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1.
J Immunol ; 193(9): 4704-11, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25246498

RESUMO

Immunodominance is a complex phenomenon that relies on a mere numerical concept, while being potentially influenced at every step of the immune response. We investigated the mechanisms leading to the establishment of CTL immunodominance in a retroviral model and found that the previously defined subdominant Env-specific CD8(+) T cells are endowed with an unexpectedly higher functional avidity than is the immunodominant Gag-recognizing counterpart. This high avidity, along with the Env Ag overload, results in a supraoptimal TCR engagement. The overstimulation makes Env-specific T lymphocytes more susceptible to apoptosis, thus hampering their expansion and leading to an unintentional "immune kamikazing." Therefore, Ag-dependent, hyperactivation-induced cell death can be regarded as a novel mechanism in the establishment of the immunodominance that restrains and opposes the expansion of high-avidity T cells in favor of lower-affinity populations.


Assuntos
Epitopos Imunodominantes/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos Virais/imunologia , Apoptose/imunologia , Linhagem Celular , Citotoxicidade Imunológica , Feminino , Produtos do Gene env/imunologia , Produtos do Gene gag/imunologia , Humanos , Camundongos , Retroviridae/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/metabolismo
2.
Immunology ; 146(1): 33-49, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25959091

RESUMO

In the Sp6 mouse plasmacytoma model, a whole-cell vaccination with Sp6 cells expressing de novo B7-1 (Sp6/B7) induced anatomically localized and cytotoxic T cell (CTL)-mediated protection against wild-type (WT) Sp6. Both WT Sp6 and Sp6/B7 showed down-regulated expression of MHC H-2 L(d). Increase of H-2 L(d) expression by cDNA transfection (Sp6/B7/L(d)) raised tumour immune protection and shifted most CTL responses towards H-2 L(d)-restricted antigenic epitopes. The tumour-protective responses were not specific for the H-2 L(d)-restricted immunodominant AH1 epitope of the gp70 common mouse tumour antigen, although WT Sp6 and transfectants were able to present it to specific T cells in vitro. Gp70 transcripts, absent in secondary lymphoid organs of naive mice, were detected in immunized mice as well as in splenocytes from naive mice incubated in vitro with supernatants of CTL-lysed Sp6 cell cultures, containing damage-associated molecular patterns (DAMPs). It has been shown that Toll-like receptor triggering induces gp70 expression. Damage-associated molecular patterns are released by CTL-mediated killing of Sp6/B7-Sp6/B7/L(d) cells migrated to draining lymph nodes during immunization and may activate gp70 expression and presentation in most resident antigen-presenting cells. The same could also apply for Mus musculus endogenous ecotropic murine leukaemia virus 1 particles present in Sp6-cytosol, discharged by dying cells and superinfecting antigen-presenting cells. The outcome of such a massive gp70 cross-presentation would probably be tolerogenic for the high-affinity AH1-gp70-specific CTL clones. In this scenario, autologous whole-tumour-cell vaccines rescue tumour-specific immunoprotection by amplification of subdominant tumour antigen responses when those against the immune dominant antigens are lost.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Antígenos H-2/imunologia , Plasmocitoma/imunologia , Animais , Antígenos de Neoplasias/biossíntese , Linfócitos T CD4-Positivos/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Feminino , Antígenos H-2/biossíntese , Antígenos H-2/genética , Proteína HMGB1/metabolismo , Vírus da Leucemia Murina/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Depleção Linfocítica , Subpopulações de Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Plasmocitoma/terapia , Linfócitos T Citotóxicos/imunologia , Vacinação
3.
Front Oncol ; 12: 964219, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36578937

RESUMO

The current level of evidence for immunotherapy in previously untreated microsatellite unstable metastatic colorectal cancer is based on recent pieces of evidence of few studies that demonstrated durable response and clinical benefit, in terms of objective response rate, disease control rate, and progression-free survival in this subgroup of patients. On the basis of combinatorial immunotherapy with nivolumab plus ipilimumab, we report the exceptional case of a complete pathological response in a 21-year-old woman presenting a clinically aggressive stage IV colorectal cancer with massive nodal and liver involvement. Extensive molecular analyses based on whole genome next-generation DNA sequencing, RNA sequencing, fluorescent multiplex immunohistochemistry, and flow cytometry provided a detailed description of tumoral and immunological characteristics of this noteworthy clinical case.

