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1.
Front Immunol ; 10: 315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30894854

RESUMO

Anti-thymocyte globulin (ATG) is a lymphocyte depleting agent applied in hematopoietic stem cell transplantation (HSCT) to prevent rejection and Graft-vs.-Host Disease (GvHD). In this study, we compared two rabbit ATG products, ATG-Genzyme (ATG-GENZ), and ATG-Fresenius (ATG-FRES), with respect to dosing, clearance of the active lymphocyte binding component, post-HSCT immune reconstitution and clinical outcome. Fifty-eigth pediatric acute leukemia patients (n = 42 ATG-GENZ, n = 16 ATG-FRES), who received a non-depleted bone marrow or peripheral blood stem cell graft from an unrelated donor were included. ATG-GENZ was given at a dosage of 6-10 mg/kg; ATG-FRES at 45-60 mg/kg. The active component of ATG from both products was cleared at different rates. Within the ATG-FRES dose range no differences were found in clearance of active ATG or T-cell re-appearance. However, the high dosage of ATG-GENZ (10 mg/kg), in contrast to the low dosage (6-8 mg/kg), correlated with prolonged persistence of active ATG and delayed T-cell reconstitution. Occurrence of serious acute GvHD (grade III-IV) was highest in the ATG-GENZ-low dosage group. These results imply that dosing of ATG-GENZ is more critical than dosing of ATG-FRES due to the difference in clearance of active ATG. This should be taken into account when designing clinical protocols.

2.
Cancer ; 125(6): 963-971, 2019 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-30521100

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a+ )/CD207+ histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH). METHODS: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015. RESULTS: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001). CONCLUSIONS: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH.


Assuntos
Sistema Hematopoético/imunologia , Histiocitose de Células de Langerhans/complicações , Fígado/imunologia , Linfo-Histiocitose Hemofagocítica/epidemiologia , Baço/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Sistema Hematopoético/patologia , Histiocitose de Células de Langerhans/imunologia , Humanos , Lactente , Recém-Nascido , Fígado/patologia , Linfo-Histiocitose Hemofagocítica/imunologia , Masculino , Prognóstico , Estudos Retrospectivos , Baço/patologia , Adulto Jovem
3.
J Crohns Colitis ; 13(6): 807-811, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-30561580

RESUMO

Mesenchymal stromal cell [MSC] therapy is a new treatment for perianal fistulas in Crohn's disease. Although MSC therapy shows a favourable safety profile, long-term safety data are limited. We detected an Epstein Barr virus [EBV]-associated B cell lymphoproliferative lesion in the rectum of a patient 4 years after local administration of MSCs for his perianal fistulas. To investigate whether MSC therapy contributed to the development of this lymphoproliferative disease, we analyzed the possibility of EBV transfer via the MSC product and the persistence of MSCs in the lymphoproliferative lesion using short tandem repeat analysis.


Assuntos
Doença de Crohn/terapia , Transtornos Linfoproliferativos/etiologia , Doenças Retais/etiologia , Fístula Retal/terapia , Doença de Crohn/complicações , Doença de Crohn/patologia , Humanos , Transtornos Linfoproliferativos/patologia , Masculino , Transplante de Células-Tronco Mesenquimais , Pessoa de Meia-Idade , Doenças Retais/patologia , Fístula Retal/etiologia , Fístula Retal/patologia , Reto/patologia
4.
Front Immunol ; 10: 3045, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31998317

RESUMO

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50-60% of LCH-patients, the somatic BRAF V600E driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAF V600E can be a source of neoantigens capable of eliciting effective antitumor CD8+ T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8+ T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8+ T cell density in n = 101 LCH-lesions, with BRAF V600E mutated lesions displaying significantly lower CD8+ T cell:CD1a+ LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8+ T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAF V600E protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAF V600E derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAF V600E expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from all five cell lines expressing this HLA subtype, KIGDFGLATEK was not detected in the HLA class I peptidomes of two distinct BRAF V600E transduced cell lines with confirmed expression of HLA-A*03:01 or HLA-A*11:01. These data indicate that the in silico predicted HLA class I binding and proteasome-generated neopeptides derived from the BRAF V600E protein are not presented by HLA class I molecules. Given that the BRAF V600E mutation is highly prevalent in chemotherapy refractory LCH-patients who may qualify for immunotherapy, this study therefore questions the efficacy of immune checkpoint inhibitor therapy in LCH.

