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1.
Recent Results Cancer Res ; 214: 93-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473850

RESUMO

As a specifically programmable, living immunotherapeutic drug, chimeric antigen receptor (CAR)-modified T cells are providing an alternative treatment option for a broad variety of diseases including so far refractory cancer. By recognizing a tumor-associated antigen, the CAR triggers an anti-tumor response of engineered patient's T cells achieving lasting remissions in the treatment of leukemia and lymphoma. During the last years, significant progress was made in optimizing the CAR design, in manufacturing CAR-engineered T cells, and in the clinical management of patients showing promise to establish adoptive CAR T cell therapy as an effective treatment option in the forefront.


Assuntos
Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos Quiméricos , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto , Humanos , Receptores de Antígenos de Linfócitos T , Linfócitos T/imunologia
2.
Recent Results Cancer Res ; 214: 129-151, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473851

RESUMO

The adoptive cell transfer (ACT) of genetically engineered T cell receptor (TCR) T cells is one of the burgeoning fields of immunotherapy, with promising results in current clinical trials. Presently, clinicaltrials.gov has over 200 active trials involving adoptive cell therapy. The ACT of genetically engineered T cells not only allows the ability to select for TCRs with desired properties such as high-affinity receptors and tumor reactivity but to further enhance those receptors allowing for better targeting and killing of cancer cells in patients. Moreover, the addition of genetic material, including cytokines and cytokine receptors, can increase the survival and persistence of the T cell allowing for complete and sustained remission of cancer targets. The potential for improvement in adoptive cell therapy is limitless, with genetic modifications targeting to improve weaknesses of ACT and to thus enhance receptor affinity and functional avidity of the genetically engineered T cells.


Assuntos
Engenharia Genética , Imunoterapia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T , Linfócitos T/citologia , Humanos
3.
Adv Exp Med Biol ; 1172: 21-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31628650

RESUMO

Molecules encoded by the Major Histocompatibility Complex (MHC) bind self or foreign peptides and display these at the cell surface for recognition by receptors on T lymphocytes (designated T cell receptors-TCR) or on natural killer (NK) cells. These ligand/receptor interactions govern T cell and NK cell development as well as activation of T memory and effector cells. Such cells participate in immunological processes that regulate immunity to various pathogens, resistance and susceptibility to cancer, and autoimmunity. The past few decades have witnessed the accumulation of a huge knowledge base of the molecular structures of MHC molecules bound to numerous peptides, of TCRs with specificity for many different peptide/MHC (pMHC) complexes, of NK cell receptors (NKR), of MHC-like viral immunoevasins, and of pMHC/TCR and pMHC/NKR complexes. This chapter reviews the structural principles that govern peptide/MHC (pMHC), pMHC/TCR, and pMHC/NKR interactions, for both MHC class I (MHC-I) and MHC class II (MHC-II) molecules. In addition, we discuss the structures of several representative MHC-like molecules. These include host molecules that have distinct biological functions, as well as virus-encoded molecules that contribute to the evasion of the immune response.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Complexo Principal de Histocompatibilidade , Receptores de Antígenos de Linfócitos T , Linfócitos T , Imunidade Adaptativa/imunologia , Animais , Humanos , Imunidade Inata/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Células Matadoras Naturais/química , Receptores de Células Matadoras Naturais/imunologia , Linfócitos T/imunologia
4.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3129-3134, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602863

RESUMO

The best time of tumor intervention is before the formation of tumor. However,due to the limited number of tumor cells,it is difficult to quantify tumor cells and immunity by the current methods available( such as CTC,ct DNA). This affects the tumor prevention in this period,and the in-depth detection,intervention and evaluation of traditional Chinese medicine( TCM)( tumor) prevention. Due to the limitations of the current detection,the evaluation system turns to detect tumor neoantigen-specific CTL( naCTL) that are directly relating to tumor cells and proliferate to high order of magnitudes after activation,and immune repertoire( TCR/BCR/HLA) effective diversity,introduces immune checkpoints,uses information of " disease" in Western medicine and " syndrome" in TCM( prevention),and sets up a multi-dimensional statistical immunity model using a variety of data analysis and related algorithms. This model can amplify the ultra-early information of tumor,indirectly evaluate the quantity and status of tumor cells,and provide quantitative measurement and new evaluation methods for the normalization of immunity and TCM( tumor) prevention. This model is not only one of important evaluation methods for resisting tumor immunity and treating TCM( tumor) prevention,but also will reveal the scientific connotation of TCM syndrome from the perspective of immunology.


