RESUMO
Immunomodulators are effective in controlling hematologic malignancy by initiating or reactivating host antitumor immunity to otherwise poorly immunogenic and immune suppressive cancers. We aimed to boost antitumor immunity in B-cell lymphoma by developing a tumor cell vaccine incorporating α-galactosylceramide (α-GalCer) that targets the immune adjuvant properties of NKT cells. In the Eµ-myc transgenic mouse model, single therapeutic vaccination of irradiated, α-GalCer-loaded autologous tumor cells was sufficient to significantly inhibit growth of established tumors and prolong survival. Vaccine-induced antilymphoma immunity required NKT cells, NK cells, and CD8 T cells, and early IL-12-dependent production of IFN-γ. CD4 T cells, gamma/delta T cells, and IL-18 were not critical. Vaccine treatment induced a large systemic spike of IFN-γ and transient peripheral expansion of both NKT cells and NK cells, the major sources of IFN-γ. Furthermore, this vaccine approach was assessed in several other hematopoietic tumor models and was also therapeutically effective against AML-ETO9a acute myeloid leukemia. Replacing α-GalCer with ß-mannosylceramide resulted in prolonged protection against Eµ-myc lymphoma. Overall, our results demonstrate a potent immune adjuvant effect of NKT cell ligands in therapeutic anticancer vaccination against oncogene-driven lymphomas, and this work supports clinical investigation of NKT cell-based immunotherapy in patients with hematologic malignancies.
Assuntos
Vacinas Anticâncer/uso terapêutico , Galactosilceramidas/administração & dosagem , Genes myc/genética , Imunoterapia , Linfoma de Células B/imunologia , Linfoma de Células B/prevenção & controle , Células T Matadoras Naturais/imunologia , Adjuvantes Imunológicos/administração & dosagem , Animais , Citotoxicidade Imunológica/imunologia , Feminino , Citometria de Fluxo , Genes Codificadores da Cadeia delta de Receptores de Linfócitos T/fisiologia , Humanos , Interferon gama/metabolismo , Interleucina-12/fisiologia , Interleucina-18/fisiologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/patologia , Linfoma de Células B/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/patologia , VacinaçãoAssuntos
Nefrite Lúpica/genética , Animais , Antígenos CD28/fisiologia , Ligante de CD40/fisiologia , Proteína Ligante Fas , Genes Codificadores da Cadeia delta de Receptores de Linfócitos T/fisiologia , Humanos , Glicoproteínas de Membrana/fisiologia , Receptores de IgG/fisiologia , Receptores de Interferon/fisiologia , Receptores do Fator de Necrose Tumoral/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Fatores de Necrose Tumoral/fisiologia , Receptor fas , Receptor de Interferon gamaRESUMO
It is generally believed that the production of influenza-specific IgG in response to viral infection is dependent on CD4 T cells. However, we previously observed that CD40-deficient mice generate influenza-specific IgG during a primary infection, suggesting that influenza infection may elicit IgG responses independently of CD4 T cell help. In the present study, we tested this hypothesis and show that mice lacking CD40 or CD4 T cells produce detectable titers of influenza-specific IgG and recover from influenza infection in a manner similar to that of normal mice. In contrast, mice completely lacking B cells succumb to influenza infection, despite the presence of large numbers of functional influenza-specific CD8 effector cells in the lungs. Consistent with the characteristics of a T-independent Ab response, long-lived influenza-specific plasma cells are not found in the bone marrow of CD40-/- and class II-/- mice, and influenza-specific IgG titers wane within 60 days postinfection. However, despite the short-lived IgG response, CD40-/- and class II-/- mice are completely protected from challenge infection with the same virus administered within 30 days. This protection is mediated primarily by B cells and Ab, as influenza-immune CD40-/- and class II-/- mice were still resistant to challenge infection when T cells were depleted. These data demonstrate that T cell-independent influenza-specific Ab promotes the resolution of primary influenza infection and helps to prevent reinfection.
Assuntos
Anticorpos Antivirais/sangue , Linfócitos T CD4-Positivos/fisiologia , Influenza Humana/imunologia , Animais , Linfócitos B/fisiologia , Antígenos CD40/fisiologia , Linfócitos T CD8-Positivos/imunologia , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/fisiologia , Genes Codificadores da Cadeia delta de Receptores de Linfócitos T/fisiologia , Antígenos de Histocompatibilidade Classe II/fisiologia , Imunidade Inata , Switching de Imunoglobulina , Imunoglobulina G/sangue , Camundongos , Camundongos Endogâmicos C57BL , RecidivaRESUMO
T cell receptor (TCR) delta and alpha variable region genes are assembled from germ-line gene segments located in a single chromosomal locus in which TCR delta segments are situated between TCR alpha segments. The TCR alpha enhancer (E alpha) located at the 3' end of the TCR alpha/delta locus functions over a long chromosomal distance to promote TCR alpha rearrangement and maximal TCR delta expression; whereas the TCR delta enhancer (E delta) is located among the TCR delta segments and functions with additional element(s) to mediate TCR delta rearrangement. We used gene-targeted mutation to evaluate whether the identity of E alpha and the position of E delta are critical for the developmental stage-specific assembly of TCR delta and alpha variable region genes. Specific replacement of E alpha with E delta, the core E alpha element (E alpha C), or the Ig heavy chain intronic enhancer (iE mu), all of which promote accessibility in the context of transgenic V(D)J recombination substrates, did not promote a significant level of TCR alpha rearrangement beyond that observed in the absence of E alpha. Therefore, the identity and full complement of E alpha-binding sites are critical for promoting accessibility within the TCR alpha locus. In the absence of the endogenous E delta element, specific replacement of E alpha with E delta also did not promote TCR delta rearrangement. However, deletion of intervening TCR alpha/delta locus sequences to restore the inserted E delta to its normal chromosomal position relative to 5' sequences rescued TCR delta rearrangement. Therefore, unlike E alpha, E delta lacks ability to function over the large intervening TCR alpha locus and or E delta function requires proximity to additional upstream element(s) to promote TCR delta accessibility.