5.
Oncoimmunology ; 5(8): e1164364, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27622056

RESUMO

Langerhans cell histiocytosis (LCH) is a neoplastic myeloid disorder with a thus far poorly understood immune component. Tertiary lymphoid structures (TLS) are lymph node-like entities which create an immune-promoting microenvironment at tumor sites. We analyzed the presence and clinical relevance of TLS in n = 104 H&E-stained, therapy-naive LCH lesions of non-lymphoid origin and applied immunohistochemistry to a smaller series. Lymphoid-follicular aggregates were detected in 34/104 (33%) lesions. In line with the lymphocyte recruitment capacity of MECA-79(+) high endothelial venules (HEVs), MECA-79(+)-expressing-LCH lesions (37/77, 48%) contained the most CD3(+) T-lymphocytes (p = 0.003). TLS were identified in 8/15 lesions and contained T-and B-lymphocytes, Follicular Dendritic Cells (FDC), HEVs and the chemokines CXCL13 and CCL21 representing key cellular components and TLS-inducing factors in conventional lymph nodes (LN). Lymphoid-follicular aggregates were most frequently detected in patients presenting with unifocal LCH (24/70, 34%) as compared to patients with poly-ostotic or multi-system LCH (7/30, 23%, p = 0.03). In addition, patients with lymphoid-follicular aggregates-containing lesions had the lowest risk to develop new LCH lesions (p = 0.04). The identification of various stages of TLS formation within LCH lesions may indicate a key role for the immune system in controlling aberrant histiocytes which arise in peripheral tissues.

7.
Oncoimmunology ; 5(3): e1084463, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28255525

RESUMO

PURPOSE: Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder characterized by tissue accumulating CD1a+ histiocytes which frequently carry somatic mutations. Irrespective of mutation status, these LCH-cells display constitutively active kinases belonging to the MAPK pathway. We evaluated, in retrospect, the contribution of individual components of the MAPK-activating and chemotaxis-promoting TNF-CXCR4-CXCL12 axis to LCH manifestation and outcome. EXPERIMENTAL DESIGN: CXCR4, CXCL12 and TNF protein expression was immunohistochemically analyzed in 70 LCH-affected biopsies. The presence of CXCR4+CD1a+ cells in peripheral blood (PB) and/or bone marrow (BM) samples was evaluated by flowcytometry in 13 therapy-naive LCH-patients. RESULTS: CXCL12 was detected in 68/70 (97%) biopsies. CXCR4+LCH-cells were present in 50/70 (71%) biopsies; their presence was associated with higher levels of intralesional TNF. Circulating CD1a+CXCR4+ cells were detected in 4/13 (31%) therapy-naïve LCH-patients which displayed BRAFV600E (2/4), MAP2K1 (1/4) or no (1/4) mutations in their tissues. These CD11c co-expressing CD1a+CXCR4+cells migrated to CXCL12 in chemotaxis assays. Lesional CXCR4+LCH-cells were detected in 18/20 cases who presented with LCH manifestation at multiple sites and in 5/23 (22%) patients who developed additional lesions after initially presenting with a single lesion. The CXCR4 status at onset proved to be an independent risk factor for LCH reactivation in multivariate analysis (odds ratio 10.4, p = 0.034). CONCLUSIONS: This study provides the first evidence that CXCR4 is involved in the homing and retention of LCH-cells in CXCL12-expressing tissues and qualifies CXCR4 as a candidate prognostic marker for less favorable disease outcome.