Assuntos
Medicamentos de Ervas Chinesas , Neoplasias/imunologia , Neoplasias/prevenção & controle , Antígenos HLA , Humanos , Medicina Tradicional Chinesa , Receptores de Antígenos de Linfócitos B , Receptores de Antígenos de Linfócitos T
5.
Rinsho Ketsueki ; 60(9): 1221-1228, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597847

RESUMO

Gene and protein expression profiling has clarified that tumor cells in angioimmunoblastic T-cell lymphoma (AITL) have T follicular helper (TFH) cell characteristics. In AITL, typical genomic abnormalities have been reported that combine G17V RHOA mutations, gene mutations involved in epigenetic pathways, and those involved in T-cell receptor signal pathways. Besides AITL, some lymphomas display a TFH phenotype, prompting the proposal of a new disease classification encompassing those. Interestingly, lymphomas with TFH phenotype characteristics also share most genomic abnormalities with AITL. Furthermore, because AITL genomic abnormalities are highly disease specific, they can be used for diagnosis. Although AITL is a refractory disease, several new drugs have been approved for relapsed and refractory cases. Precision medicine targeting genomic aberrations characteristic of AITL is being investigated.


Assuntos
Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/terapia , Linfoma de Células T/diagnóstico , Linfoma de Células T/terapia , Humanos , Mutação , Fenótipo , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais , Linfócitos T Auxiliares-Indutores , Proteína rhoA de Ligação ao GTP/genética
6.
Rinsho Ketsueki ; 60(9): 1351-1357, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597863

RESUMO

The adoptive transfer of chimeric antigen receptor (CAR)-modified autologous T cells targeted at the B-cell antigen CD19 is highly effective in patients with relapsed or refractory B-cell malignancies. In Japan, tisagenlecleucel has been approved in March 2019, whereas axicabtagene ciloleucel, lisocabtagene maraleucel, and TBI-1501 have been tested in clinical trials. In addition, allogeneic CD19 CAR T cells from family or third-party donors have been developed for treating B-cell malignancies. Moreover, CAR T-cell therapies for acute myeloid leukemia (AML), T-cell leukemia, and multiple myeloma are still under development. Our group is currently preparing a phase I study on granulocyte macrophage colony-stimulating factor receptor-targeted CAR T cells in pediatric and adult patients with AML.


Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/uso terapêutico , Adulto , Criança , Ensaios Clínicos Fase I como Assunto , Humanos , Japão
7.
Cancer Immunol Immunother ; 68(10): 1701-1712, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31542797

RESUMO

Since the first bone marrow transplantation, adoptive T cell therapy (ACT) has developed over the last 80 years to a highly efficient and specific therapy for infections and cancer. Genetic engineering of T cells with antigen-specific receptors now provides the possibility of generating highly defined and efficacious T cell products. The high sensitivity of engineered T cells towards their targets, however, also bears the risk of severe off-target toxicities. Therefore, different safety strategies for engineered T cells have been developed that enable removal of the transferred cells in case of adverse events, control of T cell activity or improvement of target selectivity. Receptor avidity is a crucial component in the balance between safety and efficacy of T cell products. In clinical trials, T cells equipped with high avidity T cell receptor (TCR)/chimeric antigen receptor (CAR) have been mostly used so far because of their faster and better response to antigen recognition. However, over-activation can trigger T cell exhaustion/death as well as side effects due to excessive cytokine production. Low avidity T cells, on the other hand, are less susceptible to over-activation and could possess better selectivity in case of tumor antigens shared with healthy tissues, but complete tumor eradication may not be guaranteed. In this review we describe how 'optimal' TCR/CAR affinity can increase the safety/efficacy balance of engineered T cells, and discuss simultaneous or sequential infusion of high and low avidity receptors as further options for efficacious but safe T cell therapy.


