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1.
Clin Lymphoma Myeloma Leuk ; 20(11): 720-723, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32727701
2.
Bull Cancer ; 107(12S): S130-S139, 2020 Dec.
Artigo em Francês | MEDLINE | ID: mdl-32560899

RESUMO

Microtransplantation (MT) is based on injection of HLA-mismatched G-CSF mobilized hematopoietic stem cells, in combination with chemotherapy but without use of conditioning regimen nor immunosuppressive drugs. As a result, a transient microchimerism is induced without engraftment. Its efficacy relies both on host immune system stimulation (recipient versus tumor) and on a graft versus tumor effect. Data are scarce and concern mostly Asian patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (HR-MDS). In comparison to conventional treatment without MT, higher complete remission rates and longer disease free survival and overall survival have been reported. Safety seems acceptable. The most frequent adverse event is non-severe cytokine release syndrome. Risk of GVHD remains very low. Here, we summarize the published data and detail the practical aspects of the procedure. Current data are not strong enough to provide recommendations on indications. Nevertheless, it seems reasonable to propose MT to patients with AML or HR-MDS, regardless of age, presenting an indication for allogeneic stem cell transplantation but ineligible for it. MT is still under investigation and rather be proposed within clinical trials.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Fatores Etários , Antineoplásicos/uso terapêutico , Quimerismo , Terapia Combinada/métodos , Síndrome da Liberação de Citocina/etiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Fator Estimulador de Colônias de Granulócitos , Mobilização de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Hematopoéticas/normas , Reação Hospedeiro-Enxerto/imunologia , Humanos , Leucemia Mieloide Aguda/etnologia , Intervalo Livre de Progressão , Sociedades Médicas
3.
Biol Blood Marrow Transplant ; 26(7): e161-e166, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32389803

RESUMO

With the COVID-19 pandemic and the ensuing barriers to the collection and transport of donor cells, it is often necessary to collect and cryopreserve grafts before initiation of transplantation conditioning. The effect on transplantation outcomes in nonmalignant disease is unknown. This analysis examined the effect of cryopreservation of related and unrelated donor grafts for transplantation for severe aplastic anemia in the United States during 2013 to 2019. Included are 52 recipients of cryopreserved grafts who were matched for age, donor type, and graft type to 194 recipients who received noncryopreserved grafts. Marginal Cox regression models were built to study the effect of cryopreservation and other risk factors associated with outcomes. We recorded higher 1-year rates of graft failure (hazard ratio [HR], 2.26; 95% confidence interval, 1.17 to 4.35; P = .01) and of 1-year overall mortality (HR, 3.13; 95% CI, 1.60 to 6.11; P = .0008) after transplantation of cryopreserved compared with noncryopreserved grafts, with adjustment for sex, performance score, comorbidity, cytomegalovirus serostatus, and ABO blood group match. The incidence of acute and chronic graft-versus-host disease did not differ between the 2 groups. Adjusted probabilities of 1-year survival were 73% (95% CI, 60% to 84%) in the cryopreserved graft group and 91% (95% CI, 86% to 94%) in the noncryopreserved graft group. These data support the use of noncryopreserved grafts whenever possible in patients with severe aplastic anemia.


Assuntos
Anemia Aplástica/terapia , Transplante de Medula Óssea/métodos , Infecções por Coronavirus/epidemiologia , Criopreservação/métodos , Rejeição de Enxerto/patologia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco de Sangue Periférico/métodos , Pneumonia Viral/epidemiologia , Doença Aguda , Adolescente , Adulto , Idoso , Anemia Aplástica/imunologia , Anemia Aplástica/mortalidade , Anemia Aplástica/patologia , Criança , Pré-Escolar , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/mortalidade , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Estudos Retrospectivos , Irmãos , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Estados Unidos/epidemiologia , Doadores não Relacionados
4.
Eur J Immunol ; 50(6): 770-778, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32383480

