ag available for stimulation (45, 46). Renca-HA cells do not express the B7 costimulatory molecule (data not shown), thus it would be anticipated that only those cells with relatively high avidity for HA epitopes could be activated in the absence of appropriate costimulatory signals (38, 45, 47, 48, 49, 50, 51). In conventional BALB/c mice, it is possible that Renca-HA cells may themselves directly stimulate high avidity CTLp. Considering that HA is expressed at relatively high levels by these cells, it would be of interest to determine whether the HA-specific immune response in BALB/c mice is as effective in a situation in which the Ag density is somewhat lower. Future experiments will address this issue.
Importantly, Ins-HA mice that had received the Renca-HA cells demonstrated progressive growth of the tumor and did not demonstrate KdHA-specific CTL. The failure of tumor cells to activate residual low avidity KdHA-specific T cells present in Ins-HA mice is consistent with a requirement for high epitope density as well as costimulation to stimulate these cells. These requirements were fulfilled by the use of influenza PR8 or Vacc-KdHA as the immunogen. Priming the Ins-HA mice with either of these viruses resulted in a population of memory cells that was able to subsequently eliminate the Renca-HA cells. It has been proposed that tolerance to self epitopes most affects those T cells that are specific for dominant epitopes, and may spare T cells with specificity for cryptic epitopes from these same proteins (14, 52). The fact that recognition of the dominant Kd-restricted HA epitope presented by Vacc-KdHA was sufficient for tumor rejection, indicates that low avidity cells, specific for dominant epitopes, can be recruited for tumor elimination. The priming of CTL specific for this KdHA epitope may have been facilitated by the generation of a helper response to vaccinia Ags, bypassing tolerance of HA-specific CD4+ T cells that we previously demonstrated in Ins-HA mice (37). We have ruled out a need for the participation of HA-specific Abs in the tumor rejection process as, following immunization of Ins-HA mice with PR8, HA-specific Abs were readily observed in the serum of the Ins-HA mice; none was detected in sera from mice that had been immunized with Vacc-KdHA (data not shown).
Our results present the rather paradoxical findings that, although tolerance to a self epitope presented by the pancreas can be maintained, the immune response to this same epitope can succeed in preventing growth of tumor cell expressing the same Ag. Several factors may contribute to this observation. First, it has been demonstrated that T cell avidity can determine the success of in vivo T cell function. For example, low avidity CTL are unable to function in viral clearance in vivo (53, 54). KdHA-specific CTL obtained from Ins-HA mice represent such low avidity T cells, and accordingly, the inability of these primed T cells to cause diabetes is most likely due to their low avidity, rather then their access to the pancreas. Indeed, histologic examination revealed that although CD8+ T cells are present at the periphery of the islets, they remained intact. However, it still remains to be explained how these same T cells succeed in tumor elimination. One factor that cannot be dismissed easily is that trauma induced by the tumor injection may be accompanied by a degree of inflammation that facilitates rejection by a primed T cell response. Perhaps the simplest explanation would be that there is a higher density of KdHA epitope presented on the transfected Renca-HA cells than on the islet ß cell. Thus, it would be predicted that tumor cells expressing less KdHA epitope may not be eliminated in Ins-HA mice preimmunized with influenza. Alternatively, other factors may exist that protect the ß cells by dampening the activation status of the T cells.
This study demonstrates the successful use of a vaccine vector expressing a self epitope that is capable of eliciting an immune response against tumor cells expressing the same self epitope; yet at the same time, tolerance to peripherally expressed HA is maintained. This model is analogous to expression of a variety of naturally occurring Ags that are up-regulated in their expression in tumor cells. Indeed, recent findings from several laboratories have demonstrated the success of vaccination against p53 and its antigenic peptides in preventing growth of tumors that express high levels of this tumor-associated protein (33, 36). Although low level expression of p53 is known to occur in a variety of tissues (55, 56, 57), no experiments were conducted that determined whether or not self-tolerance had affected the T cell repertoire available for recognition of epitopes from p53 expressed by the tumor cells. Recent studies comparing responses to epitopes of p53 in p53-deficient and p53-sufficient mice have demonstrated a reduction in the response to A2-restricted epitopes that is attributable to self-tolerance (58). Thus, it is likely that some degree of tolerance to p53 normally occurs, and that immunization succeeded in mobilizing the residual repertoire.