Assuntos
Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Afinidade de Anticorpos , Engenharia Genética , Humanos , Imunoterapia Adotiva/efeitos adversos
8.
Cancer Immunol Immunother ; 68(9): 1401-1415, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31414180

RESUMO

Although CAR T-cell therapy has demonstrated tremendous clinical efficacy especially in hematological malignancies, severe treatment-associated toxicities still compromise the widespread application of this innovative technology. Therefore, developing novel approaches to abrogate CAR T-cell-mediated side effects is of great relevance. Several promising strategies pursue the selective antibody-based depletion of adoptively transferred T cells via elimination markers. However, given the limited half-life and tissue penetration, dependence on the patients' immune system and on-target/off-side effects of proposed monoclonal antibodies, we sought to exploit αCAR-engineered T cells to efficiently eliminate CAR T cells. For comprehensive and specific recognition, a small peptide epitope (E-tag) was incorporated into the extracellular spacer region of CAR constructs. We provide first proof-of-concept for targeting this epitope by αE-tag CAR T cells, allowing an effective killing of autologous E-tagged CAR T cells both in vitro and in vivo whilst sparing cells lacking the E-tag. In addition to CAR T-cell cytotoxicity, the αE-tag-specific T cells can be empowered with cancer-fighting ability in case of relapse, hence, have versatile utility. Our proposed methodology can most probably be implemented in CAR T-cell therapies regardless of the targeted tumor antigen aiding in improving overall safety and survival control of highly potent gene-modified cells.


Assuntos
Epitopos de Linfócito T/genética , Imunoterapia Adotiva/métodos , Fragmentos de Peptídeos/genética , Neoplasias da Próstata/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Citotoxicidade Imunológica , Epitopos de Linfócito T/imunologia , Engenharia Genética , Humanos , Masculino , Camundongos , Recidiva Local de Neoplasia , Células PC-3 , Neoplasias da Próstata/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Zhonghua Nei Ke Za Zhi ; 58(9): 668-672, 2019 Sep 01.
Artigo em Chinês | MEDLINE | ID: mdl-31461818

RESUMO

Objective: To retrospectively analyze the efficacy and safety of modified cell infusion method in reducing the incidence of febrile non-hemolytic transfusion reaction (FNHTR). Methods: A total of 69 patients were enrolled in the clinical trial of CD(19) chimeric antigen receptor T (CAR-T) cell treatment from February 2017 to October 2018. Study group received the modified cell infusion method, that 1×10(6) CAR-T cells were re-suspended in 2 mg human serum albumin with total volume of 20 ml and injected intravenously. The control group was intravenously administrated with CAR-T cell in 100 ml normal saline. The incidence of FNHTR, cytokine releasing syndrome (CRS) grade, cytokine level and efficacy were compared. Results: (1)The incidence of FNHTR in the study group was 21.1%, significantly lower than that in the control group (71%)(P=0.000). (2)There was no statistical difference in cell proliferation between the study group and the control group on day 4, 7, 14 and 21 after CAR-T cell infusion (P=10.223, 3.254, 5.551, 7.605). (3)There was no statistical difference in CRS grading between the study group and the control group (P=0.767). There was no statistical difference in the levels of interleukin 2 receptor (IL-2R), IL-6, tumor necrosis factor (TNF)-α between the two groups. (4)The C-reaction protein (CRP) level of the study group was lower than that of the control group on day 4 and 7 (P=0.026, 0.007). (5)There was no statistical difference of response rates in acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL) patients between the two groups (P(ALL)=0.842; P(NHL)=0.866). Conclusion: The modified cell infusion method in CD(19) CAR-T cell treatment reduces the incidence of treatment-related FNHTR. It does not affect the proliferation of CAR-T cells in vivo, the grading of CRS and the response rates.