8.
J Interferon Cytokine Res ; 35(10): 831-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26381039

RESUMO

Langerhans cell histiocytosis (LCH) lesions are characterized by neoplastic CD1a(+)/Langerin(+) histiocytes (LCH-cells) and display many features of chronic inflammation. Cancer cells can escape immune-surveillance through intra-tumoral secretion of immune-suppressive cytokines. We therefore studied by immunohistochemistry the local cytokine milieu and phenotypic characteristics of T-cells and LCH-cells present in LCH lesions collected from 25 therapy naïve patients. LCH biopsies predominantly expressed interleukin-10 (IL-10) (10/25), transforming growth factor-beta (TGF-ß) (9/25), or both cytokines (6/25). The absolute number of CD3(+)T-cells and the CD3(+)FOXP3(-) conventional cell (T-CONV) versus the CD3(+)FOXP3(+) regulatory T-cell (T-REG) was comparable for each suppressive cytokine profile (5:1). IL-10-expressing lesions contained, however, a higher proportion of T-CONV expressing the activation markers CD25 98% (38%-100%) and inducible costimulatory molecule (ICOS) 86% (47%-100%) than lesions wherein solely TGF-ß was detected (CD25(+) 20% (6%-54%); ICOS(+) 29% (7%-51%)). Virtually all T-REG expressed CD25 and ICOS in IL-10 lesions, whereas TGF-ß(+) lesions contained a lower proportion of ICOS(+) T-REG (P=0.05). IL-10(+) lesions contained more LCH-cells expressing high intensity of ICOS ligand (ICOSL) compared with TGF-ß(+) lesions (P=0.03). ICOS expression by lesion-infiltrating T-CONV and T-REG positively correlated to the extent of ICOSL expression by LCH-cells (P=0.004). Our study points out that the combined detection of interlesional IL-10 and ICOSL expression by LCH-cells is associated with the highest prevalence of activated T-CONV. Immune profiling of LCH-affected tissues obtained at the time of diagnosis may set the stage for the development of new types of therapies, which aim at local boosting of immune cells that recognize and eliminate neoplastic LCH-cells.


Assuntos
Citocinas/metabolismo , Histiocitose de Células de Langerhans/imunologia , Histiocitose de Células de Langerhans/metabolismo , Imunomodulação , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adolescente , Adulto , Antígenos de Superfície/metabolismo , Biópsia , Criança , Pré-Escolar , Feminino , Histiocitose de Células de Langerhans/diagnóstico , Histiocitose de Células de Langerhans/terapia , Humanos , Imuno-Histoquímica , Imunofenotipagem , Lactente , Interleucina-10/metabolismo , Masculino , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Adulto Jovem
9.
Cell Immunol ; 295(2): 112-7, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25880102

RESUMO

Risk factors for graft-versus-host disease (GVHD) following allogeneic hematopoietic stem-cell transplantation (HCST) include: HLA mismatches, sex-mismatch, and stem-cell source. We retrospectively analyzed if HLA- and sex-mismatching quantitatively affects the composition of GVHD-induced T-cell infiltrates. We quantified absolute numbers of CD4+ and CD8+ T cells present in tissue sections from skin biopsies of 23 pediatric HSCT-recipients with GVHD. HSCT with a sex-mismatched unrelated donor was associated with an increased number of CD4+ T cells when compared to a sex-matched unrelated donor (p=0.01). The absolute numbers of skin-infiltrating T cells were increased in patients expressing T-cell epitopes derived from the recipient's mismatched HLA, so called predicted indirectly recognizable HLA epitopes (PIRCHE). The combined expression of PIRCHE with a sex-mismatch resulted in the highest number of skin-infiltrating T cells. Our results indicate that an increased number of recipient-specific T-cell epitopes is associated with accumulation of CD4+ and CD8+ T cells in the skin.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Epitopos de Linfócito T/imunologia , Doença Enxerto-Hospedeiro/imunologia , Antígenos HLA/imunologia , Transplante de Células-Tronco Hematopoéticas , Biópsia , Criança , Feminino , Doença Enxerto-Hospedeiro/sangue , Humanos , Imuno-Histoquímica , Masculino , Microscopia Confocal , Valor Preditivo dos Testes , Estudos Retrospectivos , Estatísticas não Paramétricas
10.
Stem Cells Transl Med ; 3(8): 899-910, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24904175

