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1.
Ann Hematol ; 100(4): 969-978, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33594448

RESUMO

A head-to-head comparison of outcomes of unrelated donor allogeneic peripheral blood stem cell transplantation for AML between reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) regimens using thymoglobulin for GVHD prophylaxis is limited. We evaluated outcomes of 122 AML patients who received either busulfan (Bu)/fludarabine (Flu)/low-dose total body irradiation (TBI) as RIC (n = 64, 52%) or Bu/Flu as MAC (n = 58, 48%), and thymoglobulin 4.5 mg/kg total dose between day - 3 to - 1 for GVHD prophylaxis. Grades III-IV acute GVHD (aGVHD) was lower with Bu/Flu/TBI compared with Bu/Flu (6.2% vs 26.1%, p = 0.009). At 1 year, Bu/Flu/TBI was associated with similar chronic GVHD (41.2% vs 44.8%, p = 0.75), OS (61.9% vs 56.9%, p = 0.69), relapse rate (29.9% vs 20.7%, p = 0.24), relapse-free survival (52.8% vs 50%, p = 0.80), non-relapse mortality (17.4% vs 29.3%, p = 0.41), and GVHD-free relapse-free survival (24.2% vs 27.5%, p = 0.80) compared with Bu/Flu. Multivariable analysis did not reveal any difference in outcomes between both regimens. In summary, thymoglobulin at 4.5 mg/kg did not have any adverse impact on survival when used with RIC regimen. Both Bu/Flu/TBI and Bu/Flu conditioning regimens yielded similar survival.


Assuntos
Soro Antilinfocitário/uso terapêutico , Bussulfano/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Imunossupressores/uso terapêutico , Leucemia Mieloide Aguda/terapia , Agonistas Mieloablativos/uso terapêutico , Transplante de Células-Tronco de Sangue Periférico , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Idoso , Aloenxertos , Bussulfano/efeitos adversos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Infecções/epidemiologia , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Agonistas Mieloablativos/efeitos adversos , Intervalo Livre de Progressão , Estudos Retrospectivos , Linfócitos T , Tacrolimo/uso terapêutico , Resultado do Tratamento , Doadores não Relacionados , Vidarabina/efeitos adversos , Vidarabina/uso terapêutico , Irradiação Corporal Total
2.
Nat Commun ; 12(1): 805, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547295

RESUMO

Efforts to improve the prognosis of steroid-resistant gut acute graft-versus-host-disease (SR-Gut-aGVHD) have suffered from poor understanding of its pathogenesis. Here we show that the pathogenesis of SR-Gut-aGVHD is associated with reduction of IFN-γ+ Th/Tc1 cells and preferential expansion of IL-17-IL-22+ Th/Tc22 cells. The IL-22 from Th/Tc22 cells causes dysbiosis in a Reg3γ-dependent manner. Transplantation of IFN-γ-deficient donor CD8+ T cells in the absence of CD4+ T cells produces a phenocopy of SR-Gut-aGVHD. IFN-γ deficiency in donor CD8+ T cells also leads to a PD-1-dependent depletion of intestinal protective CX3CR1hi mononuclear phagocytes (MNP), which also augments expansion of Tc22 cells. Supporting the dual regulation, simultaneous dysbiosis induction and depletion of CX3CR1hi MNP results in full-blown Gut-aGVHD. Our results thus provide insights into SR-Gut-aGVHD pathogenesis and suggest the potential efficacy of IL-22 antagonists and IFN-γ agonists in SR-Gut-aGVHD therapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Disbiose/imunologia , Doença Enxerto-Hospedeiro/imunologia , Interferon gama/imunologia , Interleucinas/imunologia , Fagócitos/imunologia , Animais , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/transplante , Receptor 1 de Quimiocina CX3C/genética , Receptor 1 de Quimiocina CX3C/imunologia , Modelos Animais de Doenças , Disbiose/genética , Disbiose/microbiologia , Disbiose/patologia , Microbioma Gastrointestinal/imunologia , Regulação da Expressão Gênica , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/microbiologia , Doença Enxerto-Hospedeiro/patologia , Interferon gama/deficiência , Interferon gama/genética , Interleucina-17/deficiência , Interleucina-17/genética , Interleucina-17/imunologia , Interleucinas/genética , Intestinos/imunologia , Intestinos/microbiologia , Intestinos/patologia , Depleção Linfocítica , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas a Pancreatite/genética , Proteínas Associadas a Pancreatite/imunologia , Fagócitos/citologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores , Linfócitos T Reguladores , Irradiação Corporal Total
3.
PLoS One ; 15(10): e0240154, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33007050