4.
Front Oncol ; 11: 708073, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660275

RESUMO

Prostate cancer (PCa) is the second leading cause of malignancy-related mortality in males in the Western world. Although treatment like prostatectomy and radiotherapy for localized cancer have good results, similar positive outcomes are not achieved in metastatic PCa. Consequently, these aggressive and metastatic forms of PCa urgently need new methods of treatment. We already described an efficient and specific second-generation (2G) Chimeric Antigen Receptor (CAR) against Prostate Specific Membrane Antigen (PSMA), a glycoprotein overexpressed in prostate cancer and also present on neovasculature of several tumor entities. In an attempt to improve efficacy and in vivo survival of anti-PSMA 2G CAR-T cells, we developed a third generation (3G) CAR containing two costimulatory elements, namely CD28 and 4-1BB co-signaling domains, in addition to CD3ζ. Differently from what described for other 3G receptors, our third generation CAR disclosed an antitumor activity in vitro similar to the related 2G CAR that comprises the CD28 co-signaling domain only. Moreover, the additional costimulatory domain produced detrimental effects, which could be attributed to an increased activation-induced cell death (AICD). Indeed, such "superstimulation" resulted in an exhausted phenotype of CAR-T cells, after prolonged in vitro restimulation, a higher frequency of cell death, and an impairment in yielding sufficient numbers of transgenic T lymphocytes. Thus, the optimal combination of costimulatory domains for CAR development should be assessed cautiously and evaluated case-by-case.

5.
Cell Mol Immunol ; 18(5): 1197-1210, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33762685

RESUMO

One of the main goals of vaccine research is the development of adjuvants that can enhance immune responses and are both safe and biocompatible. We explored the application of the natural polymer hyaluronan (HA) as a promising immunological adjuvant for protein-based vaccines. Chemical conjugation of HA to antigens strongly increased their immunogenicity, reduced booster requirements, and allowed antigen dose sparing. HA-based bioconjugates stimulated robust and long-lasting humoral responses without the addition of other immunostimulatory compounds and proved highly efficient when compared to other adjuvants. Due to its intrinsic biocompatibility, HA allowed the exploitation of different injection routes and did not induce inflammation at the inoculation site. This polymer promoted rapid translocation of the antigen to draining lymph nodes, thus facilitating encounters with antigen-presenting cells. Overall, HA can be regarded as an effective and biocompatible adjuvant to be exploited for the design of a wide variety of vaccines.


Assuntos
Adjuvantes Imunológicos/farmacologia , Ácido Hialurônico/farmacologia , Vacinas/farmacologia , Alarminas/metabolismo , Animais , Materiais Biocompatíveis/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Fluorescência , Ácido Hialurônico/química , Imunidade Humoral/efeitos dos fármacos , Inflamação/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Peso Molecular , Ovalbumina/imunologia , Fatores de Tempo
6.
Oncogene ; 39(42): 6544-6555, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32917954