RESUMO

Beneficial effects of mesenchymal stromal cells (MSCs) in patients with severe steroid-refractory acute graft-versus-host disease (aGvHD) have been reported. However, controversy exists about the effect of MSCs on virus-specific T cells. We evaluated 56 patients with grade II-IV aGvHD who responded to steroids (n = 21) or were steroid refractory receiving either MSCs (n = 22) or other second-line therapy (n = 13). Although the overall incidence of cytomegalovirus (CMV), Epstein-Barr virus, and human adenovirus (HAdV) infections was not significantly increased, HAdV infection was associated with decreased survival in children treated with MSCs. Thus, we investigated in vitro the effects of MSCs on virus-specific T cells. Both CMV-specific and, to a lesser extent, HAdV-specific T-cell activation and proliferation were negatively affected by MSCs either after induction of a response in peripheral blood mononuclear cells (PBMCs) or after restimulation of virus-specific T-cell lines. In patient-derived PBMCs, CMV-specific proliferative responses were greatly decreased on first-line treatment of aGvHD with systemic steroids and slowly recovered after MSC administration and tapering of steroids. HAdV-specific T-cell proliferation could not be detected. In contrast, the proportion of CMV- and HAdV-specific effector T cells, measured as interferon-γ-secreting cells, remained stable or increased after treatment with MSCs. In conclusion, although in vitro experimental conditions indicated a negative impact of MSCs on CMV- and HAdV-specific T-cell responses, no solid evidence was obtained to support such an effect of MSCs on T-cell responses in vivo. Still, the susceptibility of steroid-refractory severe aGvHD patients to viral reactivation warrants critical viral monitoring during randomized controlled trials on second-line treatment including MSCs.


Assuntos
Infecções por Adenovirus Humanos/mortalidade , Infecções por Citomegalovirus/mortalidade , Doença Enxerto-Hospedeiro/cirurgia , Transplante de Células-Tronco Mesenquimais/mortalidade , Células-Tronco Mesenquimais/imunologia , Doença Aguda , Infecções por Adenovirus Humanos/diagnóstico , Infecções por Adenovirus Humanos/imunologia , Infecções por Adenovirus Humanos/virologia , Fatores Etários , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Criança , Técnicas de Cocultura , Infecções por Citomegalovirus/diagnóstico , Infecções por Citomegalovirus/imunologia , Infecções por Citomegalovirus/virologia , Resistência a Medicamentos , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Incidência , Interferon gama/metabolismo , Ativação Linfocitária , Transplante de Células-Tronco Mesenquimais/efeitos adversos , Fatores de Risco , Índice de Gravidade de Doença , Esteroides/uso terapêutico , Linfócitos T/imunologia , Linfócitos T/virologia , Fatores de Tempo , Resultado do Tratamento
11.
Chimerism ; 5(2): 56-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24933732

RESUMO

Allogeneic hematopoietic stem cell transplantation (HSCT) is a widely applied treatment for disorders mainly involving the hematopoietic system. The success of this treatment depends on many different patient- and donor-specific factors. Based on higher CD34+ yields and superior clinical outcomes associated with the use of male donors, males are generally seen as the preferred HSCT donor. In addition, female donors are notorious for bearing memory type lymphocytes induced by previous pregnancies; such alloimmune cells may provoke unwanted immune reactions such as graft-vs.-host disease in transplant recipients. Consequently, many transplant centers try to avoid parous donors, particularly when searching the best unrelated donor for a male patient. We recently showed that parous women with female offspring have an anti-male directed tolerogenic immune status comparable to that of nulliparous donors. As discussed in this article addendum, the sex of the donor's offspring combined with the presence of HY-specific T regulator cells are possibly better selection criteria than parity status per se.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Histocompatibilidade , Paridade , Doadores de Tecidos , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Masculino , Fatores Sexuais
12.
Chimerism ; 5(2): 24-39, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24762743