RESUMO

The immune system is tightly regulated by a subset of T cells defined as regulatory T cells (Tregs). Tregs maintain immune homeostasis by restraining unwarranted immune cell activation and effector function. Here, we discuss an important but underappreciated role of proteases in controlling Treg function. Proteases regulate a number of vital processes that determine T cell immune responses and some of them such as furin, ADAM (through regulating LAG receptor), MALT, and asparaginyl endopeptidase are implicated in Treg immunobiology. Targeted protease inhibition, using either small molecule inhibitors or gene deficient mice has demonstrated their specificity in modulating Treg function in experimental murine models. These data further highlight the ability of proteases to specifically regulate Tregs but no other T effector lineages. Taken together, it is apparent that incorporating proteases as targets within Treg cell engineering protocols may enable generation of robust Treg cellular therapeutics. These engineered Tregs may possess enhanced regulatory function along with resistance to lineage deviation in inflammatory disease such as colitis and graft versus host disease. Within this review, we summarize research on the role of proteases in regulating Treg function and discuss the translational potential of harnessing Treg function by targeting protease driven regulatory pathways.


Assuntos
Proteínas ADAM/imunologia , Caspases/imunologia , Colite , Furina/imunologia , Doença Enxerto-Hospedeiro , Imunoterapia , Linfócitos T Reguladores/imunologia , Animais , Engenharia Celular , Colite/imunologia , Colite/patologia , Colite/terapia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Camundongos , Linfócitos T Reguladores/patologia
5.
PLoS One ; 15(5): e0233497, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32442182

RESUMO

Mixed hematopoietic chimerism enables donor-specific tolerance for solid organ grafts. This study evaluated the influence of different serological major histocompatibility complex disparities on chimerism development, graft-versus-host disease incidence and subsequently on solid organ tolerance in a rat model. For bone marrow transplantation conditioning total body irradiation was titrated using 10, 8 or 6 Gray. Bone marrow transplantation was performed across following major histocompatibility complex mismatched barriers: complete disparity, MHC class II, MHC class I or non-MHC mismatch. Recipients were clinically monitored for graft-versus-host disease and analyzed for chimerism using flow cytometry. After a reconstitution of 100 days, composition of peripheral leukocytes was determined. Mixed chimeras were challenged with heart grafts from allogeneic donor strains to define the impact of donor MHC class disparities on solid organ tolerance on the basis of stable chimerism. After myeloablation with 10 Gray of total body irradiation, chimerism after bone marrow transplantation was induced independent of MHC disparity. MHC class II disparity increased the incidence of graft-versus-host disease and reduced induction of stable chimerism upon myelosuppressive total body irradiation with 8 and 6 Gray, respectively. Stable mixed chimeras showed tolerance towards heart grafts from donors with MHC matched to either bone marrow donors or recipients. Isolated matching of MHC class II with bone marrow donors likewise led to stable tolerance as opposed to matching of MHC class I. In summary, MHC class II disparity was critically associated with the onset of graft-versus host disease and was identified as obstacle for successful development of chimerism after bone marrow transplantation and subsequent donor-specific solid organ tolerance.


Assuntos
Transplante de Medula Óssea , Antígenos de Histocompatibilidade Classe II/imunologia , Quimeras de Transplante/imunologia , Tolerância ao Transplante/imunologia , Aloenxertos , Animais , Doença Enxerto-Hospedeiro/imunologia , Transplante de Coração , Humanos , Masculino , Modelos Animais , Modelos Imunológicos , Transplante de Órgãos , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Doadores de Tecidos , Condicionamento Pré-Transplante , Irradiação Corporal Total
6.
Nat Rev Clin Oncol ; 17(8): 475-492, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32313224