Assuntos
Antígenos CD19/imunologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T , Reação Transfusional/prevenção & controle , Humanos , Receptores de Antígenos Quiméricos/uso terapêutico , Estudos Retrospectivos
10.
Rinsho Ketsueki ; 60(7): 824-833, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31391373

RESUMO

With the emergence of cancer immunotherapy, T cells have played important roles in inducing antitumor responses. Many types of antitumor receptors, which possess tumor-binding sites and T-cell activation sites, have been developed. For example, genetically engineered T-cell receptor, chimeric antigen receptor, and bispecific antibody can help us to educate and activate T cells specific for certain tumors. To generate optimal antitumor receptors, (1) selection/distribution of tumor antigens, (2) affinity/specificity and cross-reactivity of antitumor receptors, and (3) T-cell activation signals delivered from antitumor receptors should be considered. Accordingly, we explain how antitumor receptors recognize target antigens and summarize the mechanisms for on-target/off-target reactivity induced by T cells redirected with antitumor receptors. Furthermore, we discuss how antitumor receptors can be optimized for the development of next-generation cancer immunotherapy.


Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia Adotiva , Linfócitos T , Anticorpos Biespecíficos , Humanos , Receptores de Antígenos de Linfócitos T
11.
Expert Rev Pharmacoecon Outcomes Res ; 19(5): 529-536, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31422712

RESUMO

Introduction: The new category of chimeric antigen receptor T - cell raised hopes for a more effective treatment of large B cell lymphoma and acute lymphoblastic leukemia. Nevertheless, their soaring acquisition costs will stretch the fiscal capacity of the health systems worldwide. To this direction, the scope of this study is to provide a systematic review of their economic evaluations. Areas covered: A systematic review of the economic evaluations of tisagenlecleucel and axicabtagene was performed. Expert opinion: The available data indicate that these products demonstrate a potentially favorable cost-effectiveness ratio. Nevertheless, their budget impact is of overriding importance and it should be incorporated in any economic evaluation. Moreover, more affirmative clinical data are imperative in order to mitigate uncertainty.


Assuntos
Antígenos CD19/uso terapêutico , Linfoma Difuso de Grandes Células B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfócitos T/administração & dosagem , Antígenos CD19/administração & dosagem , Antígenos CD19/economia , Quimera , Análise Custo-Benefício , Humanos , Imunoterapia Adotiva/economia , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/economia , Leucemia-Linfoma Linfoblástico de Células Precursoras/economia
12.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1316-1320, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418399

RESUMO

Abstract  Chimeric antigen receptor-T cell(CAR-T) is a kind of genetically engineered T cells that can express tumor antigen-specific receptors on its surface, and the modified T cells can be used for cancer therapy through targeting malignant tumor cells with its specific receptor and killing tumor cells with its cytotoxicity. CAR-T has been successfully applied to treat various hematological malignancies, such as ALL, CLL, NHL and MM. It is a feasible treatment for relapsed and refractory multiple myeloma (RRMM). The achievements of CAR-T in clinical trials have been widely reported, which is expected to be a therapy to prolong patients survival. In this review, the clinical application of CAR-T in the treatment of RRMM from the following aspects:different types of CAR-T and its curative efficacy, adverse effects, opportunities and challenges are summarized beriefly.


Assuntos
Mieloma Múltiplo , Humanos , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos , Linfócitos T
14.
Clin Cancer Res ; 25(17): 5188-5190, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31266831

RESUMO

A key mechanism of resistance to chimeric antigen receptor-modified T cells (CAR-T) is loss or downregulation of target antigens. Low antigen expression on cancer cells prevents full CAR-T-cell activation and persistence. Pharmacologic modulation of target antigen expression offers a novel therapeutic strategy to drive more potent and durable responses.See related article by Ramakrishna et al., p. 5329.