There are a number of major concerns regarding the immunization of individuals with vaccines containing self epitopes. If tolerance to these epitopes is broken, then populations of CTL may be generated that not only demonstrate tumor-specific cytotoxicity, but also have the capability of engaging in autoimmune destruction of other tissues expressing the self epitope. Studies with the Ins-HA model may help to further define the limitations of this type of tumor therapy, and also elucidate the most successful forms of tumor immunotherapy.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Linda A. Sherman, 10550 North Torrey Pines Road, IMM-15, La Jolla, CA 92037. E-mail address:
3 Abbreviations used in this paper: HA, hemagglutinin; CTLp, cytotoxic T lymphocyte precursor; Ins, insulin; NP, nucleoprotein; DAB, diaminobenzidine; Vacc, vaccinia virus; WT, wild-type.
Received for publication July 3, 1997. Accepted for publication September 30, 1997.
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A. D. Gritzapis, L. G. Mahaira, S. A. Perez, N. T. Cacoullos, M. Papamichail, and C. N. Baxevanis Vaccination with Human HER-2/neu (435-443) CTL Peptide Induces Effective Antitumor Immunity against HER-2/neu-Expressing Tumor Cells In vivo. Cancer Res., May 15, 2006; 66(10): 5452 - 5460. [Abstract] [Full Text] [PDF]
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S. K. Bunt, P. Sinha, V. K. Clements, J. Leips, and S. Ostrand-Rosenberg Inflammation Induces Myeloid-Derived Suppressor Cells that Facilitate Tumor Progression J. Immunol., January 1, 2006; 176(1): 284 - 290. [Abstract] [Full Text] [PDF]
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K. Liu, J. Idoyaga, A. Charalambous, S.-i. Fujii, A. Bonito, J. Mordoh, R. Wainstok, X.-F. Bai, Y. Liu, and R. M. Steinman Innate NKT lymphocytes confer superior adaptive immunity via tumor-capturing dendritic cells J. Exp. Med., December 5, 2005; 202(11): 1507 - 1516. [Abstract] [Full Text] [PDF]
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 K. R. Ryan, D. McCue, and S. M. Anderton Fas-mediated death and sensory adaptation limit the pathogenic potential of autoreactive T cells after strong antigenic stimulation J. Leukoc. Biol., July 1, 2005; 78(1): 43 - 50. [Abstract] [Full Text] [PDF]
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L. Steinaa, P. B. Rasmussen, A. M. Wegener, L. Sonderbye, D. R. Leach, J. Rygaard, S. Mouritsen, and A. M. Gautam Linked Foreign T-Cell Help Activates Self-Reactive CTL and Inhibits Tumor Growth J. Immunol., July 1, 2005; 175(1): 329 - 334. [Abstract] [Full Text] [PDF]
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A. M. Ercolini, B. H. Ladle, E. A. Manning, L. W. Pfannenstiel, T. D. Armstrong, J.-P. H. Machiels, J. G. Bieler, L. A. Emens, R. T. Reilly, and E. M. Jaffee Recruitment of latent pools of high-avidity CD8+ T cells to the antitumor immune response J. Exp. Med., May 16, 2005; 201(10): 1591 - 1602. [Abstract] [Full Text] [PDF]
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M. A. Lyman, C. T. Nugent, K. L. Marquardt, J. A. Biggs, E. G. Pamer, and L. A. Sherman The Fate of Low Affinity Tumor-Specific CD8+ T Cells in Tumor-Bearing Mice J. Immunol., March 1, 2005; 174(5): 2563 - 2572. [Abstract] [Full Text] [PDF]
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G. Zhou, Z. Lu, J. D. McCadden, H. I. Levitsky, and A. L. Marson Reciprocal Changes in Tumor Antigenicity and Antigen-specific T Cell Function during Tumor Progression J. Exp. Med., December 20, 2004; 200(12): 1581 - 1592. [Abstract] [Full Text] [PDF]
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G. R. Leggatt, S. Narayan, G. J. P. Fernando, and I. H. Frazer Changes to peptide structure, not concentration, contribute to expansion of the lowest avidity cytotoxic T lymphocytes J. Leukoc. Biol., October 1, 2004; 76(4): 787 - 795. [Abstract] [Full Text] [PDF]