RESUMO

Allogeneic haematopoietic stem cell transplantation (allo-HSCT) was the first successful therapy for patients with haematological malignancies, predominantly owing to graft-versus-tumour (GvT) effects. Dramatic methodological changes, designed to expand eligibility for allo-HSCT to older patients and/or those with comorbidities, have led to the use of reduced-intensity conditioning regimens, in parallel with more aggressive immunosuppression to better control graft-versus-host disease (GvHD). Consequently, disease relapse has become the major cause of death following allo-HSCT. Hence, the prevention and treatment of relapse has come to the forefront and remains an unmet medical need. Despite >60 years of preclinical and clinical studies, the immunological requirements necessary to achieve GvT effects without promoting GvHD have not been fully established. Herein, we review learnings from preclinical modelling and clinical studies relating to the GvT effect, focusing on mechanisms of relapse and on immunomodulatory strategies that are being developed to overcome disease recurrence after both allo-HSCT and autologous HSCT. Emphasis is placed on discussing current knowledge and approaches predicated on the use of cell therapies, cytokines to augment immune responses and dual-purpose antibody therapies or other pharmacological agents that can control GvHD whilst simultaneously targeting cancer cells.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Efeito Enxerto vs Tumor/imunologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/imunologia , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Imunossupressão/métodos , Transplante Homólogo/efeitos adversos
7.
Biol Blood Marrow Transplant ; 26(7): 1312-1317, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32283185

RESUMO

The COVID-19 pandemic has created significant barriers to timely donor evaluation, cell collection, and graft transport for allogeneic hematopoietic stem cell transplantation (allo-HCT). To ensure availability of donor cells on the scheduled date of infusion, many sites now collect cryopreserved grafts before the start of pretransplantation conditioning. Post-transplantation cyclophosphamide (ptCY) is an increasingly used approach for graft-versus-host disease (GVHD) prophylaxis, but the impact of graft cryopreservation on the outcomes of allo-HCT using ptCY is not known. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared the outcomes of HCT using cryopreserved versus fresh grafts in patients undergoing HCT for hematologic malignancy with ptCY. We analyzed 274 patients with hematologic malignancy undergoing allo-HCT between 2013 and 2018 with cryopreserved grafts and ptCY. Eighteen patients received bone marrow grafts and 256 received peripheral blood stem cell grafts. These patients were matched for age, graft type, disease risk index (DRI), and propensity score with 1080 patients who underwent allo-HCT with fresh grafts. The propensity score, which is an assessment of the likelihood of receiving a fresh graft versus a cryopreserved graft, was calculated using logistic regression to account for the following: disease histology, Karnofsky Performance Score (KPS), HCT Comorbidity Index, conditioning regimen intensity, donor type, and recipient race. The primary endpoint was overall survival (OS). Secondary endpoints included acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), relapse/progression and disease-free survival (DFS). Because of multiple comparisons, only P values <.01 were considered statistically significant. The 2 cohorts (cryopreserved and fresh) were similar in terms of patient age, KPS, diagnosis, DRI, HCT-CI, donor/graft source, and conditioning intensity. One-year probabilities of OS were 71.1% (95% confidence interval [CI], 68.3% to 73.8%) with fresh grafts and 70.3% (95% CI, 64.6% to 75.7%) with cryopreserved grafts (P = .81). Corresponding probabilities of OS at 2 years were 60.6% (95% CI, 57.3% to 63.8%) and 58.7% (95% CI, 51.9% to 65.4%) (P = .62). In matched-pair regression analysis, graft cryopreservation was not associated with a significantly higher risk of mortality (hazard ratio [HR] for cryopreserved versus fresh, 1.05; 95% CI, .86 to 1.29; P = .60). Similarly, rates of neutrophil recovery (HR, .91; 95% CI, .80 to 1.02; P = .12), platelet recovery (HR, .88; 95% CI, .78 to 1.00; P = .05), grade III-IV acute GVHD (HR, .78; 95% CI, .50 to 1.22; P = .27), NRM (HR, 1.16; 95% CI, .86 to 1.55; P = .32) and relapse/progression (HR, 1.21; 95% CI, .97 to 1.50; P = .09) were similar with cryopreserved grafts versus fresh grafts. There were somewhat lower rates of chronic GVHD (HR, 78; 95% CI, .61 to .99; P = .04) and DFS (HR for treatment failure, 1.19; 95% CI, 1.01 to 1.29; P = .04) with graft cryopreservation that were of marginal statistical significance after adjusting for multiple comparisons. Overall, our data indicate that graft cryopreservation does not significantly delay hematopoietic recovery, increase the risk of acute GVHD or NRM, or decrease OS after allo-HCT using ptCY.


