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1.
Lancet Haematol ; 7(1): e50-e60, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669248

RESUMO

BACKGROUND: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. METHODS: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. FINDINGS: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909-2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3-4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53-2·33; p<0·0001). Among the single HLA-B-mismatched transplantations, acute GVHD risk was higher with leader mismatching than with leader matching (OR 1·73, 1·02-2·94; p=0·042 for grade 2-4) and with an M leader shared allotype compared with a T leader shared allotype (OR 1·98, 1·39-2·81; p=0·0001 for grade 3-4). The preferred HLA-B-mismatched donor is leader-matched and shares a T leader allotype. The majority (1 836 939 [91·6%]) of the 2 004 742 US registry donors have the TT or MT genotype. INTERPRETATION: The HLA-B leader informs GVHD risk after HLA-B-mismatched unrelated HCT and differentiates high-risk HLA-B mismatches from those with lower risk. The leader of the matched allotype could be considered to be as important as the leader of the mismatched allotype for GVHD. Prospective identification of leader-matched donors is feasible for most patients in need of a HCT, and could lower GVHD and increase availability of HCT therapy. These findings are being independently validated and warrant further research in prospective trials. FUNDING: The National Institutes of Health, USA.


Assuntos
Éxons/genética , Doença Enxerto-Hospedeiro/genética , Antígenos HLA-B/genética , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Feminino , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Histocompatibilidade , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos
2.
Zhonghua Nei Ke Za Zhi ; 58(11): 819-822, 2019 Nov 01.
Artigo em Chinês | MEDLINE | ID: mdl-31665857

RESUMO

The efficacy and safety of co-transplantation of unrelated donor peripheral blood stem cells (UD-PBSCs) combined with umbilical cord mesenchymal stem cells (UC-MSCs) in refractory severe aplastic anemia-Ⅱ(RSAA-Ⅱ) were analyzed retrospectively. Fifteen patients with RSAA-Ⅱ underwent UD-PBSCs and UC-MSCs co-transplantation, among whom 14 cases had hematopoietic reconstitution without severe graft versus-host disease (GVHD). The 5-year overall survival rate was 78.57%. Combination of UD-PBSCs and UC-MSCs transplantation could be a safe and effective option for RSAA-Ⅱ.


Assuntos
Anemia Aplástica/cirurgia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/fisiologia , Cordão Umbilical/fisiologia , Doadores não Relacionados , Anemia Aplástica/imunologia , Anemia Aplástica/mortalidade , Anemia Aplástica/patologia , China/epidemiologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Células-Tronco Hematopoéticas/imunologia , Humanos , Células-Tronco Mesenquimais , Células-Tronco de Sangue Periférico , Estudos Retrospectivos , Taxa de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Cordão Umbilical/imunologia
3.
Transplant Proc ; 51(9): 3136-3139, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31611115

RESUMO

Graft-vs-host disease (GVHD) after liver transplantation is a rare complication with a high mortality rate. A complex interplay between donor and recipient immunity plays a role in the development of GVHD. Infection following liver transplantation is one of the most common complications in a recipient of an organ transplant who is immunosuppressed. On clinical signs of infection, the immune reaction of the recipient can be reconstituted by withdrawal of immunosuppression in order to help combat infection. However, the discontinuation of immunosuppression could restore the donor's immune activity rather than that of the recipient. There is little information available as to whether the discontinuation of immunosuppression for severe infection could contribute to the development of GVHD in a patient who underwent ABO-incompatible (ABO-I) living donor liver transplantation (LDLT). Herein, we present a unique case of GVHD following ABO-I LDLT, for which the cessation of immunosuppression could be responsible.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Imunossupressão , Transplante de Fígado , Sistema do Grupo Sanguíneo ABO/imunologia , Incompatibilidade de Grupos Sanguíneos , Humanos , Doadores Vivos , Masculino , Pessoa de Meia-Idade
4.
Transplant Proc ; 51(6): 1982-1989, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399180