RESUMO

Microchimerism represents a condition where one individual harbors genetically distinct cell populations, and the chimeric population constitutes <1% of the total number of cells. The most common natural source of microchimerism is pregnancy. The reciprocal cell exchange between a mother and her child often leads to the stable engraftment of hematopoietic and non-hematopoietic stem cells in both parties. Interaction between cells from the mother and those from the child may result in maternal immune cells becoming sensitized to inherited paternal alloantigens of the child, which are not expressed by the mother herself. Vice versa, immune cells of the child may become sensitized toward the non-inherited maternal alloantigens of the mother. The extent of microchimerism, its anatomical location, and the sensitivity of the techniques used for detecting its presence collectively determine whether microchimerism can be detected in an individual. In this review, we focus on the clinical consequences of microchimerism in solid organ and hematopoietic stem cell transplantation, and propose concepts derived from data of epidemiologic studies. Next, we elaborate on the latest molecular methodology, including digital PCR, for determining in a reliable and sensitive way the extent of microchimerism. For the first time, tools have become available to isolate viable chimeric cells from a host background, so that the challenges of establishing the biologic mechanisms and function of these cells may finally be tackled.


Assuntos
Quimerismo , Transplante de Células-Tronco Hematopoéticas , Transplante de Órgãos , Transplantes/imunologia , Animais , Sangue Fetal/imunologia , Humanos , Tolerância Imunológica , Reação em Cadeia da Polimerase/métodos , Análise de Célula Única/métodos
13.
Blood ; 123(20): 3152-5, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24652991

RESUMO

The extracellular signal-regulated kinase (ERK) signaling pathway is activated in Langerhans cell histiocytosis (LCH) histiocytes, but only 60% of cases carry somatic activating mutations of BRAF. To identify other genetic causes of ERK pathway activation, we performed whole exome sequencing on purified LCH cells in 3 cases. One patient with wild-type BRAF alleles in his histiocytes had compound mutations in the kinase domain of ARAF. Unlike wild-type ARAF, this mutant was a highly active mitogen-activated protein kinase kinase in vitro and was capable of transforming mouse embryo fibroblasts. Mutant ARAF activity was inhibited by vemurafenib, a BRAF inhibitor, indicating the importance of fully evaluating ERK pathway abnormalities in selecting LCH patients for targeted inhibitor therapy.


Assuntos
Histiocitose de Células de Langerhans/enzimologia , Histiocitose de Células de Langerhans/genética , Mutação , Proteínas Proto-Oncogênicas A-raf/genética , Animais , Células 3T3 BALB , Ativação Enzimática , Histiocitose de Células de Langerhans/patologia , Humanos , Células de Langerhans/enzimologia , Células de Langerhans/metabolismo , Células de Langerhans/patologia , Sistema de Sinalização das MAP Quinases , Camundongos , Proteínas Proto-Oncogênicas B-raf/genética
14.
PLoS One ; 9(3): e91274, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24646895

RESUMO

BACKGROUND: Sex difference is an established risk factor for hematopoietic stem cell transplantation (HSCT)-related complications like graft versus host disease (GVHD). CD8pos cytotoxic T cells specific for Y chromosome-encoded minor Histocompatibility antigens (HY) play an important role therein. Prior to HSC donation, female donors may encounter HY antigens through fetomaternal or transmaternal cell flow, potentially leading to the induction of HY-specific cytotoxic or regulatory immune responses. Whether HY priming occurs independent of parity, and whether HY priming is dependent on the presence of male microchimerism, is as yet unknown. METHODS: We investigated the presence of HY-specific regulatory T cells (Treg) and male microchimerism in 45 healthy women with a fully documented pregnancy and family history. HY peptide-induced linked suppression, a commonly reported functional feature of CD4pos and CD8pos Treg, was measured by trans vivo Delayed Type Hypersensitivity testing. As source of HY antigens, male microchimerism was analyzed by real-time PCR and defined by the presence of male DNA in at least one purified leukocyte cell type. RESULTS: HLA class I or class II restricted HY-specific Treg were detected in 26/42 (62%) women eligible for analysis. The prevalence of HY-specific Treg was significantly higher in women who had never given birth to sons than in women with male offspring (p = 0.004). Male microchimerism could be detected in 24 out of 45 (53%) women but did not correlate with the presence of HY specific Treg. CONCLUSIONS: HY-specific Treg in women with male offspring have been described previously. Here we show for the first time that, in fact, HY specific Treg are more common in nulliparous women and in parous women with female offspring. Their presence is independent of the presence of male microchimerism. Whether HY-specific Treg presence in female stem cell grafts might decrease the GVHD incidence in male HSCT recipients needs to be investigated.