RESUMO

BACKGROUND: The burden of HPV-associated premalignant and malignant cervical lesions remains high in HIV+ women even under ART treatment. In order to identify possible underlying pathophysiologic mechanisms, we studied activation and HIV co-receptor expression in cervical T-cell populations in relation to HIV, HPV and cervical lesion status. METHODS: Cervical cytobrush (n = 468: 253 HIV- and 215 HIV+; 71% on ART) and blood (in a subset of 39 women) was collected from women in Mbeya, Tanzania. Clinical data on HIV and HPV infection, as well as ART status was collected. T cell populations were characterized using multiparametric flow cytometry-based on their expression of markers for cellular activation (HLA-DR), and memory (CD45RO), as well as HIV co-receptors (CCR5, α4ß7). RESULTS: Cervical and blood T cells differed significantly, with higher frequencies of T cells expressing CD45RO, as well as the HIV co-receptors CCR5 and α4ß7 in the cervical mucosa. The skewed CD4/CD8 T cell ratio in blood of HIV+ women was mirrored in the cervical mucosa and HPV co-infection was linked to lower levels of mucosal CD4 T cells in HIV+ women (%median: 22 vs 32; p = 0.04). In addition, HIV and HPV infection, and especially HPV-associated cervical lesions were linked to significantly higher frequencies of HLA-DR+ CD4 and CD8 T cells (p-values < 0.05). Interestingly, HPV infection did not significantly alter frequencies of CCR5+ or α4ß7+ CD4 T cells. CONCLUSION: The increased proportion of activated cervical T cells associated with HPV and HIV infection, as well as HPV-associated lesions, together with the HIV-induced depletion of cervical CD4 T cells, may increase the risk for HPV infection, associated premalignant lesions and cancer in HIV+ women. Further, high levels of activated CD4 T cells associated with HPV and HPV-associated lesions could contribute to a higher susceptibility to HIV in HPV infected women.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Colo do Útero/patologia , Infecções por HIV/imunologia , Linfócitos Intraepiteliais/imunologia , Ativação Linfocitária/imunologia , Depleção Linfocítica , Infecções por Papillomavirus/imunologia , Adulto , Colo do Útero/imunologia , Feminino , Infecções por HIV/sangue , Antígenos HLA-DR/metabolismo , Humanos , Integrinas/metabolismo , Contagem de Linfócitos , Pessoa de Meia-Idade , Infecções por Papillomavirus/sangue , Fenótipo , Receptores CCR5/metabolismo
4.
Front Immunol ; 11: 2055, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042116

RESUMO

The clinical and laboratory features of COVID-19 are reviewed with attention to the immunologic manifestations of the disease. Recent COVID-19 publications describe a variety of clinical presentations including an asymptomatic state, pneumonia, a hemophagocytic lymphohistiocytosis like syndrome, Multisystem Inflammatory Syndrome in Children (MIS-C) but, also called Pediatric Inflammatory Multisystem Syndrome-Toxic Shock (PIMS-TS), Kawasaki Disease, and myocarditis. A common theme amongst multiple reports suggests an overexuberant autoimmune component of the disease but a common pathophysiology to explain the variations in clinical presentation has been elusive. Review of the basic science of other viral induced autoimmune disorders may give clues as to why immunosuppressive and immunomodulating regimens now appear to have some efficacy in COVID-19. Review of the immunopathology also reveals other therapies that have yet to be explored. There is potential use of T cell depleting therapies and possibly anti-CD20 therapy for COVID-19 and clinical research using these medications is warranted.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus , Imunossupressores/uso terapêutico , Depleção Linfocítica , Pandemias , Pneumonia Viral , Síndrome de Resposta Inflamatória Sistêmica , Linfócitos T , Criança , Pré-Escolar , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/terapia , Humanos , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Linfo-Histiocitose Hemofagocítica/terapia , Linfo-Histiocitose Hemofagocítica/virologia , Síndrome de Linfonodos Mucocutâneos/imunologia , Síndrome de Linfonodos Mucocutâneos/patologia , Síndrome de Linfonodos Mucocutâneos/terapia , Síndrome de Linfonodos Mucocutâneos/virologia , Miocardite/imunologia , Miocardite/terapia , Miocardite/virologia , Pneumonia Viral/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/terapia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia , Síndrome de Resposta Inflamatória Sistêmica/terapia , Síndrome de Resposta Inflamatória Sistêmica/virologia , Linfócitos T/imunologia , Linfócitos T/patologia
5.
Medicine (Baltimore) ; 99(43): e22510, 2020 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-33120740