RESUMO

OBJECTIVE: Human leukocyte antigen match is the most important donor factor affecting transplant outcome. The HLA-DPB1 mismatch on the clinical outcome of hematopoietic stem cell transplant (HSCT) is less clear. This study is the first meta-analysis to investigate the impact of HLA-DPB1 loci mismatch on clinical outcome after unrelated donor HSCT for hematologic malignant disease. METHODS: We electronically searched the PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and a related database (January 1995-December 2018) for all relevant articles. Comparative studies were carried out to investigate the impact of HLA-DPB1 loci mismatch on clinical outcome after unrelated donor HSCT, that is, the disease-free survival, engraftment, graft-vs-host disease, relapse, and transplant-related mortality (TRM). We performed a meta-analysis using Review Manager 5.3.5 software and adopted funnel plot regression to assess the publication bias. RESULTS: A total of 1570 articles were retrieved; 21 studies including 27,852 patients were assessed. Pooled comparisons of studies found that the HLA-DPB1-mismatched group had a lower rate of disease-free survival than the DPB1-matched group and lower overall survival in non-T cell-depleted transplant than the DPB1-matched group. The DPB1-mismatched group has higher incidence of acute graft-vs-host disease (aGVHD) and severe (≥ III degree) aGVHD, lower relapse rate, and higher TRM. Moreover, compared with 1-antigen mismatch, 2-antigen mismatch in DPB1 had a higher risk of TRM and a lower relapse rate, and the nonpermissive DPB1 mismatch had significantly higher rate of severe aGvHD and lower rate of disease relapse. CONCLUSIONS: This analysis confirmed that HLA-DPB1 has important influence on survival and transplant-related complications during unrelated donor HSCT, and HLA-DPB1 donor selection strategies have been proposed based on personalized algorithm.


Assuntos
Incompatibilidade de Grupos Sanguíneos/mortalidade , Cadeias beta de HLA-DP/imunologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Adulto , Incompatibilidade de Grupos Sanguíneos/imunologia , Pré-Escolar , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/mortalidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Doadores não Relacionados
5.
Nat Biotechnol ; 37(10): 1137-1144, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31427818

RESUMO

The utility of autologous induced pluripotent stem cell (iPSC) therapies for tissue regeneration depends on reliable production of immunologically silent functional iPSC derivatives. However, rejection of autologous iPSC-derived cells has been reported, although the mechanism underlying rejection is largely unknown. We hypothesized that de novo mutations in mitochondrial DNA (mtDNA), which has far less reliable repair mechanisms than chromosomal DNA, might produce neoantigens capable of eliciting immune recognition and rejection. Here we present evidence in mice and humans that nonsynonymous mtDNA mutations can arise and become enriched during reprogramming to the iPSC stage, long-term culture and differentiation into target cells. These mtDNA mutations encode neoantigens that provoke an immune response that is highly specific and dependent on the host major histocompatibility complex genotype. Our results reveal that autologous iPSCs and their derivatives are not inherently immunologically inert for autologous transplantation and suggest that iPSC-derived products should be screened for mtDNA mutations.


Assuntos
DNA Mitocondrial/genética , Epitopos/genética , Epitopos/imunologia , Doença Enxerto-Hospedeiro/imunologia , Células-Tronco Pluripotentes Induzidas , Animais , Antígenos , Transplante de Células/métodos , Células-Tronco Embrionárias , Rejeição de Enxerto/imunologia , Humanos , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutação , Transplante Autólogo
6.
Medicine (Baltimore) ; 98(29): e16390, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335688