Assuntos
Antígeno H-Y/imunologia , Tolerância Imunológica , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Sequência de Aminoácidos , Animais , Quimerismo , Feminino , Expressão Gênica , Antígeno H-Y/genética , Humanos , Masculino , Camundongos , Dados de Sequência Molecular , Gravidez , Fatores Sexuais , Linfócitos T Citotóxicos/química , Linfócitos T Reguladores/química
15.
J Clin Immunol ; 34(1): 84-93, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24254535

RESUMO

PURPOSE: Poly-ostotic Langerhans Cell Histiocytosis (LCH) can be difficult to distinguish clinically and histologically from disseminated infection in manifesting specific subtypes of Mendelian Susceptibility to Mycobacterial Disease (MSMD). In MSMD-patients, dominant negative germline mutations in the IFN-γR1 gene, in particular in exon 6, lead to autosomal dominant IFN-γ receptor 1 deficiency (ADIFNGR1) and can mimic LCH. We hypothesized that similar defects might underlie the pathogenesis of LCH. METHODS: IFN-γR1 expression was immunohistochemically determined at disease onset in biopsies from 11 LCH-patients and four ADIFNGR1-patients. IFN-γR1 function was analyzed in 18 LCH-patients and 13 healthy controls by assessing the IFN-γ-induced upregulation of Fc-gamma-receptor I (FcγRI) expression on monocytes. Pro-inflammatory cytokine production was measured after stimulation of whole blood with LPS and IFN-γ. Exon 6 of the IFN-γR1 gene was sequenced in 67 LCH-patients to determine whether mutations were present. RESULTS: IFN-γR1 expression was high in three LCH-affected biopsies, similar to ADIFNGR1-affected biopsies, but varied from negative to moderate in eight other LCH-affected biopsies. No functional differences in IFN-γ signaling were detected between LCH-patients with active or non-active disease and healthy controls. No germline mutations in exon 6 of the IFN-γR1 gene were detected in any of the 67 LCH-patients. CONCLUSIONS: In contrast to ADIFNGR1-patients, IFN-γ signaling is fully functional in LCH-patients. Either performed before, during or after treatment, these non-invasive functional assays can distinguish LCH-patients from ADIFNGR1-patients and thereby facilitate correct therapy regimens for patients with recurrent osteolytic lesions.


Assuntos
Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/metabolismo , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/metabolismo , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Pré-Escolar , Diagnóstico Diferencial , Éxons , Expressão Gênica , Predisposição Genética para Doença , Células Germinativas , Histiocitose de Células de Langerhans/diagnóstico , Humanos , Interferon gama/metabolismo , Masculino , Mutação , Infecções por Mycobacterium/diagnóstico , Especificidade de Órgãos , Transdução de Sinais
17.
Biol Blood Marrow Transplant ; 19(11): 1590-9, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23994245

RESUMO

Steroid-nonresponsive acute graft-versus-host disease (aGVHD) after hematopoietic stem cell transplantation carries a poor prognosis. Various groups have reported beneficial effects of mesenchymal stromal cell (MSC) infusion as salvage treatment. Response to treatment is typically evaluated using the diagnostic clinical criteria for aGVHD. In this study, we evaluated the usefulness of additional gastrointestinal biopsy specimens paired with serum biomarkers. In a cohort of 22 pediatric patients, persistent or recurrent diarrhea was seen in 18 children treated with MSC infusion for steroid-refractory aGVHD. To exclude other causes of gastrointestinal pathology, patients were biopsied for histological analysis. Eight of 12 patients exhibited residual tissue damage and villous atrophy, but no active aGVHD. Serum biomarkers have been identified as an alternative tool for monitoring the response to aGVHD treatment. The value of biomarkers for inflammation, tissue, and endothelial cell damage was evaluated in our cohort. Although predictive of response to treatment and survival, these markers lack the necessary specificity and sensitivity to predict response to MSC therapy. Objective endpoints for clinical trials on the treatment of steroid-refractory aGVHD remain to be defined. Thus, we recommend including biopsies and biomarkers to discriminate between ongoing aGVHD and postinflammatory malabsorption.