RESUMO

INTRODUCTION: Chimeric antigen receptor T cells (CAR-T) targeting CD19 have shown great potential for treatment of B-cell malignancies. For those patients who can not achieve complete remission (CR) or suffer from relapse after CAR-T therapy, further therapeutic strategies still remain elusive. Whether existing CAR-T cells can revitalize in vivo and eradicate tumor cells is still unknown. PATIENT CONCERNS: We report a case of diffused large B-cell lymphoma patient who had achieved CR after CD19 targeted CAR-T therapy but relapsed after 5 months. DIAGNOSIS: Five months after CAR-T cell infusion, the patient was confirmed a relapse by follow-up PET/CT scan and a mass biopsy. Flow cytometry showed a dramatically decreased percentage of CAR-T cells in peripheral blood (PB). INTERVENTIONS: A second anti-CD19 CAR-T therapy was planned with deliberation. Firstly, the patient received lymphodepletion chemotherapy with fludarabine (25 mg/m, d1-d3) and cyclophosphamide (500 mg/m d2-d3). OUTCOMES: After fludarabine and cyclophosphamide (FC) lymphodepletion chemotherapy, pre-existing CAR-T cells were revitalized and the patient developed grade 2 cytokine release syndrome (CRS) contributing to the regression of relapsed B-cell lymphoma. CONCLUSIONS: This case suggested that FC chemotherapy could revitalize CAR-T cells contributing to the regression of relapsed B-cell lymphoma. Nevertheless, further researches are required in the future as this report described only a single case.


Assuntos
Ciclofosfamida/uso terapêutico , Depleção Linfocítica , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Receptores de Antígenos Quiméricos/imunologia , Indução de Remissão , Linfócitos T/imunologia , Vidarabina/análogos & derivados , Adulto , Antígenos CD19/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Síndrome da Liberação de Citocina/etiologia , Humanos , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Vidarabina/uso terapêutico
6.
Med Microbiol Immunol ; 209(6): 681-691, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32918599

RESUMO

Chimeric Antigen Receptor (CAR)-redirected T cells show great efficacy in the patient-specific therapy of hematologic malignancies. Here, we demonstrate that a DARPin with specificity for CD4 specifically redirects and triggers the activation of CAR engineered T cells resulting in the depletion of CD4+ target cells aiming for elimination of the human immunodeficiency virus (HIV) reservoir.


Assuntos
Repetição de Anquirina , Linfócitos T CD4-Positivos/virologia , Infecções por HIV/imunologia , HIV/isolamento & purificação , Imunoterapia Adotiva , Depleção Linfocítica/métodos , Peptídeos/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Relação Dose-Resposta Imunológica , Avaliação Pré-Clínica de Medicamentos , Gammaretrovirus/genética , Vetores Genéticos/genética , Células HEK293 , Infecções por HIV/virologia , Humanos , Ativação Linfocitária , Peptídeos/química , Anticorpos de Cadeia Única/imunologia , Transdução Genética
7.
Mol Immunol ; 126: 95-100, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32795664

RESUMO

Although T cells are considered as the central component in immune-mediated diseases, supportive evidence has demonstrated that B cells also contribute to the progression of these diseases. B cells are divided into various subsets according to their secreted cytokines. Different B cell subsets play diverse roles in immune-mediated dermatoses. Regulatory B cells (Bregs) are defined functionally by their ability to secrete IL-10, which has been revealed to contribute to immunological tolerance. Drugs that deplete B cells, such as rituximab, are now used for the treatment of several immune-mediated dermatoses. In this review, we present and discuss the current knowledge on the roles of B cells in several immune-mediate dermatoses including psoriasis, pemphigus, bullous pemphigoid, and dermatomyositis, atopic dermatitis.