RESUMO

INTRODUCTION: Sjögren's syndrome (SS) often causes lymphoproliferative disorders such as malignant lymphoma and macroglobrinemia. Approximately 5% of long-term follow-up SS patients develop malignant lymphoma. Recently, the tumor necrosis factor receptor superfamily cluster of differentiation 30 (CD30) has been thought to be implicated in malignant cells in organs affected by Hodgikin lymphoma or in a prognostic marker of diffuse large B cell lymphoma. In this study, we investigated CD30 expression in lacrimal gland and conjunctiva in patients with SS. METHODS: We examined lacrimal gland and conjunctival tissues for the diagnosis from 3 female SS patients with a median age of 51 and 3 female chronic graft-versus-host disease (cGVHD) patients with a median age of 41. Histological analysis of these tissues of the remaining samples was conducted by methods including immunohistochemistry and electron microscopy (#20090277). We analyzed the expression and localization of cluster of differentiation 4 (CD4), cluster of differentiation 8 (CD8), cluster of differentiation 20 (CD20), CD30, and Interferon-γ in tissue sections prepared from lacrimal glands and conjunctiva in 3 each of SS and cGVHD patients. RESULTS: There were more B cells and plasma cells in lobules of SS-affected lacrimal glands than in those of their cGVHD-affected counterparts. Interferon-γ was expressed on endothelia of capillaries in SS-affected lacrimal gland and conjunctival tissues whereas it was expressed on fibroblasts in their GVHD-affected equivalents. Furthermore, lacrimal glands and conjunctiva disordered by SS had a greater number of CD30 cells than those disordered by cGVHD. CONCLUSION: Our results suggest that CD30 cells are increased in lacrimal glands and conjunctiva affected by SS and that a subset of SS patients are thereby at risk of development malignant lymphoma.


Assuntos
Túnica Conjuntiva , Doença Enxerto-Hospedeiro , Antígeno Ki-1 , Aparelho Lacrimal , Linfoma/diagnóstico , Síndrome de Sjogren , Adulto , Linfócitos B/imunologia , Túnica Conjuntiva/imunologia , Túnica Conjuntiva/patologia , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Humanos , Imuno-Histoquímica , Interferon gama/sangue , Antígeno Ki-1/análise , Antígeno Ki-1/imunologia , Aparelho Lacrimal/imunologia , Aparelho Lacrimal/patologia , Microscopia Eletrônica/métodos , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Plasmócitos/imunologia , Prognóstico , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia
7.
Cutis ; 103(6): E8-E11, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31348462

RESUMO

Acute graft-vs-host disease (GVHD) is a T cell-mediated reaction in which donor T lymphocytes attack host tissue in the setting of immunosuppression. The most common cause of acute GVHD is allogeneic stem cell transplantation, with solid-organ transplantation being a much less common cause. Early diagnosis and treatment are imperative to decrease morbidity and mortality. Dermatologists play a fundamental role in the diagnosis of this condition because skin involvement is among the earliest signs of acute GVHD. We present a case of acute GVHD following liver transplantation, focusing on diagnostic criteria and a comparison to acute GVHD following hematopoietic stem cell transplantation.


Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Transplante de Fígado/efeitos adversos , Doença Aguda , Idoso , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Transplante de Fígado/métodos
8.
BioDrugs ; 33(4): 401-409, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31302863

RESUMO

Three prospective controlled clinical trials and numerous small series and case reports have confirmed that durable, drug-free remission in systemic sclerosis is possible via an autologous hematopoietic stem cell transplantation. Similar results have been seen in other autoimmune diseases. The exact mechanism by which this immune "reset" was achieved in some but not all cases remains elusive, but includes major reduction of autoreactive immune competent cells, re-establishment of T- and B cell regulatory networks and normalization of tissue niche function, particularly vascular. Some aspects regarding mobilization, conditioning and graft manipulation still remain open, but clearly a significant toxicity is associated with all effective regimens at present, and therefore patient selection remains a key issue. In the hematology/oncology arena, major efforts are being made to reduce genotoxic and other collateral toxicity induced by current mobilization and conditioning protocols, which may also translate to autoimmune disease. These include developments in rapid mobilization and antibody drug conjugate conditioning technology. If effective, such low-toxicity regimens might be applied to autoimmune disease at an earlier stage before chronicity of autoimmunity has been established, thus changing the therapeutic paradigm.