RESUMO

Notwithstanding intensified therapy, a considerable fraction of T-cell acute lymphoblastic leukemia (T-ALL) patients face a dismal prognosis due to primary resistance to treatment and relapse, raising the need for more efficient and targeted therapies. Hedgehog (HH) signaling is a major developmental pathway frequently deregulated in cancer, for which a role in T-ALL is emerging. Mounting evidence suggests that ligand-independent activation of HH pathway occurs in cancer including T-ALL, emphasizing the necessity of dissecting the complex interplay between HH and other signaling pathways regulating activation. In this work, we present a therapeutically relevant crosstalk between HH signaling and the glucocorticoid receptor (NR3C1) pathway acting at the level of GLI1 transcription factor. GLI inhibitor GANT61 and dexamethasone were shown to exert a synergistic anti-leukemic effect in vitro in T-ALL cell lines and patient-derived xenografts. Mechanistically, dexamethasone-activated NR3C1 impaired GLI1 function by dynamically modulating the recruitment of PCAF acetyltransferase and HDAC1 deacetylase. Increased GLI1 acetylation was associated with compromised transcriptional activity and reduced protein stability. In summary, our study identifies a novel crosstalk between GLI1 and NR3C1 signaling pathway which could be exploited in HH-dependent malignancies to increase therapeutic efficacy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Proteínas Hedgehog/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Receptores de Glucocorticoides/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acetilação , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral , Dexametasona/farmacologia , Dexametasona/uso terapêutico , Sinergismo Farmacológico , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Proteínas Hedgehog/antagonistas & inibidores , Histona Desacetilase 1/metabolismo , Humanos , Camundongos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , Estabilidade Proteica/efeitos dos fármacos , Piridinas/farmacologia , Piridinas/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Receptores de Glucocorticoides/agonistas , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores , Proteína GLI1 em Dedos de Zinco/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
7.
Front Immunol ; 8: 197, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28289418

RESUMO

CD4+ T cells have been and are still largely regarded as the orchestrators of immune responses, being able to differentiate into distinct T helper cell populations based on differentiation signals, transcription factor expression, cytokine secretion, and specific functions. Nonetheless, a growing body of evidence indicates that CD4+ T cells can also exert a direct effector activity, which depends on intrinsic cytotoxic properties acquired and carried out along with the evolution of several pathogenic infections. The relevant role of CD4+ T cell lytic features in the control of such infectious conditions also leads to their exploitation as a new immunotherapeutic approach. This review aims at summarizing currently available data about functional and therapeutic relevance of cytotoxic CD4+ T cells in the context of viral infections and virus-driven tumors.

8.
Oncoimmunology ; 6(8): e1313371, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28919988

RESUMO

The identification of universal tumor-specific antigens shared between multiple patients and/or multiple tumors is of great importance to overcome the practical limitations of personalized cancer immunotherapy. Recent studies support the involvement of DEPDC1 in many aspects of cancer traits, such as cell proliferation, resistance to induction of apoptosis and cell invasion, suggesting that it may play key roles in the oncogenic process. In this study, we report that DEPDC1 expression is upregulated in most types of human tumors, and closely linked to a poorer prognosis; therefore, it might be regarded as a novel universal oncoantigen potentially suitable for targeting many different cancers. In this regard, we report the identification of a HLA-A*0201 allele-restricted immunogenic DEPDC1-derived epitope, which is able to induce cytotoxic T lymphocytes (CTL) exerting a strong and specific functional response in vitro toward not only peptide-loaded cells but also triple negative breast cancer (TNBC) cells endogenously expressing the DEPDC1 protein. Such CTL are also therapeutically active against human TNBC xenografts in vivo upon adoptive transfer in immunodeficient mice. Overall, these data provide evidence that this DEPDC1-derived antigenic epitope can be exploited as a new tool for developing immunotherapeutic strategies for HLA-A*0201 patients with TNBC, and potentially many other cancers.

9.
Cancer Res ; 63(9): 2158-63, 2003 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-12727834

RESUMO

The TS/A mouse mammary adenocarcinoma is a poorly immunogenic tumor widely used in preclinical models of cancer immunotherapy. CTLs have often been indicated as important in TS/A tumor destruction, but their generation in this model has been rarely studied, nor have their precise target(s) been identified. We hypothesized that the gp70 Env product of an endogenous murine leukemia virus could be a target antigen for TS/A-specific CTLs and investigated this possibility in four different TS/A cell lines engineered with the genes that encode IFN-alpha, IFN-gamma, interleukin-4, and B7.1, respectively. All tumor cell lines expressed gp70, albeit at different levels, as demonstrated by reverse transcription-PCR analysis. Transfected tumor cells exhibited a delayed growth in vivo, and partial tumor regression. Spleen cells from mice that displayed tumor regression had high percentages of CD8(+) T cells that were specifically stained with L(d) tetramers loaded with gp70(423-431), the antigenic epitope of gp70 protein. Mixed leukocyte-peptide and mixed leukocyte-tumor cultures, set up by stimulating splenocytes with the immunogenic peptide and with transfected TS/A tumor cells, respectively, resulted in similar large increases in tetramer-reactive CD8(+) T cells and showed high lytic activity specific for gp70(423-431). Finally, in a Cold Target Inhibition assay, lytic activity of a mixed leukocyte-tumor culture was inhibited in an overlapping fashion by both the TS/A line used for restimulation and 293L(d) cells loaded with gp70(423-431) peptide, but not by 293L(d) cells pulsed with an irrelevant H-2 L(d) epitope, thus demonstrating that all or most of the cytotoxic activity was directed exclusively against this antigenic epitope.