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W. C. Bartholomae, F. H. Rininsland, J. C. Eisenberg, B. O. Boehm, P. V. Lehmann, and M. Tary-Lehmann T Cell Immunity Induced by Live, Necrotic, and Apoptotic Tumor Cells J. Immunol., July 15, 2004; 173(2): 1012 - 1022. [Abstract] [Full Text] [PDF]
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C. W. Lawrence and T. J. Braciale Activation, Differentiation, and Migration of Naive Virus-Specific CD8+ T Cells during Pulmonary Influenza Virus Infection J. Immunol., July 15, 2004; 173(2): 1209 - 1218. [Abstract] [Full Text] [PDF]
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M. A. Mihalyo, A. D. H. Doody, J. P. McAleer, E. C. Nowak, M. Long, Y. Yang, and A. J. Adler In Vivo Cyclophosphamide and IL-2 Treatment Impedes Self-Antigen-Induced Effector CD4 Cell Tolerization: Implications for Adoptive Immunotherapy J. Immunol., May 1, 2004; 172(9): 5338 - 5345. [Abstract] [Full Text] [PDF]
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 M. Y. Mapara and M. Sykes Tolerance and Cancer: Mechanisms of Tumor Evasion and Strategies for Breaking Tolerance J. Clin. Oncol., March 15, 2004; 22(6): 1136 - 1151. [Abstract] [Full Text] [PDF]
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A. Vogt, P.-T. Chuang, J. Hebert, J. Hwang, Y. Lu, L. Kopelovich, M. Athar, D. R. Bickers, and E. H. Epstein Jr. Immunoprevention of Basal Cell Carcinomas with Recombinant Hedgehog-interacting Protein J. Exp. Med., March 15, 2004; 199(6): 753 - 761. [Abstract] [Full Text] [PDF]
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 T. D. Schell In Vivo Expansion of the Residual Tumor Antigen-Specific CD8+ T Lymphocytes That Survive Negative Selection in Simian Virus 40 T-Antigen-Transgenic Mice J. Virol., February 15, 2004; 78(4): 1751 - 1762. [Abstract] [Full Text] [PDF]
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C. Lane, J. Leitch, X. Tan, J. Hadjati, J. L. Bramson, and Y. Wan Vaccination-Induced Autoimmune Vitiligo Is a Consequence of Secondary Trauma to the Skin Cancer Res., February 15, 2004; 64(4): 1509 - 1514. [Abstract] [Full Text] [PDF]
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A. Cuenca, F. Cheng, H. Wang, J. Brayer, P. Horna, L. Gu, H. Bien, I. M. Borrello, H. I. Levitsky, and E. M. Sotomayor Extra-Lymphatic Solid Tumor Growth Is Not Immunologically Ignored and Results in Early Induction of Antigen-Specific T-Cell Anergy: Dominant Role of Cross-Tolerance to Tumor Antigens Cancer Res., December 15, 2003; 63(24): 9007 - 9015. [Abstract] [Full Text] [PDF]
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K. J. Young, L. S. Kay, M. J. Phillips, and L. Zhang Antitumor Activity Mediated by Double-Negative T Cells Cancer Res., November 15, 2003; 63(22): 8014 - 8021. [Abstract] [Full Text] [PDF]
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C. Cuadros, A. L. Dominguez, G. I. Frost, P. Borgstrom, and J. Lustgarten Cooperative Effect between Immunotherapy and Antiangiogenic Therapy Leads to Effective Tumor Rejection in Tolerant Her-2/neu Mice Cancer Res., September 15, 2003; 63(18): 5895 - 5901. [Abstract] [Full Text] [PDF]
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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]
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T. Azuma, T. Takahashi, A. Kunisato, T. Kitamura, and H. Hirai Human CD4+ CD25+ Regulatory T Cells Suppress NKT Cell Functions Cancer Res., August 1, 2003; 63(15): 4516 - 4520. [Abstract] [Full Text] [PDF]
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 R. Schroers, L. Shen, L. Rollins, Z. Xiao, G. Sonderstrup, K. Slawin, X. F. Huang, and S.-Y. Chen Identification of MHC Class II-restricted T-cell Epitopes in Prostate-specific Membrane Antigen Clin. Cancer Res., August 1, 2003; 9(9): 3260 - 3271. [Abstract] [Full Text] [PDF]