Assuntos
Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Imunoconjugados/uso terapêutico , Escleroderma Sistêmico/terapia , Condicionamento Pré-Transplante/métodos , Ensaios Clínicos Controlados como Assunto , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Prospectivos , Escleroderma Sistêmico/imunologia , Transplante Autólogo/efeitos adversos , Transplante Autólogo/métodos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodos , Resultado do Tratamento
9.
Transfus Apher Sci ; 58(4): 472-474, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31303512

RESUMO

Mogamulizumab (Mog), a humanized anti-CCR4 antibody, provides an important treatment option for relapsed/refractory adult T cell leukemia/lymphoma. However, administration of Mog before allogenic hematopoietic stem cell transplantation has been reported to be a risk factor for severe acute graft-versus-host disease (GVHD). The etiological hypothesis is Mogamulizumab may eradicate CCR4-positive regulatory T cells (Tregs). Theoretically, Treg homeostasis and course of GVHD can be affected by plasma exchange (PE) with decreasing plasma Mog concentration. Here, we present a case of severe acute GVHD after pretransplantation Mog, in which PE was performed for liver failure. As a result, plasma Mog concentration was decreased but it did not lead to the prompt elevation of Treg levels in peripheral blood and clinical responses of GVHD were limited to partial remission. Our case suggests that recovery of donor-derived Treg in the acute phase after HSCT is multifactorial and the single procedure of PE-based Mog depletion does not necessarily warrant the quick restoration of Treg homeostasis.


Assuntos
Anticorpos Monoclonais Humanizados , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma de Células T do Adulto , Troca Plasmática , Linfócitos T Reguladores/imunologia , Doença Aguda , Aloenxertos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Feminino , Doença Enxerto-Hospedeiro/induzido quimicamente , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucemia-Linfoma de Células T do Adulto/imunologia , Leucemia-Linfoma de Células T do Adulto/patologia , Leucemia-Linfoma de Células T do Adulto/terapia , Falência Hepática/imunologia , Falência Hepática/terapia , Pessoa de Meia-Idade
10.
Blood ; 134(12): 924-934, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31292117

RESUMO

Allogeneic hematopoietic cell transplantation involves consideration of both donor and recipient characteristics to guide the selection of a suitable graft. Sufficient high-resolution donor-recipient HLA match is of primary importance in transplantation with adult unrelated donors, using conventional graft-versus-host disease prophylaxis. In cord blood transplantation, optimal unit selection requires consideration of unit quality, cell dose and HLA-match. In this summary, the National Marrow Donor Program (NMDP) and the Center for International Blood and Marrow Transplant Research, jointly with the NMDP Histocompatibility Advisory Group, provide evidence-based guidelines for optimal selection of unrelated donors and cord blood units.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/normas , Seleção do Doador/normas , Sangue Fetal , Transplante de Células-Tronco Hematopoéticas/normas , Doadores não Relacionados , Adulto , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Seleção do Doador/métodos , Sangue Fetal/imunologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/métodos , Teste de Histocompatibilidade/métodos , Teste de Histocompatibilidade/normas , Humanos , Recém-Nascido , Sistema de Registros , Doadores não Relacionados/provisão & distribução
11.
Nat Immunol ; 20(9): 1129-1137, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358998

RESUMO

Natural killer (NK) cells can recognize virus-infected and stressed cells1 using activating and inhibitory receptors, many of which interact with HLA class I. Although early studies also suggested a functional impact of HLA class II on NK cell activity2,3, the NK cell receptors that specifically recognize HLA class II molecules have never been identified. We investigated whether two major families of NK cell receptors, killer-cell immunoglobulin-like receptors (KIRs) and natural cytotoxicity receptors (NCRs), contained receptors that bound to HLA class II, and identified a direct interaction between the NK cell receptor NKp44 and a subset of HLA-DP molecules, including HLA-DP401, one of the most frequent class II allotypes in white populations4. Using NKp44ζ+ reporter cells and primary human NKp44+ NK cells, we demonstrated that interactions between NKp44 and HLA-DP401 trigger functional NK cell responses. This interaction between a subset of HLA-DP molecules and NKp44 implicates HLA class II as a component of the innate immune response, much like HLA class I. It also provides a potential mechanism for the described associations between HLA-DP subtypes and several disease outcomes, including hepatitis B virus infection5-7, graft-versus-host disease8 and inflammatory bowel disease9,10.