Assuntos
Linfócitos B Reguladores/imunologia , Dermatite Atópica/imunologia , Dermatomiosite/imunologia , Penfigoide Bolhoso/imunologia , Pênfigo/imunologia , Psoríase/imunologia , Animais , Linfócitos B Reguladores/efeitos dos fármacos , Linfócitos B Reguladores/metabolismo , Dermatite Atópica/sangue , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Dermatomiosite/sangue , Dermatomiosite/tratamento farmacológico , Dermatomiosite/patologia , Desmogleína 3/metabolismo , Modelos Animais de Doenças , Humanos , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Interleucina-10/metabolismo , Depleção Linfocítica/métodos , Penfigoide Bolhoso/sangue , Penfigoide Bolhoso/tratamento farmacológico , Penfigoide Bolhoso/patologia , Pênfigo/sangue , Pênfigo/tratamento farmacológico , Pênfigo/patologia , Psoríase/sangue , Psoríase/tratamento farmacológico , Psoríase/patologia , Pele/imunologia , Pele/patologia
8.
Clin Exp Immunol ; 202(2): 149-161, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32671831

RESUMO

Although most autoimmune diseases are considered to be CD4 T cell- or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab, oblinutuzumab and ofatumumab that are used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities and ocrelizumab in multiple sclerosis. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of autoimmunity and COVID-19, it was hypothesised that while B cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B cell subset inhibition, that controls at least some autoimmunities, would not influence innate and CD8 T cell responses, which are central to SARS-CoV-2 elimination, nor the hypercoagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority of SARS-CoV-2-infected, CD20-depleted people with autoimmunity have recovered. However, protective neutralizing antibody and vaccination responses are predicted to be blunted until naive B cells repopulate, based on B cell repopulation kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose interruption to maintain inflammatory disease control, while allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/imunologia , Linfócitos B/imunologia , Betacoronavirus/fisiologia , Infecções por Coronavirus/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/imunologia , Vacinas Virais/imunologia , Animais , Antígenos CD20/imunologia , Infecções por Coronavirus/prevenção & controle , Humanos , Depleção Linfocítica , Vacinação
10.
Leukemia ; 34(10): 2766-2775, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32393841

RESUMO

The ideal stem cell graft source remains unknown in haploidentical haematopietic cell transplantation (haplo-HCT) with posttransplantation cyclophosphamide (PTCy). This study compared outcomes of bone marrow (BM) versus peripheral blood (PB) stem cell graft for haplo-HCT in acute lymphoblastic leukemia (ALL). A total of 314 patients with ALL (BM-157; PB-157) were included in this study. The cumulative incidence of engraftment at day 30 was higher in the PB group compared with BM (93% vs. 88%, p < 0.01). The incidences of acute graft-versus-host disease (GVHD) and chronic GVHD were not significantly different between the study cohorts. In the multivariate analysis, there were tendencies toward a higher incidence of grade II-IV acute GVHD (hazard ratio (HR) = 1.52, p = 0.07), chronic GVHD (HR = 1.58, p = 0.05), and nonrelapse mortality (NRM) (HR = 1.66, p = 0.06) in patients receiving PB versus BM graft, respectively. The use of PB grafts was associated with lower leukemia-free survival (LFS) (HR = 1.43, p = 0.05), overall survival (OS) (HR = 1.59, p = 0.02), and GVHD-free, relapse-free survival (GRFS) (HR = 1.42, p = 0.03) compared with BM grafts. There was no difference in relapse incidence (HR = 1.23, p = 0.41) between the study groups. In conclusion, use of BM graft results in better survival after haplo-HCT with PTCy in patients with ALL, compared with PB stem cell graft.