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J. W. Hodge, D. W. Grosenbach, W. M. Aarts, D. J. Poole, and J. Schlom Vaccine Therapy of Established Tumors in the Absence of Autoimmunity Clin. Cancer Res., May 1, 2003; 9(5): 1837 - 1849. [Abstract] [Full Text] [PDF]
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M. P. Rubinstein, A. N. Kadima, M. L. Salem, C. L. Nguyen, W. E. Gillanders, M. I. Nishimura, and D. J. Cole Transfer of TCR Genes into Mature T Cells Is Accompanied by the Maintenance of Parental T Cell Avidity J. Immunol., February 1, 2003; 170(3): 1209 - 1217. [Abstract] [Full Text] [PDF]
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C. E. Touloukian, W. W. Leitner, R. E. Schnur, P. F. Robbins, Y. Li, S. Southwood, A. Sette, S. A. Rosenberg, and N. P. Restifo Normal Tissue Depresses While Tumor Tissue Enhances Human T Cell Responses In Vivo to a Novel Self/Tumor Melanoma Antigen, OA1 J. Immunol., February 1, 2003; 170(3): 1579 - 1585. [Abstract] [Full Text] [PDF]
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B. Yu, S. Kusmartsev, F. Cheng, M. Paolini, Y. Nefedova, E. Sotomayor, and D. Gabrilovich Effective Combination of Chemotherapy and Dendritic Cell Administration for the Treatment of Advanced-Stage Experimental Breast Cancer Clin. Cancer Res., January 1, 2003; 9(1): 285 - 294. [Abstract] [Full Text] [PDF]
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A. Castilleja, D. Carter, C. L. Efferson, N. E. Ward, K. Kawano, B. Fisk, A. P. Kudelka, D. M. Gershenson, J. L. Murray, C. A. O'Brian, et al. Induction of Tumor-Reactive CTL by C-Side Chain Variants of the CTL Epitope HER-2/neu Protooncogene (369-377) Selected by Molecular Modeling of the Peptide: HLA-A2 Complex J. Immunol., October 1, 2002; 169(7): 3545 - 3554. [Abstract] [Full Text] [PDF]
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A. D. Higgins, M. A. Mihalyo, and A. J. Adler Effector CD4 Cells Are Tolerized Upon Exposure to Parenchymal Self-Antigen J. Immunol., October 1, 2002; 169(7): 3622 - 3629. [Abstract] [Full Text] [PDF]
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C. A. Lawendowski, G. M. Giurleo, Y. Y. Huang, G. J. Franklin, J. M. Kaplan, B. L. Roberts, and C. A. Nicolette Solid-Phase Epitope Recovery: A High Throughput Method for Antigen Identification and Epitope Optimization J. Immunol., September 1, 2002; 169(5): 2414 - 2421. [Abstract] [Full Text] [PDF]
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J. Hernandez, S. Aung, K. Marquardt, and L. A. Sherman Uncoupling of Proliferative Potential and Gain of Effector Function by CD8+ T Cells Responding to Self-Antigens J. Exp. Med., August 5, 2002; 196(3): 323 - 333. [Abstract] [Full Text] [PDF]
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C. Ohlen, M. Kalos, L. E. Cheng, A. C. Shur, D. J. Hong, B. D. Carson, N. C.T. Kokot, C. G. Lerner, B. D. Sather, E. S. Huseby, et al. CD8+ T Cell Tolerance to a Tumor-associated Antigen Is Maintained at the Level of Expansion Rather than Effector Function J. Exp. Med., June 3, 2002; 195(11): 1407 - 1418. [Abstract] [Full Text] [PDF]
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J.-Y. Sun, R. S. Krouse, S. J. Forman, D. Senitzer, I. Sniecinski, S. Chatterjee, and K. K. Wong Jr. Immunogenicity of a p210BCR-ABL Fusion Domain Candidate DNA Vaccine Targeted to Dendritic Cells by a Recombinant Adeno-associated Virus Vector in Vitro Cancer Res., June 1, 2002; 62(11): 3175 - 3183. [Abstract] [Full Text] [PDF]
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R. Schroers, X. F. Huang, J. Hammer, J. Zhang, and S.-Y. Chen Identification of HLA DR7-restricted Epitopes from Human Telomerase Reverse Transcriptase Recognized by CD4+ T-Helper Cells Cancer Res., May 1, 2002; 62(9): 2600 - 2605. [Abstract] [Full Text] [PDF]