Assuntos
Antígenos HLA-DP/imunologia , Imunidade Inata/imunologia , Células Matadoras Naturais/imunologia , Receptor 2 Desencadeador da Citotoxicidade Natural/imunologia , Linhagem Celular , Doença Enxerto-Hospedeiro/imunologia , Hepatite B/imunologia , Humanos , Doenças Inflamatórias Intestinais/imunologia , Células Jurkat
12.
Arch Immunol Ther Exp (Warsz) ; 67(5): 311-323, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31177288

RESUMO

Excessive inflammatory environment in a course of chronic graft-versus-host disease (cGvHD) is associated with T-cell trafficking into inflamed tissues. This study focused on the identification of IL-17-producing cells in the tissue biopsies of cGvHD patients. Forty-one biopsy specimens of cGvHD lesions of the skin (n = 27), gastrointestinal tract (n = 9) and oral mucosa (n = 5), examined in 24 patients, were morphologically defined according to the NIH criteria and analyzed for the presence of cellular infiltrations including: IL-17+, FOXP3+ and CCR6+ cells. IL-17+ cells were identified in 26/27 skin and in all gut and oral mucosa biopsies, being more frequent in mucosa lesions than in the skin (11/14 vs 14/26, respectively; NS: not significant). Double staining documented that CD138+/IL-17+ cells were commonly seen in the gut than in the skin (5/8 vs 3/11, respectively; NS). In the skin, cells expressing trafficking receptor CCR6+ were more frequent than IL-17+ cells compared to the mucosa (23/26 vs 2/13, respectively; p < 0.0001). CCR6 was present on a majority of IL-17+ cells in all examined skin biopsies but only in 6 out of 11 digestive tract biopsies (p = 0.0112). FOXP3+ cells were identified only in five patients (with mild lesions) at least in one biopsy. In this study group, results documented that local expansion of IL-17-producing cells in the digestive tract correlate with moderate and severe clinical symptoms of cGvHD, in contrast to the skin, where IL-17+ cells are rather scarcely present (p = 0.0301) and the course of cGvHD is slowly progressing with final organ deterioration.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Interleucina-17/metabolismo , Linfócitos/metabolismo , Adulto , Doença Crônica , Feminino , Fatores de Transcrição Forkhead/metabolismo , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/patologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/imunologia , Mucosa Bucal/patologia , Especificidade de Órgãos , Receptores CCR6/metabolismo , Estudos Retrospectivos , Pele/imunologia , Pele/patologia , Adulto Jovem
13.
J Immunol Res ; 2019: 3538963, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205954

RESUMO

Humanized mouse models can well be modified to study specific aspects of Graft-versus-Host Disease (GvHD). This paper shows the results of both macrophage depletion and (early) B-cell depletion in a humanized mouse model using RAG2-/- γc-/- mice injected with HuPBMCs. Macrophage depletion showed a significant decrease in survival and also lead to a change in the histomorphology of the xenogeneic reaction. Higher levels of infiltrating B-cells were observed in various organs of mice depleted for macrophages. With (early) B-cell depletion using Rituximab, a clear improvement on clinical symptoms was observed, even when probably only inactivated B-cells were deleted. However, the histological examinations only showed a significant morphological effect on liver fibrosis. This may be related to a difference in the mRNA levels of TGF-ß. Also, lower mRNA levels of Tregs in some organs were observed after Rituximab treatment, which contradicts that a higher number of Tregs would always be related to less severe GvHD. Our data show that both macrophage depletion and (early) B-cell depletion in a xenogeneic mouse model can influence the clinical, histological, and cytokine production of a GvHD response.


Assuntos
Linfócitos B/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Leucócitos Mononucleares/imunologia , Cirrose Hepática/imunologia , Macrófagos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Depleção Linfocítica , Camundongos , Camundongos SCID
14.
Int Immunopharmacol ; 72: 479-486, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31051404

