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1.
J Immunol ; 188(4): 1782-8, 2012 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-22246626

RESUMO

We have recently shown that effective cytokine gene therapy of solid tumors in HLA-A2 transgenic (HHD) mice lacking murine MHC class I molecule expression results in the generation of HLA-A2-restricted CD8(+) T effector cells selectively recognizing tumor blood vessel-associated pericytes and/or vascular endothelial cells. Using an HHD model in which HLA-A2(neg) tumor (MC38 colon carcinoma or B16 melanoma) cells are not recognized by the CD8(+) T cell repertoire, we now show that vaccines on the basis of tumor-associated blood vessel Ags (TBVA) elicit protective Tc1-dependent immunity capable of mediating tumor regression or extending overall survival. Vaccine efficacy was not observed if (HLA-A2(neg)) wild-type C57BL/6 mice were instead used as recipient animals. In the HHD model, effective vaccination resulted in profound infiltration of tumor lesions by CD8(+) (but not CD4(+)) T cells, in a coordinate reduction of CD31(+) blood vessels in the tumor microenvironment, and in the "spreading" of CD8(+) T cell responses to alternate TBVA that were not intrinsic to the vaccine. Protective Tc1-mediated immunity was durable and directly recognized pericytes and/or vascular endothelial cells flow-sorted from tumor tissue but not from tumor-uninvolved normal kidneys harvested from these same animals. Strikingly, the depletion of CD8(+), but not CD4(+), T cells at late time points after effective therapy frequently resulted in the recurrence of disease at the site of the regressed primary lesion. This suggests that the vaccine-induced anti-TBVA T cell repertoire can mediate the clinically preferred outcomes of either effectively eradicating tumors or policing a state of (occult) tumor dormancy.


Assuntos
Vasos Sanguíneos/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/imunologia , Células Endoteliais/imunologia , Antígeno HLA-A2/imunologia , Neoplasias Experimentais/imunologia , Pericitos/imunologia , Animais , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/administração & dosagem , Linhagem Celular Tumoral , Genes MHC Classe I , Antígeno HLA-A2/genética , Ativação Linfocitária/imunologia , Melanoma Experimental/irrigação sanguínea , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias Experimentais/irrigação sanguínea , Molécula-1 de Adesão Celular Endotelial a Plaquetas/imunologia , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/imunologia
2.
Chem Commun (Camb) ; 60(56): 7164-7167, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38912670

RESUMO

We report here a concise synthesis of the anti-tumor-promoting (-)-larikaempferic acid methyl ester, a novel and rearranged abietane-type diterpene natural product containing a unique tetracyclic skeleton with a trans-hydrindane, an oxabicyclo[3.2.1]octane, and six stereogenic centers. Our synthesis starts with the cheap and abundant abietic acid and features an oxidative C-C bond cleavage followed by a transannular aldol reaction to skeletally rearrange the 6-6-6 tricyclic carbon skeleton of abietic acid to the desired 6-5-7 tricyclic carbon skeleton and an intramolecular oxa-Michael addition to form the oxa bridge. This skeletal rearrangement strategy enabled us to synthesize (-)-larikaempferic acid methyl ester in 9 steps.

3.
Nat Med ; 11(11): 1230-7, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16227990

RESUMO

Immunodeficiency is a barrier to successful vaccination in individuals with cancer and chronic infection. We performed a randomized phase 1/2 study in lymphopenic individuals after high-dose chemotherapy and autologous hematopoietic stem cell transplantation for myeloma. Combination immunotherapy consisting of a single early post-transplant infusion of in vivo vaccine-primed and ex vivo costimulated autologous T cells followed by post-transplant booster immunizations improved the severe immunodeficiency associated with high-dose chemotherapy and led to the induction of clinically relevant immunity in adults within a month after transplantation. Immune assays showed accelerated restoration of CD4 T-cell numbers and function. Early T-cell infusions also resulted in significantly improved T-cell proliferation in response to antigens that were not contained in the vaccine, as assessed by responses to staphylococcal enterotoxin B and cytomegalovirus antigens (P < 0.05). In the setting of lymphopenia, combined vaccine therapy and adoptive T-cell transfer fosters the development of enhanced memory T-cell responses.


Assuntos
Imunoterapia Adotiva , Linfócitos T/imunologia , Transferência Adotiva , Adulto , Idoso , Feminino , Humanos , Linfopenia/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Vacinas Pneumocócicas/uso terapêutico , Resultado do Tratamento , Vacinação
4.
Mol Ther ; 19(4): 805-14, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21189473

RESUMO

HLA-A2 transgenic mice bearing established HLA-A2(neg) B16 melanomas were effectively treated by intratumoral (i.t.) injection of syngeneic dendritic cells (DCs) transduced to express high levels of interleukin (IL)-12, resulting in CD8(+) T cell-dependent antitumor protection. In this model, HLA-A2-restricted CD8(+) T cells do not directly recognize tumor cells and therapeutic benefit was associated with the crosspriming of HLA-A2-restricted type-1 CD8(+) T cells reactive against antigens expressed by stromal cells [i.e., pericytes and vascular endothelial cells (VEC)]. IL-12 gene therapy-induced CD8(+) T cells directly recognized HLA-A2(+) pericytes and VEC flow-sorted from B16 tumor lesions based on interferon (IFN)-γ secretion and translocation of the lytic granule-associated molecule CD107 to the T cell surface after coculture with these target cells. In contrast, these CD8(+) T effector cells failed to recognize pericytes/VEC isolated from the kidneys of tumor-bearing HHD mice. The tumor-associated stromal antigen (TASA)-derived peptides studied are evolutionarily conserved and could be recognized by CD8(+) T cells harvested from the blood of HLA-A2(+) normal donors or melanoma patients after in vitro stimulation. These TASA and their derivative peptides may prove useful in vaccine formulations against solid cancers, as well as, in the immune monitoring of HLA-A2(+) cancer patients receiving therapeutic interventions, such as IL-12 gene therapy.