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C. M. zum Buschenfelde, C. Hermann, B. Schmidt, C. Peschel, and H. Bernhard Antihuman Epidermal Growth Factor Receptor 2 (HER2) Monoclonal Antibody Trastuzumab Enhances Cytolytic Activity of Class I-restricted HER2-specific T Lymphocytes Against HER2-overexpressing Tumor Cells Cancer Res., April 1, 2002; 62(8): 2244 - 2247. [Abstract] [Full Text] [PDF]
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L. T. Nguyen, A. R. Elford, K. Murakami, K. M. Garza, S. P. Schoenberger, B. Odermatt, D. E. Speiser, and P. S. Ohashi Tumor Growth Enhances Cross-Presentation Leading to Limited T Cell Activation without Tolerance J. Exp. Med., February 11, 2002; 195(4): 423 - 435. [Abstract] [Full Text] [PDF]
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T. A. Cordaro, K. E. de Visser, F. H. Tirion, T. N. M. Schumacher, and A. M. Kruisbeek Can the Low-Avidity Self-Specific T Cell Repertoire Be Exploited for Tumor Rejection? J. Immunol., January 15, 2002; 168(2): 651 - 660. [Abstract] [Full Text] [PDF]
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 A C Armstrong and R E Hawkins Vaccines in oncology: background and clinical potential Br. J. Radiol., November 1, 2001; 74(887): 991 - 1002. [Abstract] [Full Text] [PDF]
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K. E. de Visser, T. A. Cordaro, H. W. H. G. Kessels, F. H. Tirion, T. N. M. Schumacher, and A. M. Kruisbeek Low-Avidity Self-Specific T Cells Display a Pronounced Expansion Defect That Can Be Overcome by Altered Peptide Ligands J. Immunol., October 1, 2001; 167(7): 3818 - 3828. [Abstract] [Full Text] [PDF]
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J. Hernandez, S. Aung, W. L. Redmond, and L. A. Sherman Phenotypic and Functional Analysis of Cd8+ T Cells Undergoing Peripheral Deletion in Response to Cross-Presentation of Self-Antigen J. Exp. Med., September 17, 2001; 194(6): 707 - 718. [Abstract] [Full Text] [PDF]
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A. G. Cawthon, H. Lu, and M. A. Alexander-Miller Peptide Requirement for CTL Activation Reflects the Sensitivity to CD3 Engagement: Correlation with CD8{alpha}{beta} Versus CD8{alpha}{alpha} Expression J. Immunol., September 1, 2001; 167(5): 2577 - 2584. [Abstract] [Full Text] [PDF]
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C. Meyer zum Buschenfelde, J. Metzger, C. Hermann, N. Nicklisch, C. Peschel, and H. Bernhard The Generation of Both T Killer and Th Cell Clones Specific for the Tumor-Associated Antigen HER2 Using Retrovirally Transduced Dendritic Cells J. Immunol., August 1, 2001; 167(3): 1712 - 1719. [Abstract] [Full Text] [PDF]
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S. R. Riddell Progress in cancer vaccines by enhanced self-presentation PNAS, July 31, 2001; 98(16): 8933 - 8935. [Full Text] [PDF]
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H. T. C. Kreuwel, J. A. Biggs, I. M. Pilip, E. G. Pamer, D. Lo, and L. A. Sherman Defective CD8+ T Cell Peripheral Tolerance in Nonobese Diabetic Mice J. Immunol., July 15, 2001; 167(2): 1112 - 1117. [Abstract] [Full Text] [PDF]
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S. C. Eck and L. A. Turka Adoptive Transfer Enables Tumor Rejection Targeted against a Self-Antigen without the Induction of Autoimmunity Cancer Res., April 1, 2001; 61(7): 3077 - 3083. [Abstract] [Full Text]
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J. Hernandez, A. Ko, and L. A. Sherman CTLA-4 Blockade Enhances the CTL Responses to the p53 Self-Tumor Antigen J. Immunol., March 15, 2001; 166(6): 3908 - 3914. [Abstract] [Full Text] [PDF]