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative method for blood cancers and other blood disorders, but is limited by the development of graft-versus-host disease (GVHD). GVHD results in inflammatory damage to the host liver, gastrointestinal tract and skin, resulting in high rates of morbidity and mortality in HSCT recipients. Activation of the A2A receptor has been previously demonstrated to reduce disease in allogeneic mouse models of GVHD. This study aimed to investigate the effect of A2A activation on disease development in a humanised mouse model of GVHD. Immunodeficient non-obese diabetic-severe combined immunodeficiency-interleukin (IL)-2 receptor γnull (NSG) mice injected with human (h) peripheral blood mononuclear cells (hPBMCs), were treated with either the A2A agonist CGS 21680 or control vehicle. Contrary to the beneficial effect of A2A activation in allogeneic mouse models, CGS 21680 increased weight loss, and failed to reduce the clinical score or increase survival in this humanised mouse model of GVHD. Moreover, CGS 21680 reduced T regulatory cells and increased serum human IL-6 concentrations. Conversely, CGS 21680 reduced serum human tumour necrosis factor (TNF)-α concentrations and leukocyte infiltration into the liver, indicating that A2A activation can, in part, reduce molecular and histological GVHD in this model. Notably, CGS 21680 also prevented healthy weight gain in NSG mice not engrafted with hPBMCs suggesting that this compound may be suppressing appetite or metabolism. Therefore, the potential benefits of A2A activation in reducing GVHD in HSCT recipients may be limited and confounded by adverse impacts on weight, decreased T regulatory cell frequency and increased IL-6 production.


Assuntos
Agonistas do Receptor A2 de Adenosina/uso terapêutico , Adenosina/análogos & derivados , Doença Enxerto-Hospedeiro/tratamento farmacológico , Fenetilaminas/uso terapêutico , Adenosina/efeitos adversos , Adenosina/uso terapêutico , Agonistas do Receptor A2 de Adenosina/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Camundongos , Fenetilaminas/efeitos adversos , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
15.
Ann Hematol ; 98(8): 1867-1875, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30993415

RESUMO

Refractory skin ulcers due to severe chronic graft-versus-host disease (cGVHD) remain to be associated with significant morbidity and mortality.We performed an allogeneic donor skin transplantation in seven adult patients after allogeneic hematopoietic stem cell transplantation for cGVHD-associated refractory skin ulcers. While four patients received a split skin graft (SSG), in one patient, a full thickness skin graft for two small refractory ulcers of the ankle was performed, and one patient received in vitro expanded donor keratinocyte grafts derived from hair roots of the original unrelated donor. In one additional patient, a large deep fascial defect of the lower leg was covered with an autologous greater omentum free graft before coverage with an allogeneic SSG. An additional patient was treated with an autologous scrotal skin graft for a refractory ulcer associated with deep sclerosis of cGVHD after unrelated donor transplantation.All skin grafts engrafted and resulted in permanent coverage of the grafted ulcers without any signs of immunological mediated damage. In the patient receiving in vitro expanded keratinocyte grafts, two localized ulcers were permanently covered by donor skin while this approach failed to cover extensive circular ulcers of the lower legs.Allogeneic donor skin grafts are a valuable treatment option in refractory ulcers due to cGVHD but are restricted mainly to related donors while keratinocyte grafts from unrelated donors remain experimental. In male patients lacking a related donor, autologous scrotal skin graft may be an alternative option.


Assuntos
Procedimentos Cirúrgicos Dermatológicos/métodos , Doença Enxerto-Hospedeiro/cirurgia , Transplante de Células-Tronco Hematopoéticas , Queratinócitos/transplante , Úlcera Cutânea/cirurgia , Condicionamento Pré-Transplante/métodos , Adulto , Doença Crônica , Ciclofosfamida/uso terapêutico , Feminino , Sobrevivência de Enxerto/fisiologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/terapia , Humanos , Imunossupressores/uso terapêutico , Queratinócitos/citologia , Queratinócitos/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Irmãos , Pele/imunologia , Pele/patologia , Úlcera Cutânea/imunologia , Úlcera Cutânea/patologia , Úlcera Cutânea/terapia , Transplante Autólogo , Transplante Homólogo , Doadores não Relacionados , Irradiação Corporal Total
16.
J Immunol ; 202(10): 3053-3064, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30979817