Assuntos
Transplante de Medula Óssea/métodos , Infecções por Coronavirus/epidemiologia , Criopreservação/métodos , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Linfoma/terapia , Síndromes Mielodisplásicas/terapia , Pneumonia Viral/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Ciclofosfamida/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Teste de Histocompatibilidade , Humanos , Leucemia/imunologia , Leucemia/mortalidade , Leucemia/patologia , Linfoma/imunologia , Linfoma/mortalidade , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Pandemias , Irmãos , Análise de Sobrevida , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Estados Unidos/epidemiologia , Doadores não Relacionados/provisão & distribução
8.
Cell Immunol ; 352: 104113, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32331794

RESUMO

Human placenta-derived mesenchymal stromal cells (hPMSCs) are promising candidates for the treatment of graft-versus-host disease (GVHD), which is associated with high IL-1ß levels. In this study, the effects of IL-1ß and hPMSCs on each other were investigated by analyzing the proportion of Th1, Th2 and CD4+IL-10+ T cells and PD-L1 expression, as well as the adhesion, migration, and proliferation of hPMSCs. The results showed that hPMSCs decreased IL-1ß levels and downregulated Th1/Th2 and Th1/CD4+IL-10+ T cells ratios in the GVHD model. The in vitro results revealed that IL-1ß strengthened the hPMSCs capacity to reduce the Th1/Th2 and Th1/CD4+IL-10+ T cell ratios, inhibited the adhesion and proliferation of hPMSCs and increased PD-L1 expression on hPMSCs via the JAK and NF-κB pathways. Overall, these findings suggested that hPMSCs alleviate GVHD by decreasing IL-1ß level and maintaining the balance among different T cell subsets. IL-1ß enhanced the ability of hPMSCs to balance different T cell subsets and inhibited hPMSCs adhesion and proliferation by regulating PD-L1 expression via the JAK and NF-κB pathways.


Assuntos
Antígeno B7-H1/imunologia , Interleucina-1beta/imunologia , Células-Tronco Mesenquimais/imunologia , Placenta/imunologia , Animais , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Adesão Celular/imunologia , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Proliferação de Células/fisiologia , Células Cultivadas , Técnicas de Cocultura , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Humanos , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Placenta/citologia , Placenta/metabolismo , Gravidez , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th1/imunologia , Células Th1/metabolismo , Células Th2/imunologia , Células Th2/metabolismo
9.
Crit Rev Oncol Hematol ; 150: 102944, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32247246

RESUMO

BACKGROUND: Graft-versus-host disease (GVHD) is a leading cause of death in patients after hematopoietic stem-cell transplantation (HSCT). Previous studies have shown different efficacy of GVHD prophylaxis therapies. METHODS: We reviewed 46 randomized controlled trials (including 8050 participants) systematically from Jun 20, 2004 to Aug 20, 2019. These investigations compared the following drugs or their combination at therapeutic dose range for GVHD after HSCT. The main results were based on the proportion of patients who respond to these therapies. RESULTS: Cyclosporine + methotrexate + Anti-T cell globulin (ATG), tacrolimus + methotrexate + ATG, tacrolimus + bortezomib + sirolimus and cyclosporine + marrow mesenchymal stem cells (MMSCs) were significantly more efficacious than corticosteroids alone (OR: 12.15, 6.71, 6.25, 3.73). corticosteroids alone were less efficacious than all the other GVHD prophylaxis therapies tested. CONCLUSION: Cyclosporine + methotrexate + ATG may be the best choice when starting treatment for GVHD.