Assuntos
Terapia Genética/métodos , Interleucina-12/metabolismo , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Animais , Linfócitos T CD8-Positivos , Linhagem Celular Tumoral , Interleucina-12/genética , Melanoma Experimental/metabolismo , Camundongos , Reação em Cadeia da Polimerase Via Transcriptase Reversa
5.
Open Access J Urol ; 2: 125-41, 2010 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-24198621

RESUMO

Renal cell carcinoma (RCC) remains a significant health concern that frequently presents as metastatic disease at the time of initial diagnosis. Current first-line therapeutics for the advanced-stage RCC include antiangiogenic drugs that have yielded high rates of objective clinical response; however, these tend to be transient in nature, with many patients becoming refractory to chronic treatment with these agents. Adjuvant immunotherapies remain viable candidates to sustain disease-free and overall patient survival. In particular, vaccines designed to optimize the activation, maintenance, and recruitment of specific immunity within or into the tumor site continue to evolve. Based on the integration of increasingly refined immunomonitoring systems in both translational models and clinical trials, allowing for the improved understanding of treatment mechanism(s) of action, further refined (combinational) vaccine protocols are currently being developed and evaluated. This review provides a brief history of RCC vaccine development, discusses the successes and limitations in such approaches, and provides a rationale for developing combinational vaccine approaches that may provide improved clinical benefits to patients with RCC.

6.
Transplantation ; 90(5): 494-501, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21451445

RESUMO

BACKGROUND: Cellular treatments for repairing diseased tissues represent a promising clinical strategy. Umbilical cord tissue-derived cells (UTC) are a unique source of cells with a low immunogenic profile and potential for tissue repair. By using UTC from miniature swine, we previously demonstrated that despite their low immunogenic phenotype, UTC could induce an immune response under certain inflammatory conditions and after multiple subcutaneous (SC) injections. Given that repeat dosing of cells may be necessary to achieve a lasting therapeutic benefit, in this study, we examined approaches to avoid an immune response to multiple SC injections of UTC. METHODS: By using in vitro and in vivo measures of sensitization to SC cellular injections, we assessed the effects of varying the location of administration site, prolongation of timing between injections, and use of immunosuppressive treatments on repeated cellular injections in Massachusetts General Hospital major histocompatibility complex-defined miniature swine. RESULTS: Although under normal conditions, a single SC injection of major histocompatibility complex-mismatched UTC did not induce a detectable immune response, multiple SC injections of UTC demonstrated rapid humoral and cell-mediated immune responses. Avoidance of an immune response to repeat SC injection was achieved by concurrent immunosuppression with each dose of UTC. CONCLUSIONS: UTC and other similar cell types believed to be nonimmunogenic have the potential to induce immune responses under certain conditions. These studies provide important considerations and guidelines for preclinical studies investigating allogeneic cellular therapies.


Assuntos
Transplante de Células/efeitos adversos , Transplante de Células/métodos , Imunidade Celular , Imunidade Humoral , Terapia de Imunossupressão , Cordão Umbilical/citologia , Cordão Umbilical/imunologia , Animais , Ciclosporina/administração & dosagem , Esquema de Medicação , Feminino , Glucocorticoides/administração & dosagem , Imunossupressores/administração & dosagem , Injeções Subcutâneas , Isoanticorpos/biossíntese , Masculino , Prednisolona/administração & dosagem , Suínos , Porco Miniatura , Fatores de Tempo , Imunologia de Transplantes
7.
Blood ; 111(1): 430-8, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17909081

RESUMO

Umbilical cord tissue provides a unique source of cells with potential for tissue repair. Umbilical cord tissue-derived cells (UTCs) are MHC class I (MHCI) dull and negative for MHC class II (MHCII), but can be activated to increase MHCI and to express MHCII with IFN-gamma stimulation. Mesenchymal stem cells with similar characteristics have been inferred to be nonimmunogenic; however, in most cases, immunogenicity was not directly assessed. Using UTC from Massachusetts General Hospital MHC-defined miniature swine, we assessed immunogenicity across a full MHC barrier. Immunogenicity was assessed by in vitro assays including mixed lymphocyte reaction (MLR) and flow cytometry to detect serum alloantibody. A single injection of MHC-mismatched unactivated UTCs did not induce a detectable immune response. When injected in an inflamed region, injected repeatedly in the same region or stimulated with IFN-gamma prior to injection, UTCs were immunogenic. As clinical cellular repair strategies may involve injection of allogeneic cells into inflamed regions of damaged tissue or repeated doses of cells to achieve the desired benefit, our results on the immunogenicity of these cells in these circumstances may have important implications for optimal success and functional improvement for this cellular treatment strategy for diseased tissues.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Sangue Fetal/citologia , Células-Tronco Hematopoéticas/imunologia , Animais , Especificidade de Anticorpos , Células Cultivadas , Sangue Fetal/imunologia , Citometria de Fluxo , Células-Tronco Hematopoéticas/citologia , Humanos , Imunofenotipagem , Teste de Cultura Mista de Linfócitos , Transplante de Pele/imunologia , Suínos , Porco Miniatura , Imunologia de Transplantes , Transplante Homólogo
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