RESUMO

Acute graft-versus-host disease (aGVHD) hinders the efficacy of allogeneic hematopoietic cell transplantation (HCT). Plasma levels of soluble membrane-bound ST2 (ST2) are elevated in human and murine aGVHD and correlated to type 1 T cells response. ST2 signals through the adapter protein MyD88. The role of MyD88 in T cells during aGVHD has yet to be elucidated. We found that knocking out MyD88 in the donor T cells protected against aGVHD independent of IL-1R and TLR4 signaling in two murine HCT models. This protection was entirely driven by MyD88-/- CD4 T cells. Transplanting donor MyD88-/- conventional T cells (Tcons) with wild-type (WT) or MyD88-/- regulatory T cells (Tregs) lowered aGVHD severity and mortality. Transcriptome analysis of sorted MyD88-/- CD4 T cells from the intestine 10 d post-HCT showed lower levels of Il1rl1 (gene of ST2), Ifng, Csf2, Stat5, Batf, and Jak2 Transplanting donor ST2-/- Tcons with WT or ST2-/- Tregs showed a similar phenotype with what we observed when using donor MyD88-/- Tcons. Decreased ST2 was confirmed at the protein level with less secretion of soluble ST2 and more expression of ST2 compared with WT T cells. Our data suggest that Treg suppression from lack of MyD88 signaling in donor Tcons during alloreactivity uses the ST2 but not the IL-1R or TLR4 pathways, and ST2 represents a potential aGVHD therapeutic target sparing Tregs.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Proteína 1 Semelhante a Receptor de Interleucina-1/deficiência , Fator 88 de Diferenciação Mieloide/deficiência , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Doença Aguda , Animais , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/imunologia , Transdução de Sinais/genética , Linfócitos T Reguladores/patologia , Transplante Homólogo
17.
Acta Derm Venereol ; 99(9): 777-782, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30938827

RESUMO

Patients treated with haematopoietic stem cell transplantation are at increased risk of cutaneous malignant neoplasms. There are no reports on the characteristics of melanocytic lesions in patients with chronic graft versus host disease and the value of recognizing these difficult lesions in high-risk patients. The objective of this study is to describe the clinical and dermoscopic characteristics of melanocytic lesions in patients with chronic graft versus host disease in order to understand their morphology. A prospective cross-sectional study was performed; 10 melanocytic lesions on the trunk and extremities were selected from each patient. A statistically significant association was found between regression and high total dermoscopic score and 7-point checklist score. Lesions were excised or included in short-term digital follow-up. Melanocytic lesions in patients with chronic graft versus host disease developing after allogeneic-haematopoietic stem cell transplantation exhibit marked structural and colour changes similar to melanoma. This is believed to result from the inflammatory process associated with graft versus host disease.


Assuntos
Dermoscopia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Melanócitos/patologia , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia , Pele/patologia , Adulto , Doença Crônica , Estudos Transversais , Diagnóstico Diferencial , Feminino , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/cirurgia , Humanos , Masculino , Melanócitos/imunologia , Melanoma/imunologia , Melanoma/patologia , Pessoa de Meia-Idade , Nevo Pigmentado/imunologia , Valor Preditivo dos Testes , Estudos Prospectivos , Pele/imunologia , Neoplasias Cutâneas/imunologia
18.
Graefes Arch Clin Exp Ophthalmol ; 257(7): 1341-1351, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30944986

RESUMO

PURPOSE: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cells transplantation, occurring in about half of transplanted patients. This condition seems to be the result of a progressive immune-mediated damage that can involve various tissues, including the eyes. The ocular surface system is the ocular structure most frequently impaired, and dry eye disease is considered the hallmark of ocular GVHD. Given the increasing prevalence and the frequent severe involvement of the ocular surface with vision-threatening complications, ocular GVHD represents a current diagnostic and therapeutic challenge. The purpose of this literature review is to describe all the clinical manifestations occurring in the setting of ocular GVHD, and to further report the outcomes of conventional and novel therapies. METHODS: A literature search about ocular GVHD was performed in PubMed, Scopus, Medline databases, and ClinicalTrials.gov as well as through the reference lists of identified publications until January 2019. We have included RCTs, prospective observational studies, prospective and retrospective cohort studies, pilot studies, and review articles. RESULTS: Overall, 107 articles, 3 book chapters, and 6 ongoing registered clinical trials were collected and analyzed. Ocular GVHD can affect all the structures of the entire ocular surface system, including lacrimal and meibomian glands, cornea, conjunctiva, eyelids, nasolacrimal duct, and tears. Current medical treatment is mainly focused on lubrication and control of drainage, tear evaporation, and ocular surface inflammation. Surgical treatment may be necessary in severe, recalcitrant, or complicated cases. Amniotic membrane and tectonic keratoplasty can be valid options to restore the integrity of the cornea. Recently, conjunctival and limbal transplantation from the same living-related bone marrow donor has been proposed to manage both dry eye and limbal stem cell deficiency, without any risk of immunologic rejection. CONCLUSION: This review provides an up-to-date analysis on clinical findings and current and future management of ocular GVHD. A correct and prompt diagnosis along with an appropriate and aggressive treatment are fundamental for avoiding the occurrence of vision-threatening complications.