Assuntos
Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos T , Linhagem Celular Tumoral , Ativação Linfocitária , Linfócitos T/imunologia
16.
Rinsho Ketsueki ; 60(6): 716-722, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281165

RESUMO

Recent remarkable advancements in cancer immunotherapy have rendered adoptive T cell therapy an option of clinical treatment of patients with cancer following the success of immune checkpoint inhibitors. In 2017, the FDA approved adoptive cell therapy with chimeric antigen receptor (CAR) gene-modified T cells as a treatment for patients with acute lymphocytic leukemia and diffuse large cell lymphoma. In February this year, it was announced that this therapy will also be approved in Japan soon. Adoptive therapy with T-cell receptor (TCR) gene-modified T cells is a promising therapy for patients with hematological malignancy and solid tumors that follow the success of CAR-T cell therapy. This review aims to summarize the recent progress and issues of TCR gene-modified T-cell therapy with the introduction of our recent study.


Assuntos
Neoplasias Hematológicas/terapia , Imunoterapia Adotiva , Neoplasias/terapia , Linfócitos T , Genes Codificadores dos Receptores de Linfócitos T , Humanos , Japão , Receptores de Antígenos de Linfócitos T
17.
Adv Exp Med Biol ; 1143: 217-229, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31338822

RESUMO

Cancer immunotherapy has been shown to be an efficacious therapeutic approach in the treatment of cancers including hematopoietic malignancies. Induction of T cell cytotoxicity against tumors by adoptive cell therapies (ACT), cancer vaccines, gene therapies, and monoclonal antibody therapies has been intensively studied. In particular, immune checkpoint blockade and chimeric antigen receptor T (CAR-T) cell therapies are the recent clinical successes in cancer immunotherapy. This article introduces the main concepts and addresses the most relevant clinical modalities of cellular immunotherapies for hematological malignancies: antigen non-specific T cell therapy, genetically modified T cell receptor (TCR) T cell therapy, chimeric antigen receptor (CAR) T cell therapy, and CAR-T cell clinical trials in leukemia, lymphoma, and multiple myeloma. Clinical trials have shown encouraging results, but future studies may need to incorporate novel CAR constructs or targets with enhanced safety and efficacy to ensure long-term benefits.


Assuntos
Neoplasias Hematológicas , Imunoterapia Adotiva , Neoplasias Hematológicas/terapia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T
18.
Gan To Kagaku Ryoho ; 46(6): 967-973, 2019 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-31273158

RESUMO

Recently, accumulating discoveries in the field of immunology have been applied in clinical settings along with rapid progression of basic and pre-clinical research. Especially, advancement of gene modification technologies has contributed to unlock a way to novel cancer immunotherapy. One representative is chimeric antigen receptor-expressing T(CAR-T)cell therapy which was approved by FDA in August, 2017 as first gene-modified cell therapy. However, such technologies are still work-in-progress and there are many obstacles to be overcome for their full development. So called 4th generation CAR-T cells, in which CAR-T cells are engineered to secrete some kinds of cytokine and/or chemokine, have revealed their prominent potential to eradicate established solid tumors, which are usually resistant to conventional CAR-T cells. Another example of gene-modified cells for cancer immunotherapy is T cell receptor(TCR)-T cells, which are T cells engineered to express tumor antigen-specific TCR. Targeting neoantigens, mutated proteins to be expressed only in cancer cells and scarcely in normal ones, is attracting attempt for TCR-T cell approach. In addition, due to unique immunological functions, other lymphocyte subsets such as natural killer(NK)cells, invariant natural killer T(iNKT)cells, and gd-type T cells gain attention as effector cells to be gene-modified. Furthermore, off-the-shelf cell therapy, in which patients receive cell products made from allogeneic non-self immune cells, is nowunder development. It should be noted that development of "personalized" medicine, which aims to customize drugs to be suitable for each patient and different types of tumor, and "universal" technologies, which are crucial to generate uniform quality of cell products and to decrease manufacturing time and cost, are highly important for further advance of cancer immunotherapy.