Assuntos
Transplante de Medula Óssea , Mobilização de Células-Tronco Hematopoéticas , Depleção Linfocítica , Transplante de Células-Tronco de Sangue Periférico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Transplante Haploidêntico , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Causas de Morte , Terapia Combinada , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Masculino , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Transplante de Células-Tronco de Sangue Periférico/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Modelos de Riscos Proporcionais , Linfócitos T , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento
11.
Leukemia ; 34(10): 2688-2703, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32358567

RESUMO

Acute myeloid leukemia (AML) initiating and sustaining cells maintain high cell-surface similarity with their cells-of-origin, i.e., hematopoietic stem and progenitor cells (HSPCs), and identification of truly distinguishing leukemia-private antigens has remained elusive to date. To nonetheless utilize surface antigen-directed immunotherapy in AML, we here propose targeting both, healthy and malignant human HSPC, by chimeric antigen receptor (CAR) T-cells with specificity against CD117, the cognate receptor for stem cell factor. This approach should spare most mature hematopoietic cells and would require CAR T termination followed by subsequent transplantation of healthy HSPCs to rescue hematopoiesis. We successfully generated anti-CD117 CAR T-cells from healthy donors and AML patients. Anti-CD117 CAR T-cells efficiently targeted healthy and leukemic CD117-positive cells in vitro. In mice xenografted with healthy human hematopoiesis, they eliminated CD117-expressing, but not CD117-negative human cells. Importantly, in mice xenografted with primary human CD117-positive AML, they eradicated disease in a therapeutic setting. Administration of ATG in combination with rituximab, which binds to the co-expressed CAR T-cell transduction/selection marker RQR8, led to CAR T-cell depletion. Thus, we here provide the first proof of concept for the generation and preclinical efficacy of CAR T-cells directed against CD117-expressing human hematopoietic cells.


Assuntos
Imunoterapia Adotiva , Proteínas Proto-Oncogênicas c-kit/antagonistas & inibidores , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Biomarcadores , Biópsia , Medula Óssea/metabolismo , Medula Óssea/patologia , Linhagem Celular Tumoral , Modelos Animais de Doenças , Expressão Gênica , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/terapia , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Imunofenotipagem , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Depleção Linfocítica , Camundongos , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Cancer Immunol Immunother ; 69(10): 2063-2073, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32447412

RESUMO

Although metastatic disease is responsible for the majority of cancer deaths, tests of novel immunotherapies in mouse tumour models often focus on primary tumours without determining whether these therapies also target metastatic disease. This study examined the impact of depleting Foxp3+ regulatory T cells (Treg), on lung metastases, using a mouse model of breast cancer. After Treg-depletion, generation of an immune response to the primary tumour was a critical determinant for limiting development of metastasis. Indeed, resection of the primary tumour abrogated any effect of Treg-depletion on metastases. In addition, whilst the immune response, generated by the primary tumour, prevented metastases development, it had little impact on controlling established disease. Collectively, the data indicate that metastatic cells in the lung are not controlled by immune responses induced by the primary tumour. These findings indicate that targeting Tregs alone will not suffice for treating lung metastases.


Assuntos
Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Depleção Linfocítica/métodos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Reguladores/imunologia , Neoplasias de Mama Triplo Negativas/imunologia , Animais , Feminino , Fatores de Transcrição Forkhead/metabolismo , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Camundongos , Linfócitos T Reguladores/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia
14.
Mult Scler Relat Disord ; 43: 102195, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32460086

RESUMO

OBJECTIVE: To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease. METHODS: In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system. Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19, and the disposition after the diagnosis. We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography. We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models. RESULTS: Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group. Only two patients required hospitalization. No patient required intensive care. In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030), and history of sick contact (p-values<0.001) were associated with the risk of being in the COVID-19-suspect group. Being on B-cell depleting antibodies (as compared to non-cell depleting, non-cell trafficking inhibitor DMTs) was associated with a 2.6-fold increase in the risk of being in the COVID-19-suspect group. (RR: 3.55, 95%CI: 1.45, 8.68, p-value=0.005). CONCLUSIONS: The course of infection in patients with MS suspected of having COVID-19 was mild to moderate, and all patients had a full recovery. B-cell depleting antibodies may increase the susceptibility to contracting COVID-19.