Assuntos
Síndromes do Olho Seco/cirurgia , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunidade Celular , Túnica Conjuntiva/patologia , Córnea/patologia , Síndromes do Olho Seco/metabolismo , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Humanos , Lágrimas/metabolismo
19.
Transpl Immunol ; 55: 101205, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30946889

RESUMO

Graft-versus-host disease (GVHD) constitutes the most frequent complications after the allogeneic hematopoietic stem cell transplantation for a variety of hematological malignancies. In the present study, we explored the prophylactic potential of adipose tissue-derived mesenchymal stem cells (AD-MSCs) in controlling GVHD in murine models with a special focus on bone marrow aplasia related with acute GVHD. The CB6F1 mice were induced GVHD by the injection intravenously of C57BL/6 (B6-Ly-5.1) splenocytes without conditioning irradiation or chemotherapy. AD-MSCs from C3H mice were injected intravenously via tail veins. GVHD was assessed using flowcytometry analysis of peripheral blood cells and histopathologic analysis of target organs. Histopathological analyses revealed that AD-MSCs markedly suppressed the infiltration of lymphocytes into liver as well as the aplasia in bone marrow. This study is the first to clarify the effectiveness of AD-MSCs against bone marrow aplasia in GVHD, supporting a rationale of AD-MSCs for ameliorating bone marrow suppression and infectivity after allo-HSCT in human clinics.


Assuntos
Doenças da Medula Óssea , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/imunologia , Tecido Adiposo , Aloenxertos , Animais , Doenças da Medula Óssea/etiologia , Doenças da Medula Óssea/imunologia , Doenças da Medula Óssea/patologia , Doenças da Medula Óssea/terapia , Modelos Animais de Doenças , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/patologia , Doença Enxerto-Hospedeiro/terapia , Células-Tronco Mesenquimais/patologia , Camundongos
20.
Int J Mol Sci ; 20(6)2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30897843

RESUMO

Viral infections and reactivations remain a serious obstacle to successful hematopoietic stem cell transplantation (HSCT). When antiviral drug treatment fails, adoptive virus-specific T-cell transfer provides an effective alternative. Assuming that naive T cells (TN) are mainly responsible for GvHD, methods were developed to generate naive T-cell-depleted products while preserving immune memory against viral infections. We compared two major strategies to deplete potentially alloreactive T cells: CD45RA and CD62L depletion and analyzed phenotype and functionality of the resulting CD45RA-/CD62L- naive T-cell-depleted as well as CD45RA⁺/CD62L⁺ naive T-cell-enriched fractions in the CMV pp65 and IE1 antigen model. CD45RA depletion resulted in loss of terminally differentiated effector memory T cells re-expressing CD45RA (TEMRA), and CD62L depletion in loss of central memory T cells (TCM). Based on these differences in target cell-dependent and target cell-independent assays, antigen-specific T-cell responses in CD62L-depleted fraction were consistently 3⁻5 fold higher than those in CD45RA-depleted fraction. Interestingly, we also observed high donor variability in the CD45RA-depleted fraction, resulting in a substantial loss of immune memory. Accordingly, we identified donors with expected response (DER) and unexpected response (DUR). Taken together, our results showed that a naive T-cell depletion method should be chosen individually, based on the immunophenotypic composition of the T-cell populations present.


Assuntos
Imunoterapia/métodos , Selectina L/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Subpopulações de Linfócitos T/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citomegalovirus/imunologia , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/metabolismo , Humanos , Imunofenotipagem , Microesferas , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
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