Assuntos
Imunoterapia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T , Antígenos de Neoplasias , Humanos , Imunoterapia Adotiva , Células Matadoras Naturais
19.
Mol Biol (Mosk) ; 53(3): 456-466, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31184611

RESUMO

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for hematopoietic malignancies. The graft-derived donor lymphocytes are capable of eliminating the residual recipient malignant cells in the course of allogeneic immune response, thus decreasing the chances of a relapse of the disease. Foreign peptides of the recipient presented by the MHC molecules are able to elicit the immune response immunologically. These polymorphic peptides are known as minor histocompatibility antigens (MiHAs). MiHAs occur due to the nonsynonymous single nucleotide polymorphisms in human genome. Transfusion of T cells specific to MiHAs presented predominantly in the cells of hematopoietic origin will allow the targeted elimination of residual malignant clones avoiding undesirable damage to healthy tissues. To induce the immune response, the donor must be homozygous by the MiHA allele and the recipient must either be homozygous or heterozygous by the alternative MiHA allele. The therapeutic mismatch occurs in 25% of cases under the optimal frequency of allelic variants. Minor antigen ACC-1Y originates from polymorphism in the BCL-2A1 gene; its immunogenic mismatch occurrence approaches the theoretical maximum. In addition, BCL2A1 is overexpressed in cells of various lymphomas. ACC-1Y is presented on allele HLA-A*24:02, which is relatively frequent in the Russian population. Combination of these factors makes the minor antigen ACC-1Y a promising target for immunotherapy. Transfusion of donor CD8^(+) lymphocytes modified with transgenic MiHA-specific TCR is one of the promising methods of posttransplant leukemia therapy and relapse prophylaxis. We obtained a sequence of high-affinity ACC-1Y-specific TCR after the antigen-specific expansion of T cells derived from a healthy ACC-IY^(-/-) donor. We cloned this sequence into the lentiviral vector and obtained the assembled viral particles. Further, we transduced the CD8^(+) lymphocyte culture and demonstrated its antigen-specific cytotoxic activity. It is suggested that CD8^(+) lymphocytes modified by the described method could be potentially transferred to recipients as a therapy against relapse after allo-HSCT.


Assuntos
Engenharia Celular , Transplante de Células-Tronco Hematopoéticas , Antígenos de Histocompatibilidade Menor/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/metabolismo , Aloenxertos , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Humanos , Antígenos de Histocompatibilidade Menor/genética , Receptores de Antígenos de Linfócitos T/genética , Federação Russa , Prevenção Secundária/métodos
20.
Mol Immunol ; 112: 274-282, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31226552

RESUMO

The viral peptides presentation by major histocompatibility complex class I (MHC I) molecules play a pivotal role in T-cell recognition and the subsequent virus clearance. This process is delicately adjusted by the variant residues of MHC I, especially the residues in the peptide binding groove (PBG). In a series of MHC I molecules, a salt bridge is formed above the N-terminus of the peptides. However, the potential impact of the salt bridge on peptide binding and T-cell receptor (TCR) recognition of MHC I, as well as the corresponding molecular basis, are still largely unknown. Herein, we determined the structures of HLA-B*4001 and H-2Kd in which two different types of salt bridges (Arg62-Glu163 or Arg66-Glu163) across the PBG were observed. Although the two salt bridges led to different conformation shifts of both the MHC I α helix and the peptides, binding of the peptides with the salt bridge residues was relatively conserved. Furthermore, through a series of in vitro and in vivo investigations, we found that MHC I mutations that disrupt the salt bridge alleviate peptide binding and can weaken the TCR recognition of MHC I-peptide complexes. Our study may provide key references for understanding MHC I-restricted peptide recognition by T-cells.


Assuntos
Apresentação do Antígeno/imunologia , Genes MHC Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Peptídeos/imunologia , Ligação Proteica/imunologia , Linfócitos T/imunologia , Animais , Sítios de Ligação/imunologia , Feminino , Antígenos HLA-B/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Conformação Proteica , Receptores de Antígenos de Linfócitos T/imunologia
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