Assuntos
Soro Antilinfocitário/uso terapêutico , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunossupressores/uso terapêutico , Bortezomib/uso terapêutico , Ciclosporina/uso terapêutico , Quimioterapia Combinada , Doença Enxerto-Hospedeiro/imunologia , Humanos , Metotrexato/uso terapêutico , Metanálise em Rede , Ensaios Clínicos Controlados Aleatórios como Assunto , Sirolimo/uso terapêutico , Tacrolimo/uso terapêutico , Transplante Homólogo , Resultado do Tratamento
10.
J Vis Exp ; (157)2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32250356

RESUMO

Allogeneic bone marrow transplantation (BMT) is an effective therapy for hematological malignancies due to the graft-versus-leukemia (GVL) effect to eradicate tumors. However, its application is limited by the development of graft-versus-host disease (GVHD), a major complication of BMT. GVHD is evoked when T-cells in the donor grafts recognizealloantigen expressed by recipient cells and mount unwanted immunological attacks against recipient healthy tissues. Thus, traditional therapies are designed to suppress donor T-cell alloreactivity. However, these approaches substantially impair the GVL effect so that the recipient's survival is not improved. Understanding the effects of therapeutic approaches on BMT, GVL, and GVHD, is thus essential. Due to the antigen-presenting and cytokine-secreting capacities to stimulate donor T-cells, recipient dendritic cells (DCs) play a significant role in the induction of GVHD. Therefore, targeting recipient DCs becomes a potential approach for controlling GVHD. This work provides a description of a novel BMT platform to investigate how host DCs regulate GVH and GVL responses after transplantation. Also presented is an effective BMT model to study the biology of GVHD and GVL after transplantation.


Assuntos
Transplante de Medula Óssea , Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Linfócitos T/imunologia , Animais , Humanos
11.
PLoS One ; 15(4): e0231222, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32251446

RESUMO

IL-17A and IL-17F cytokines are important regulators of acute graft-versus-host-disease (GVHD). However, contrary effects of these cytokines in inflammatory diseases have been reported. To investigate the effects of donor-derived IL-17A and IL-17F on GVHD, we made use of single (Il17a-/- or Il17f-/-) and double deficient (Il17af-/-) allogeneic donor CD4+ T cells. We could demonstrate that transplantation of Il17af-/- CD4+ donor T cells led to aggravated GVHD. However, this phenotype was not observed after transplantation of single, Il17a-/- or Il17f-/-, deficient CD4+ T cells, suggesting redundant effects of IL-17A and IL-17F. Moreover, Il17af-/- cell recipients showed an increase of systemic IFNγ, indicating a heightened pro-inflammatory state, as well as infiltration of IFNγ-secreting CD4+ T cells in the recipients' intestinal tract. These recipients exhibited significant gut leakage, and markedly macrophage infiltration in the gastrointestinal epithelial layer. Moreover, we saw evidence of impaired recovery of gut epithelial cells in recipients of Il17af-/- CD4+ T cells. In this study, we show that IL-17A/F double deficiency of donor CD4+ T cells leads to accelerated GVHD and therefore highlight the importance of these cytokines. Together, IL-17 cytokines might serve as a brake to an intensified Th1 response, leading to the exacerbated gut damage in acute GVHD.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Interleucina-17/metabolismo , Intestinos/imunologia , Células Th1/citologia , Animais , Transplante de Medula Óssea , Linfócitos T CD4-Positivos/citologia , Células CACO-2 , Proliferação de Células , Microbioma Gastrointestinal , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , RNA Ribossômico 16S/metabolismo
12.
Cancer Immunol Res ; 8(6): 756-768, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32209636

RESUMO

Natural killer (NK) cells provide a natural defense against MHC-I-negative tumors, such as melanoma. Donor lymphocyte infusion (DLI) containing NK cells, a form of adoptive immunotherapy used after allogenic bone marrow transplantation (allo-BMT), promotes antitumor immune responses but is often associated with life-threatening complications such as graft-versus-host disease (GvHD). Here, we showed that without prior allo-BMT, DLI provoked melanoma control associated with the infiltration and persistence of the transferred NK cells. This allograft acceptance did not correlate with an increase of GvHD; instead it correlated with the expansion and activation of tumor-infiltrating NK cells that expressed the cytotoxic molecules (e.g., IFNγ and granzyme B) and maturation signatures (e.g., CD11bhiCD27lo and KLRGhi/CD43hi). The development of beneficial tumor-infiltrating NK cells of DLI origin required host CD4+ T-cell help in part by producing IL2, as well as by limiting regulatory CD4+ T cells (Treg). IL2 blockade impaired the NK-dependent melanoma control, which could not be rescued by IL2 administration beyond CD4+ T-cell help. Our findings linked NK allograft acceptance-CD4+ T-cell help crosstalk to melanoma development without the need of allo-BMT. We thereby helped define that tumor-infiltrating NK cells of DLI origin may serve as effective therapeutic targets for controlling melanoma.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Naturais/imunologia , Melanoma Experimental/terapia , Linfócitos T Reguladores/imunologia , Doadores de Tecidos/provisão & distribução , Animais , Transplante de Medula Óssea , Feminino , Doença Enxerto-Hospedeiro/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Melanoma Experimental/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
13.
Ann Palliat Med ; 9(2): 459-462, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32156137