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J. M. Moser, J. D. Altman, and A. E. Lukacher Antiviral Cd8+ T Cell Responses in Neonatal Mice: Susceptibility to Polyoma Virus-Induced Tumors Is Associated with Lack of Cytotoxic Function by Viral Antigen-Specific T Cells J. Exp. Med., March 5, 2001; 193(5): 595 - 606. [Abstract] [Full Text] [PDF]
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C. Ohlen, M. Kalos, D. J. Hong, A. C. Shur, and P. D. Greenberg Expression of a Tolerizing Tumor Antigen in Peripheral Tissue Does Not Preclude Recovery of High-Affinity CD8+ T Cells or CTL Immunotherapy of Tumors Expressing the Antigen J. Immunol., February 15, 2001; 166(4): 2863 - 2870. [Abstract] [Full Text] [PDF]
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A. D. Sette, C. Oseroff, J. Sidney, J. Alexander, R. W. Chesnut, K. Kakimi, L. G. Guidotti, and F. V. Chisari Overcoming T Cell Tolerance to the Hepatitis B Virus Surface Antigen in Hepatitis B Virus-Transgenic Mice J. Immunol., January 15, 2001; 166(2): 1389 - 1397. [Abstract] [Full Text] [PDF]
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E. M. Hiltbold, A. M. Vlad, P. Ciborowski, S. C. Watkins, and O. J. Finn The Mechanism of Unresponsiveness to Circulating Tumor Antigen MUC1 Is a Block in Intracellular Sorting and Processing by Dendritic Cells J. Immunol., October 1, 2000; 165(7): 3730 - 3741. [Abstract] [Full Text] [PDF]
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P. Mukherjee, A. R. Ginardi, C. S. Madsen, C. J. Sterner, M. C. Adriance, M. J. Tevethia, and S. J. Gendler Mice with Spontaneous Pancreatic Cancer Naturally Develop MUC-1-Specific CTLs That Eradicate Tumors When Adoptively Transferred J. Immunol., September 15, 2000; 165(6): 3451 - 3460. [Abstract] [Full Text] [PDF]
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R. T. Reilly, M. B. C. Gottlieb, A. M. Ercolini, J.-P. H. Machiels, C. E. Kane, F. I. Okoye, W. J. Muller, K. H. Dixon, and E. M. Jaffee HER-2/neu Is a Tumor Rejection Target in Tolerized HER-2/neu Transgenic Mice Cancer Res., July 1, 2000; 60(13): 3569 - 3576. [Abstract] [Full Text]
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E. V. Fedoseyeva, F. Boisgerault, N. G. Anosova, W. S. Wollish, P. Arlotta, P. E. Jensen, S. J. Ono, and G. Benichou CD4+ T Cell Responses to Self- and Mutated p53 Determinants During Tumorigenesis in Mice J. Immunol., June 1, 2000; 164(11): 5641 - 5651. [Abstract] [Full Text] [PDF]
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T. A. Colella, T. N.J. Bullock, L. B. Russell, D. W. Mullins, W. W. Overwijk, C. J. Luckey, R. A. Pierce, N. P. Restifo, and V. H. Engelhard Self-Tolerance to the Murine Homologue of a Tyrosinase-Derived Melanoma Antigen: Implications for Tumor Immunotherapy J. Exp. Med., April 3, 2000; 191(7): 1221 - 1232. [Abstract] [Full Text] [PDF]
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B. Ludewig, A. F. Ochsenbein, B. Odermatt, D. Paulin, H. Hengartner, and R. M. Zinkernagel Immunotherapy with Dendritic Cells Directed against Tumor Antigens Shared with Normal Host Cells Results in Severe Autoimmune Disease J. Exp. Med., March 6, 2000; 191(5): 795 - 804. [Abstract] [Full Text] [PDF]
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T. N. J. Bullock, T. A. Colella, and V. H. Engelhard The Density of Peptides Displayed by Dendritic Cells Affects Immune Responses to Human Tyrosinase and gp100 in HLA-A2 Transgenic Mice J. Immunol., March 1, 2000; 164(5): 2354 - 2361. [Abstract] [Full Text] [PDF]
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J. Hernandez, P. P. Lee, M. M. Davis, and L. A. Sherman The Use of HLA A2.1/p53 Peptide Tetramers to Visualize the Impact of Self Tolerance on the TCR Repertoire J. Immunol., January 15, 2000; 164(2): 596 - 602. [Abstract] [Full Text] [PDF]