Assuntos
Infecções por Coronavirus/imunologia , Hospedeiro Imunocomprometido/imunologia , Fatores Imunológicos/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Pneumonia Viral/imunologia , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Linfócitos B/imunologia , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/fisiopatologia , Tosse , Estudos Transversais , Crotonatos/uso terapêutico , Fumarato de Dimetilo/uso terapêutico , Suscetibilidade a Doenças , Dispneia , Epidemias , Feminino , Febre , Cloridrato de Fingolimode/uso terapêutico , Acetato de Glatiramer/uso terapêutico , Hospitalização/estatística & dados numéricos , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Interferons/uso terapêutico , Irã (Geográfico)/epidemiologia , Pulmão/diagnóstico por imagem , Depleção Linfocítica , Masculino , Esclerose Múltipla/complicações , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/epidemiologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/epidemiologia , Natalizumab/uso terapêutico , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/fisiopatologia , Rituximab/uso terapêutico , Índice de Gravidade de Doença , Toluidinas/uso terapêutico , Tomografia Computadorizada por Raios X
15.
Int J Mol Sci ; 21(5)2020 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-32121269

RESUMO

Resolution of deep venous thrombosis involves coordinated inflammatory processes. T cells regulate inflammation in vivo and modulate vascular remodeling in other settings, but their role in venous thrombus resolution remains undefined. To determine the role of T cells in venous thrombus resolution in vivo, stasis induced thrombi were created by vena cava ligation in outbred CD-1 mice. CD4 and CD8 positive T cells, as determined by flow cytometry, were present in thrombi both during thrombus formation and resolution. Depletion of the CD4 and CD8 positive T cells by antibody treatment selectively impaired thrombus resolution compared to animals treated with isotype control antibodies, without an effect on venous thrombus formation. Quantitation of intra-thrombus macrophage numbers, fibrinolytic marker expression, and gelatinolytic activity by zymography revealed that T cell depletion decreased the number of macrophages, reduced the expression of fibrinolytic marker urokinase plasminogen activator (uPA), and decreased the activity of matrix metalloprotinease-9 (MMP-9). These data implicate CD4 and CD8 positive T cells in functionally contributing to venous thrombus resolution, thus representing a potential therapeutic target, but also underscoring potential risks involved in T cell depletion used clinically for solid organ and hematopoietic transplantation procedures.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Depleção Linfocítica , Trombose Venosa/imunologia , Animais , Linfócitos B/imunologia , Contagem de Células , Fibrinólise , Gelatina/metabolismo , Macrófagos/patologia , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Trombose Venosa/patologia
16.
Cancer Immunol Immunother ; 69(7): 1279-1292, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32185408

RESUMO

The presence of activated T cells in colorectal cancer tissues is a strong predictor of patient survival. Our previous studies have shown that regulatory T cells (Treg) are able to reduce T cell transendothelial migration in vitro and accumulation of effector T cells in intestinal tumors in vivo in the murine APCMin/+ model for microsatellite stable intestinal tumors. In this study, we investigated the effect of Treg depletion on the density and effector functions of different TCRαß+ and TCRγδ+ T cell populations in intestinal tumors. We used the APCMin/+\DEREG mouse model, which harbor a diphtheria toxin receptor under the control of the FOXP3 promoter, to deplete Treg in tumor bearing mice. We found that the density of conventional TCRαß+CD8αß+ T cells was significantly increased in Treg-depleted tumors in comparison with Treg-proficient tumors. Furthermore, TCRαß+CD8αß+ T cells showed increased proliferation and activation as well as increased Granzyme B and IFN-γ production in Treg-depleted tumors. In sharp contrast, the densities and effector functions of TCRαß+CD8αα+ T cells and TCRγδ+ T cells remained unchanged by Treg depletion. We also documented a distinct population of IL-17A+TNF+ TCRγδ+CD8- T cells in tumors, which were not affected by Treg depletion. We conclude that Treg depletion affects only conventional TCRαß+CD8αß+ T cells in intestinal tumors, while unconventional T cells and T cells in unaffected tissue are not altered. Immunotherapies aimed at depleting Treg from tumors may thus be a viable option for reinvigoration of conventional cytotoxic T cells with a Th1 cytokine profile.