RESUMO

Pulmonary graft versus host disease (GVHD) features irreversible airflow obstruction, which treatment typically involves immunosuppressive regimens. Regardless of whether GVHD is caused by immune overreaction or infection caused by immunologic suppression, the end result is death. Therefore, it is crucial to maintain a balance. We assessed 15 patients after hematopoietic stem cell transplantation (HSCT) in our hospital and collected CD4 cell percentage, forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC) data from the same period. Here, we present a dynamic evaluation of the correlativity between the CD4 cell percentage and FEV1 that can predict state balance in pulmonary GVHD patients.


Assuntos
Contagem de Linfócito CD4 , Linfócitos T CD8-Positivos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Adulto , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Capacidade Vital
14.
Arthritis Rheumatol ; 72(8): 1385-1395, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32182396

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) is characterized by fibrosis, vascular disease, and inflammation. Adenosine signaling plays a central role in fibroblast activation. We undertook this study to evaluate the therapeutic effects of adenosine depletion with PEGylated adenosine deaminase (PEG-ADA) in preclinical models of SSc. METHODS: The effects of PEG-ADA on inflammation, vascular remodeling, and tissue fibrosis were analyzed in Fra-2 mice and in a B10.D2→BALB/c (H-2d ) model of sclerodermatous chronic graft-versus-host disease (GVHD). The effects of PEG-ADA were confirmed in vitro in a human full-thickness skin model. RESULTS: PEG-ADA effectively inhibited myofibroblast differentiation and reduced pulmonary fibrosis by 34.3% (with decreased collagen expression) (P = 0.0079; n = 6), dermal fibrosis by 51.8% (P = 0.0006; n = 6), and intestinal fibrosis by 17.7% (P = 0.0228; n = 6) in Fra-2 mice. Antifibrotic effects of PEG-ADA were also demonstrated in sclerodermatous chronic GVHD (reduced by 38.4%) (P = 0.0063; n = 8), and in a human full-thickness skin model. PEG-ADA treatment decreased inflammation and corrected the M2/Th2/group 2 innate lymphoid cell 2 bias. Moreover, PEG-ADA inhibited proliferation of pulmonary vascular smooth muscle cells (reduced by 40.5%) (P < 0.0001; n = 6), and prevented thickening of the vessel walls (reduced by 39.6%) (P = 0.0028; n = 6) and occlusions of pulmonary arteries (reduced by 63.9%) (P = 0.0147; n = 6). Treatment with PEG-ADA inhibited apoptosis of microvascular endothelial cells (reduced by 65.4%) (P = 0.0001; n = 6) and blunted the capillary rarefication (reduced by 32.5%) (P = 0.0199; n = 6). RNA sequencing demonstrated that treatment with PEG-ADA normalized multiple pathways related to fibrosis, vasculopathy, and inflammation in Fra-2 mice. CONCLUSION: Treatment with PEG-ADA ameliorates the 3 cardinal features of SSc in pharmacologically relevant and well-tolerated doses. These findings may have direct translational implications, as PEG-ADA has already been approved by the Food and Drug Administration for the treatment of patients with ADA-deficient severe combined immunodeficiency disease.