Assuntos
Adenocarcinoma/imunologia , Epitopos Imunodominantes/imunologia , Neoplasias Mamárias Experimentais/imunologia , Proteínas Oncogênicas de Retroviridae/imunologia , Retroviridae/imunologia , Linfócitos T Citotóxicos/imunologia , Proteínas do Envelope Viral/imunologia , Animais , Antígenos de Neoplasias/imunologia , Antígeno B7-1/biossíntese , Feminino , Interferon-alfa/biossíntese , Interferon gama/biossíntese , Interleucina-4/biossíntese , Ativação Linfocitária/imunologia , Neoplasias Mamárias Experimentais/genética , Camundongos , Camundongos Endogâmicos BALB C , Proteínas Oncogênicas de Retroviridae/biossíntese , Proteínas Oncogênicas de Retroviridae/genética , Transfecção , Proteínas do Envelope Viral/biossíntese , Proteínas do Envelope Viral/genética
10.
Immunol Lett ; 175: 16-20, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27131431

RESUMO

Immune selective pressure occurring during cancer immunoediting shapes tumor features revealed at clinical presentation. However, in the "Escape" phase, the tumor itself has the chance to influence the immunological response. Therefore, the capacity of the immune response to sculpt the tumor characteristics is only one side of the coin and even the opposite is likely true, i.e. that an antigen can shape the immune response in a sort of "reverse immunoediting". This reciprocal modeling probably occurs continuously, whenever the immune system encounters a tumor/foreign antigen, and can be operative in the pathogen/immune system interplay, thus possibly permeating the protective immunity as a whole. In line with this view, the characterization of a T cell response as well as the design of both active and passive immunotherapy strategies should also take into account all Ag features (type, load and presentation). Overall, we suggest that the "reverse immunoediting" hypothesis could help to dissect the complex interplay between antigens and the immune repertoire, and to improve the outcome of immunotherapeutic approaches, where T cell responses are manipulated and reprogrammed.


Assuntos
Vacinas Anticâncer/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/imunologia , Linfócitos T/imunologia , Evasão Tumoral , Animais , Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Reprogramação Celular , Deleção Clonal , Humanos , Tolerância Imunológica , Imunidade Celular , Vigilância Imunológica , Ativação Linfocitária , Neoplasias/terapia , Linfócitos T/transplante
11.
Lung Cancer ; 79(2): 180-6, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23218791

RESUMO

Survivin is expressed in lung cancer and in most cancer tissues and has a significant impact on prognosis. This work aimed to comparatively assess survivin expression and significance in Non-Small (NSCLC) and Small Cell Lung Cancers (SCLC). Sixty-five NSCLC and 35 SCLC samples were analyzed by semi-quantitative real-time RT-PCR. Survivin mRNA levels were significantly higher in tumors than in normal tissue, and in SCLC than in NSCLC samples. Immunohistochemistry and FISH analyses were performed in 59 and 26 tumor specimens, respectively. In SCLC survivin was only present in cytoplasm, while in some NSCLC cases it also showed nuclear or mixed patterns. FISH analysis did not disclose survivin gene amplification, except for one NSCLC case. Finally, 90 samples were genotyped for the -31G/C SNP of survivin promoter by direct sequencing; the -31G/C SNP genotype status showed a significant association only with nodal NSCLC metastasis, but not with survivin expression in any tumor group. A better prognosis was correlated to higher levels of survivin mRNA and to the presence of at least one G allele at -31 SNP in NSCLC, while these parameters did not correlate with overall survival in SCLC. Moreover, this SNP would appear to have no effect on the risk of lung cancer in our samples. The different prognostic role played by survivin in NSCLC and SCLC highlights the biological differences between these lung tumor histotypes and stresses the need to clarify the molecular pathways leading to their neoplastic transformation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas Inibidoras de Apoptose/genética , Proteínas Inibidoras de Apoptose/metabolismo , Neoplasias Pulmonares/genética , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/secundário , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Feminino , Expressão Gênica , Genótipo , Humanos , Estimativa de Kaplan-Meier , Pulmão/metabolismo , Neoplasias Pulmonares/metabolismo , Metástase Linfática , Masculino , Polimorfismo de Nucleotídeo Único , Prognóstico , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Curva ROC , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Survivina
12.
J Immunol ; 176(3): 1999-2006, 2006 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-16424232