Assuntos
Proteína da Polipose Adenomatosa do Colo/fisiologia , Antígenos CD8/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias Intestinais/imunologia , Linfócitos do Interstício Tumoral/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Feminino , Humanos , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/patologia , Ativação Linfocitária , Depleção Linfocítica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo
17.
Ann Hematol ; 99(11): 2649-2657, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32206854

RESUMO

Posttransplantation lymphoproliferation disorder (PTLD) is a life-threatening complication after hematopoietic stem cell transplantation (HSCT). Anti-CD20 antibody is the most widely used antibody to eliminate infected B cells. Few studies have focused on prognostic factors predicting the outcome of EBV (Epstein-Barr virus)-PTLD. We conducted a retrospective analysis of 2571 haplo-HSCTs performed between 2010 and 2017 at the Peking University Institute of Hematology; seventy patients who had been treated with rituximab for PTLD were enrolled. The overall EBV-related PTLD frequency was 3.1%. With a median follow-up time of 365 days (range, 54-2659), the overall survival rate was 51.43% (36/70). The cumulative incidence of EBV-PTLD complete remission with anti-CD20 antibody monotherapy was 68.57% (48/70). EBV-PTLD-related mortality was 11.43% (8/70), while the transplantation-related mortality was 38.57% (27/70). Multivariate analysis showed that a decrease in EBV viral load 1 week after therapy was associated with high response rate of EBV-PTLD (p = 0.007, 0.106 (0.021-0.549)), low PTLD-related mortality (p = 0.010, HR 0.058 (0.007-0.503)), and transplantation-related mortality (p = 0.051, HR 0.441 (0.194-1.003)). For EBV-PTLD patients after haplo-HSCT who received rituximab as first-line therapy, non-decreased EBV viral load 1 week after anti-CD20 therapy could be high risk factor for poor outcomes.


Assuntos
Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 4 , Transtornos Linfoproliferativos , Rituximab/administração & dosagem , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Infecções por Vírus Epstein-Barr/etiologia , Infecções por Vírus Epstein-Barr/mortalidade , Feminino , Seguimentos , Humanos , Incidência , Depleção Linfocítica , Transtornos Linfoproliferativos/tratamento farmacológico , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rituximab/efeitos adversos , Taxa de Sobrevida
18.
Am J Pathol ; 190(6): 1224-1235, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32201264

RESUMO

Intratracheal instillation of apoptotic cells enhances resolution of experimental lung inflammation by incompletely understood mechanisms. We report that this intervention induces functional regulatory T lymphocytes (Tregs) in mouse lung experimentally inflamed by intratracheal administration of lipopolysaccharide. Selective depletion demonstrated that Tregs were necessary for maximal apoptotic cell-directed enhancement of resolution, and adoptive transfer of additional Tregs was sufficient to promote resolution without administering apoptotic cells. After intratracheal instillation, labeled apoptotic cells were observed in most CD11c+CD103+ myeloid dendritic cells migrating to mediastinal draining lymph nodes and bearing migratory and immunoregulatory markers, including increased CCR7 and ß8 integrin (ITGB8) expression. In mice deleted for αv integrin in the myeloid line to reduce phagocytosis of dying cells by CD103+ dendritic cells, exogenous apoptotic cells failed to induce transforming growth factor-ß1 expression or Treg accumulation and failed to enhance resolution of lipopolysaccharide-induced lung inflammation. We conclude that in murine lung, myeloid phagocytes encountering apoptotic cells can deploy αv integrin-mediated mechanisms to induce Tregs and enhance resolution of acute inflammation.


Assuntos
Apoptose/fisiologia , Integrina alfaV/metabolismo , Pneumonia/metabolismo , Linfócitos T Reguladores/metabolismo , Transferência Adotiva , Animais , Fatores de Transcrição Forkhead/metabolismo , Ativação Linfocitária , Depleção Linfocítica , Camundongos , Fagocitose/fisiologia , Pneumonia/patologia
19.
Leukemia ; 34(7): 1907-1923, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32047237