Assuntos
Adenosina Desaminase/farmacologia , Escleroderma Sistêmico/tratamento farmacológico , Pele/patologia , Animais , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Fibroblastos/efeitos dos fármacos , Fibrose/tratamento farmacológico , Fibrose/imunologia , Fibrose/patologia , Antígeno 2 Relacionado a Fos/metabolismo , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Imunidade Inata/efeitos dos fármacos , Inflamação , Camundongos , Camundongos Endogâmicos BALB C , Modelos Anatômicos , Fibrose Pulmonar/tratamento farmacológico , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/patologia , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Pele/efeitos dos fármacos , Pele/imunologia , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/imunologia , Doenças Vasculares/patologia
16.
J Immunol ; 204(6): 1674-1688, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32060138

RESUMO

Notch signaling is emerging as a critical regulator of T cell activation and function. However, there is no reliable cell surface indicator of Notch signaling across activated T cell subsets. In this study, we show that Notch signals induce upregulated expression of the Gcnt1 glycosyltransferase gene in T cells mediating graft-versus-host disease after allogeneic bone marrow transplantation in mice. To determine if Gcnt1-mediated O-glycosylation could be used as a Notch signaling reporter, we quantified the core-2 O-glycoform of CD43 in multiple T cell subsets during graft-versus-host disease. Pharmacological blockade of Delta-like Notch ligands abrogated core-2 O-glycosylation in a dose-dependent manner after allogeneic bone marrow transplantation, both in donor-derived CD4+ and CD8+ effector T cells and in Foxp3+ regulatory T cells. CD43 core-2 O-glycosylation depended on cell-intrinsic canonical Notch signals and identified CD4+ and CD8+ T cells with high cytokine-producing ability. Gcnt1-deficient T cells still drove lethal alloreactivity, showing that core-2 O-glycosylation predicted, but did not cause, Notch-dependent T cell pathogenicity. Using core-2 O-glycosylation as a marker of Notch signaling, we identified Ccl19-Cre+ fibroblastic stromal cells as critical sources of Delta-like ligands in graft-versus-host responses irrespective of conditioning intensity. Core-2 O-glycosylation also reported Notch signaling in CD8+ T cell responses to dendritic cell immunization, Listeria infection, and viral infection. Thus, we uncovered a role for Notch in controlling core-2 O-glycosylation and identified a cell surface marker to quantify Notch signals in multiple immunological contexts. Our findings will help refine our understanding of the regulation, cellular source, and timing of Notch signals in T cell immunity.


Assuntos
Transplante de Medula Óssea/efeitos adversos , Linfócitos T CD8-Positivos/metabolismo , Doença Enxerto-Hospedeiro/imunologia , N-Acetilglucosaminiltransferases/metabolismo , Receptores Notch/metabolismo , Animais , Biomarcadores/metabolismo , Linfócitos T CD8-Positivos/imunologia , Modelos Animais de Doenças , Estudos de Viabilidade , Feminino , Citometria de Fluxo/métodos , Glicosilação/efeitos dos fármacos , Humanos , Leucossialina/metabolismo , Ligantes , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos , Sensibilidade e Especificidade , Sialomucinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Células Estromais/imunologia , Células Estromais/metabolismo , Transplante Homólogo/efeitos adversos , Regulação para Cima
18.
Autoimmun Rev ; 19(4): 102493, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32062034

RESUMO

Chronic graft-versus-host disease (cGVHD) remains the main complication of allogeneic hematopoietic stem cell transplantation, limiting its chances for a successful outcome. The over-activity of CD4+ effector T cells and the excessive production of pro-inflammatory cytokines are followed by the development of immune-mediated inflammation and fibrosis of multiple organs. This is the reason for adopting T cell targeting therapies such as cyclosporine A, tacrolimus and mycophenolate mofetil. However, 40% of treated cGVHD patients remain unresponsive, which results in increased morbidity and mortality. Given the complexity of cGVHD pathogenesis, the involvement of B cells as an important player also needs to be explored. Function of aberrant B cells and secretion of relevant cytokines such as B cell activating factor (BAFF) have been found to correlate with cGVHD severity and have therefore become therapeutic targets. Better understanding of the role of B cells and their efficient targeting could improve the outcome of cGVHD.