RESUMO

Identification of reliable surrogate predictors for evaluation of cancer vaccine efficacy is a critical issue in immunotherapy. We analyzed quantitative and qualitative CD8+ T cell parameters in a large pool of BALB/c mice that were DNA-vaccinated against P1A self tumor-specific Ag. After immunization, mice were splenectomized and kept alive for a subsequent tumor challenge to correlate results of immune monitoring assays with tumor regression or progression in each individual animal, and to assess the prognostic value of the assays. The parameters tested were 1) percentage of in vivo vaccine-induced tumor-specific CD8+ T cells; 2) results of ELISPOT tests from fresh splenocytes; 3) percentage of tumor-specific CD8+ T cells in culture after in vitro restimulation; 4) in vitro increase of tumor-specific CD8+ T cell population expressed as fold of expansion; and 5) antitumor lytic activity of restimulated cultures. Except for the ELISPOT assay, each parameter tested was shown by univariate statistical analysis to correlate with tumor regression. However, multivariate analysis revealed that only in vitro percentage of Ag-specific CD8+ T cells was an independent prognostic factor that predicted tumor outcome. These findings should be considered in the design of new immune monitoring systems used in cancer immunotherapy studies.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Monitorização Imunológica , Neoplasias Experimentais/diagnóstico , Vacinas de DNA/administração & dosagem , Animais , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Testes Imunológicos de Citotoxicidade/estatística & dados numéricos , Ensaio de Imunoadsorção Enzimática/estatística & dados numéricos , Feminino , Contagem de Linfócitos/estatística & dados numéricos , Camundongos , Camundongos Endogâmicos BALB C , Monitorização Imunológica/métodos , Monitorização Imunológica/estatística & dados numéricos , Análise Multivariada , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/imunologia , Valor Preditivo dos Testes , Prognóstico , Vacinas de DNA/imunologia
14.
J Immunol ; 174(9): 5398-406, 2005 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-15843538

RESUMO

The CD8(+) T cell response to Moloney-murine leukemia virus (M-MuLV)-induced Ags is almost entirely dominated by the exclusive expansion of lymphocytes that use preferential TCRVbeta chain rearrangements. In mice lacking T cells expressing these TCRVbeta, we demonstrate that alternative TCRVbeta can substitute for the lack of the dominant TCRVbeta in the H-2-restricted M-MuLV Ag recognition. We show that, at least for the H-2(b)-restricted response, the shift of TCR usage is not related to a variation of the immunodominant M-MuLV epitope recognition. After virus immunization, all the potentially M-MuLV-reactive lymphocytes are primed, but only the deletion of dominant Vbeta rescues the alternative Vbeta response. The mechanism of clonal T cell "immunodomination" that guides the preferential Vbeta expansion is likely the result of a proliferative advantage of T cells expressing dominant Vbeta, due to differences in TCR affinity and/or cosignal requirements. In this regard, a CD8 involvement is strictly required for the virus-specific cytotoxic activity of CTL expressing alternative, but not dominant, Vbeta gene rearrangements. The ability of T cells expressing alternative TCRVbeta rearrangements to mediate tumor protection was evaluated by a challenge with M-MuLV tumor cells. Although T cells expressing alternative Vbeta chains were activated and expanded, they were not able to control tumor growth in a long-lasting manner due to their incapacity of conversion and accumulation in the T central memory pool.