RESUMO

Overcoming graft-versus-host disease (GvHD) without increasing relapse and severe infections is a major challenge after allogeneic hematopoietic stem-cell transplantation (HSCT). ATIR101 is a haploidentical, naïve cell-enriched T-cell product, depleted of recipient-alloreactive T cells to minimize the risk of GvHD and provide graft-versus-infection and -leukemia activity. Safety and efficacy of ATIR101 administered after T-cell-depleted haploidentical HSCT (TCD-haplo + ATIR101) without posttransplant immunosuppressors were evaluated in a Phase 2, multicenter study of 23 patients with acute leukemia and compared with an observational cohort undergoing TCD-haplo alone (n = 35), matched unrelated donor (MUD; n = 64), mismatched unrelated donor (MMUD; n = 37), and umbilical cord blood (UCB; n = 22) HSCT. The primary endpoint, 6-month non-relapse mortality (NRM), was 13% with TCD-haplo + ATIR101. One year post HSCT, TCD-haplo + ATIR101 resulted in lower NRM versus TCD-haplo alone (P = 0.008). GvHD-free, relapse-free survival (GRFS) was higher with TCD-haplo + ATIR101 versus MMUD and UCB (both P < 0.03; 1-year rates: 56.5%, 27.0%, and 22.7%, respectively) and was not statistically different from MUD (1 year: 40.6%). ATIR101 grafts with high third-party reactivity were associated with fewer clinically relevant viral infections. Results suggest that haploidentical, selective donor-cell depletion may eliminate requirements for posttransplant immunosuppressors without increasing GvHD risk, with similar GRFS to MUD. Following these results, a randomized Phase 3 trial versus posttransplant cyclophosphamide had been initiated.


Assuntos
Doença Enxerto-Hospedeiro/mortalidade , Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Mieloide Aguda/mortalidade , Depleção Linfocítica/mortalidade , Doadores não Relacionados/estatística & dados numéricos , Adulto , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Condicionamento Pré-Transplante , Adulto Jovem
20.
Cancer Immunol Immunother ; 69(5): 745-758, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32047957

RESUMO

BACKGROUND: Osteosarcoma (OS) is the most common malignant bone tumor and the prognosis of advanced cases is still poor. Recently, there have been several reports suggesting the relationship between innate immunity and OS, but the detailed mechanism is unknown. We demonstrate the relationship between OS and Toll-like receptor 4 (TLR4) which is one of the most important factors in innate immunity. METHODS: We established a syngenic mouse tumor model using C3H/HeN, C3H/HeJ mouse and a highly metastatic OS cell line, LM8. TLR4 activation with lipopolysaccharide (LPS) was performed on both mice and its influence on the progression of OS was evaluated. We also performed CD8 + cells depletion to examine the influence on TLR4 activation effects. RESULTS: Tumor volume of C3H/HeN mice was significantly smaller and overall survival of C3H/HeN mice was significantly longer than C3H/HeJ mice. We found more CD8+ cells infiltrating in lung metastases of C3H/HeN mice and depletion of CD8+ cells canceled the antitumor effects of LPS. CONCLUSION: TLR4 activation by LPS increased CD8+ cells infiltrating into lung metastases and suppressed OS progression in the mouse model. TLR4 activation may suppress the progression of OS via stimulating CD8+ cells and can be expected as a novel treatment for OS.


Assuntos
Neoplasias Ósseas/imunologia , Neoplasias Pulmonares/imunologia , Osteossarcoma/imunologia , Linfócitos T Citotóxicos/imunologia , Receptor 4 Toll-Like/metabolismo , Adjuvantes Imunológicos/administração & dosagem , Adolescente , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/mortalidade , Neoplasias Ósseas/patologia , Neoplasias Ósseas/terapia , Linhagem Celular Tumoral/transplante , Quimioterapia Adjuvante , Criança , Pré-Escolar , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Lipídeo A/administração & dosagem , Lipídeo A/análogos & derivados , Lipopolissacarídeos/administração & dosagem , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/secundário , Neoplasias Pulmonares/terapia , Depleção Linfocítica , Masculino , Camundongos , Pessoa de Meia-Idade , Osteossarcoma/mortalidade , Osteossarcoma/secundário , Osteossarcoma/terapia , Prognóstico , Intervalo Livre de Progressão , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/metabolismo , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/imunologia , Carga Tumoral/imunologia , Adulto Jovem
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