Assuntos
Autoimunidade/efeitos dos fármacos , Autoimunidade/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/imunologia , Doença Crônica/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas , Humanos
19.
Cytotherapy ; 22(3): 149-157, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32089448

RESUMO

Forkhead box P3 (FOXP3)+ regulatory T cell (Treg) reconstitution after unrelated donor umbilical cord blood transplantation in chemotherapy-naïve children is incompletely characterized. We studied 21 children with nonmalignant diseases receiving an identical alemtuzumab-containing regimen. We hypothesized that Treg recovery may be perturbed in patients not only by acute graft-versus-host disease (aGVHD) but also by viremia. Tregs and their memory and naïve subsets were serially monitored for proliferation and apoptosis along with conventional T cells (Tcon). A "reconstitution index" (RI) was calculated relative to pretransplantation values for each parameter. At 3 months post-UCBT, the RI of Tregs was faster compared with other immune components tested and was most rapid in patients free of aGVHD and viremia. There were significantly fewer Tregs in patients experiencing grade I-II aGVHD and/or viremia, leading to an imbalance between Tregs-Tcon ratios. Central and effector memory Tregs were most affected at this time point when they dominated in the circulation. Impaired Treg proliferation without increased apoptosis accounted for the reduced Treg-Tcon ratio. In patients affected with grade II aGVHD and viremia, the overall reduction in circulating Treg pool were associated with a more oligoclonal T-cell receptor ß repertoire. Taken together, aGVHD and viremia can lead to defective Treg expansion homeostasis.


Assuntos
Alemtuzumab/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Linfócitos T Reguladores/imunologia , Condicionamento Pré-Transplante , Viremia/imunologia , Adolescente , Proliferação de Células , Criança , Pré-Escolar , Feminino , Homeostase , Humanos , Lactente , Subpopulações de Linfócitos/imunologia , Masculino , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Subpopulações de Linfócitos T/imunologia , Viremia/patologia
20.
J Leukoc Biol ; 107(6): 1069-1079, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32022317

RESUMO

γδT cells play an important role in cancer immunosurveillance and are able to distinguish malignant cells from their healthy counterparts via their γδTCR. This characteristic makes γδT cells an attractive candidate for therapeutic application in cancer immunotherapy. Previously, we have identified a novel CD8α-dependent tumor-specific allo-HLA-A*24:02-restricted Vγ5Vδ1TCR with potential therapeutic value when used to engineer αßT cells from HLA-A*24:02 harboring individuals. αßT cells engineered to express this defined Vγ5Vδ1TCR (TEG011) have been suggested to recognize spatial changes in HLA-A*24:02 present selectively on tumor cells but not their healthy counterparts. However, in vivo efficacy and toxicity studies of TEG011 are still limited. Therefore, we extend the efficacy and toxicity studies as well as the dynamics of TEG011 in vivo in a humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mouse model to allow the preparation of a first-in-men clinical safety package for adoptive transfer of TEG011. Mice treated with TEG011 did not exhibit any graft-versus-host disease-like symptoms and extensive analysis of pathologic changes in NSG-A24:02 mice did not show any off-target toxicity of TEG011. However, loss of persistence of TEG011 in tumor-bearing mice was associated with the outgrowth of extramedullary tumor masses as also observed for mock-treated mice. In conclusion, TEG011 is well tolerated without harming HLA-A*24:02+ expressing healthy tissues, and TEG011 persistence seems to be crucial for long-term tumor control in vivo.


Assuntos
Antígeno HLA-A24/genética , Receptores de Antígenos de Linfócitos T gama-delta/genética , Neoplasias de Tecidos Moles/prevenção & controle , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Engenharia Celular , Expressão Gênica , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Antígeno HLA-A24/imunologia , Humanos , Imunoterapia/métodos , Células K562 , Masculino , Camundongos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Transdução de Sinais , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/imunologia , Neoplasias de Tecidos Moles/patologia , Linfócitos T Reguladores/patologia , Linfócitos T Reguladores/transplante , Transdução Genética , Irradiação Corporal Total
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