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C. T. Nugent, D. J. Morgan, J. A. Biggs, A. Ko, I. M. Pilip, E. G. Pamer, and L. A. Sherman Characterization of CD8+ T Lymphocytes That Persist After Peripheral Tolerance to a Self Antigen Expressed in the Pancreas J. Immunol., January 1, 2000; 164(1): 191 - 200. [Abstract] [Full Text] [PDF]
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J. Shimizu, S. Yamazaki, and S. Sakaguchi Induction of Tumor Immunity by Removing CD25+CD4+ T Cells: A Common Basis Between Tumor Immunity and Autoimmunity J. Immunol., November 15, 1999; 163(10): 5211 - 5218. [Abstract] [Full Text] [PDF]
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H. T. C. Kreuwel, D. J. Morgan, T. Krahl, A. Ko, N. Sarvetnick, and L. A. Sherman Comparing the Relative Role of Perforin/Granzyme Versus Fas/Fas Ligand Cytotoxic Pathways in CD8+ T Cell-Mediated Insulin-Dependent Diabetes Mellitus J. Immunol., October 15, 1999; 163(8): 4335 - 4341. [Abstract] [Full Text] [PDF]
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E. M. Sotomayor, I. Borrello, E. Tubb, J. P. Allison, and H. I. Levitsky In vivo blockade of CTLA-4 enhances the priming of responsive T cells but fails to prevent the induction of tumor antigen-specific tolerance PNAS, September 28, 1999; 96(20): 11476 - 11481. [Abstract] [Full Text] [PDF]
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A. van Elsas, A. A. Hurwitz, and J. P. Allison Combination Immunotherapy of B16 Melanoma Using Anti-Cytotoxic T Lymphocyte-Associated Antigen 4 (Ctla-4) and Granulocyte/Macrophage Colony-Stimulating Factor (Gm-Csf)-Producing Vaccines Induces Rejection of Subcutaneous and Metastatic Tumors Accompanied by Autoimmune Depigmentation J. Exp. Med., August 2, 1999; 190(3): 355 - 366. [Abstract] [Full Text] [PDF]
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J. J. Molldrem, P. P. Lee, C. Wang, R. E. Champlin, and M. M. Davis A PR1-Human Leukocyte Antigen-A2 Tetramer Can Be Used to Isolate Low-Frequency Cytotoxic T Lymphocytes from Healthy Donors That Selectively Lyse Chronic Myelogenous Leukemia Cancer Res., June 1, 1999; 59(11): 2675 - 2681. [Abstract] [Full Text] [PDF]
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D. J. Morgan, C. Kurts, H. T. C. Kreuwel, K. L. Holst, W. R. Heath, and L. A. Sherman Ontogeny of T cell tolerance to peripherally expressed antigens PNAS, March 30, 1999; 96(7): 3854 - 3858. [Abstract] [Full Text] [PDF]
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J. Lustgarten, J. Marks, and L. A. Sherman Redirecting Effector T Cells Through Their IL-2 Receptors J. Immunol., January 1, 1999; 162(1): 359 - 365. [Abstract] [Full Text] [PDF]
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R. Romieu, M. Baratin, M. Kayibanda, V. Lacabanne, M. Ziol, J.-G. Guillet, and M. Viguier Cutting Edge: Passive But Not Active CD8+ T Cell-Based Immunotherapy Interferes with Liver Tumor Progression in a Transgenic Mouse Model J. Immunol., November 15, 1998; 161(10): 5133 - 5137. [Abstract] [Full Text] [PDF]
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R. M. Tempero, M. L. VanLith, K. Morikane, G. J. Rowse, S. J. Gendler, and M. A. Hollingsworth CD4+ Lymphocytes Provide MUC1-Specific Tumor Immunity In Vivo That Is Undetectable In Vitro and Is Absent in MUC1 Transgenic Mice J. Immunol., November 15, 1998; 161(10): 5500 - 5506. [Abstract] [Full Text] [PDF]
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B. Minev, J. Hipp, H. Firat, J. D. Schmidt, P. Langlade-Demoyen, and M. Zanetti Cytotoxic T cell immunity against telomerase reverse transcriptase in humans PNAS, April 25, 2000; 97(9): 4796 - 4801. [Abstract] [Full Text] [PDF]
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), Renca
+ KdHA peptide (
), and Renca-HA (
) tumor cells.
Animal was sacrificed and used as
described in Figure 7