Assuntos
Apresentação de Antígeno/imunologia , Produtos do Gene gag/imunologia , Produtos do Gene gag/metabolismo , Rejeição de Enxerto/imunologia , Vírus da Leucemia Murina de Moloney/imunologia , Sarcoma Experimental/imunologia , Linfócitos T Citotóxicos/imunologia , Infecções Tumorais por Vírus/imunologia , Animais , Apresentação de Antígeno/genética , Linhagem Celular Tumoral , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Produtos do Gene gag/biossíntese , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Rejeição de Enxerto/virologia , Antígenos H-2/imunologia , Antígeno de Histocompatibilidade H-2D , Imunidade Inata/genética , Epitopos Imunodominantes/genética , Epitopos Imunodominantes/imunologia , Depleção Linfocítica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Sarcoma Experimental/prevenção & controle , Linfócitos T Citotóxicos/metabolismo , Linfócitos T Citotóxicos/virologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/virologia , Infecções Tumorais por Vírus/prevenção & controle
15.
J Immunol ; 171(10): 5172-9, 2003 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-14607917

RESUMO

The weakly immunogenic murine P1A Ag is a useful experimental model for the development of new vaccination strategies that could potentially be used against human tumors. An i.m. DNA-based immunization procedure, consisting of three inoculations with the P1A-coding pBKCMV-P1A plasmid at 10-day intervals, resulted in CTL generation in all treated BALB/c mice. Surprisingly, gene gun skin bombardment with the pBKCMV-P1A vector did not induce CTL, nor was it protective against a lethal challenge with the syngeneic P1A-positive J558 tumor cell line. To speed up the immunization procedure, we pretreated the tibialis anterior muscles with cardiotoxin, which induces degeneration of myocytes while sparing immature satellite cells. The high muscle-regenerative activity observable after cardiotoxin inoculation was associated with infiltration of inflammatory cells and expression of proinflammatory cytokines. A single pBKCMV-P1A plasmid inoculation in cardiotoxin-treated BALB/c mice allowed for sustained expansion of P1A-specific CTL and the induction of strong lytic activity in <2 wk. Cardiotoxin adjuvanticity could not be replaced by another muscle-degenerating substance, such as bupivacaine, or by MF59, a Th1 response-promoting adjuvant. Although this vaccination schedule failed to induce tumor rejection in all immunized mice, the analysis of CD8 T cell responses at an individual mouse level disclosed that the cytotoxic activity of P1A-specific CTL was correlated to the antitumor efficacy. These results highlight the critical need to identify reliable, specific immunological parameters that may predict success or failure of an immune response against cancer.


Assuntos
Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Citotoxicidade Imunológica , Epitopos de Linfócito T/imunologia , Sarcoma de Mastócitos/imunologia , Sarcoma de Mastócitos/prevenção & controle , Linfócitos T Citotóxicos/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Antígenos de Neoplasias/genética , Biolística , Vacinas Anticâncer/uso terapêutico , Divisão Celular/imunologia , Linhagem Celular Tumoral , Células Cultivadas , Proteínas Cardiotóxicas de Elapídeos/administração & dosagem , Relação Dose-Resposta Imunológica , Epitopos de Linfócito T/administração & dosagem , Epitopos de Linfócito T/genética , Feminino , Imunidade Inata/genética , Esquemas de Imunização , Imuno-Histoquímica , Injeções Intramusculares , Ativação Linfocitária/genética , Sarcoma de Mastócitos/mortalidade , Sarcoma de Mastócitos/patologia , Camundongos , Camundongos Endogâmicos BALB C , Músculo Esquelético/química , Músculo Esquelético/imunologia , Músculo Esquelético/patologia , Transplante de Neoplasias/imunologia , Plasmídeos , Taxa de Sobrevida , Linfócitos T Citotóxicos/citologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologia , Vacinas de DNA/uso terapêutico
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