Assuntos
Neoplasias Gastrointestinais/terapia , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Doença Aguda , Adolescente , Biomarcadores Tumorais/metabolismo , Criança , Pré-Escolar , Feminino , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/cirurgia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/etiologia , Humanos , Lactente , Recém-Nascido , Masculino , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo
18.
PLoS One ; 7(12): e50896, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23226545

RESUMO

The C-type lectin-like receptor CD161 is a well-established marker for human IL17-producing T cells, which have been implicated to contribute to the development of graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). In this study, we analyzed CD161(+) T cell recovery, their functional properties and association with GVHD occurrence in allo-SCT recipients. While CD161(+)CD4(+) T cells steadily recovered, CD161(hi)CD8(+) T cell numbers declined during tapering of Cyclosporine A (CsA), which can be explained by their initial growth advantage over CD161(neg/low)CD8(+) T cells due to ABCB1-mediated CsA efflux. Interestingly, occurrence of acute and chronic GVHD was significantly correlated with decreased levels of circulating CD161(+)CD4(+) as well as CD161(hi)CD8(+) T cells. In addition, these subsets from transplanted patients secreted high levels of IFNγ and IL17. Moreover, we found that CCR6 co-expression by CD161(+) T cells mediated specific migration towards CCL20, which was expressed in GVHD biopsies. Finally, we demonstrated that CCR6(+) T cells indeed were present in these CCL20(+) GVHD-affected tissues. In conclusion, we showed that functional CD161(+)CCR6(+) co-expressing T cells disappear from the circulation and home to GVHD-affected tissue sites. These findings support the hypothesis that CCR6(+)CD161-expressing T cells may be involved in the immune pathology of GVHD following their CCL20-dependent recruitment into affected tissues.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/terapia , Interleucina-17/biossíntese , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores CCR6/metabolismo , Transplante de Células-Tronco , Linfócitos T/imunologia , Adulto , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , Movimento Celular/efeitos dos fármacos , Quimiocina CCL20/metabolismo , Ciclosporina/farmacologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Teste de Histocompatibilidade , Humanos , Memória Imunológica/efeitos dos fármacos , Interferon gama/biossíntese , Interleucina-17/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fenótipo , Linfócitos T/efeitos dos fármacos , Transplante Homólogo , Adulto Jovem
19.
Biol Blood Marrow Transplant ; 18(3): 381-7, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22062805

RESUMO

HY-specific T cells are presumed to play a role in acute graft-versus-host disease (aGVHD) after female-to-male stem cell transplantation (SCT). However, infiltrates of these T cells in aGVHD-affected tissues have not yet been reported. We evaluated the application of HLA-A2/HY dextramers for the in situ detection of HY-specific T cells in cryopreserved skin biopsy specimens. We applied the HLA-A2/HY dextramers on cryopreserved skin biopsy specimens from seven male HLA-A2(+) pediatric patients who underwent stem cell transplantation with confirmed aGVHD involving the skin. The dextramers demonstrated the presence of HY-specific T cells. In skin biopsy specimens of three male recipients of female grafts, 68% to 78% of all skin-infiltrating CD8(+) T cells were HY-specific, whereas these cells were absent in biopsy specimens collected from sex-matched patient-donor pairs. Although this study involved a small and heterogeneous patient group, our results strongly support the hypothesis that HY-specific T cells are actively involved in the pathophysiology of aGVHD after sex-mismatched stem cell transplantation.


Assuntos
Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/métodos , Pele/imunologia , Linfócitos T/imunologia , Adolescente , Criança , Pré-Escolar , Criopreservação , Imunofluorescência , Doença Enxerto-Hospedeiro/patologia , Humanos , Masculino , Microscopia Confocal , Pele/patologia , Linfócitos T/patologia
20.
Pediatr Blood Cancer ; 55(2): 344-8, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20582977

RESUMO

Chemokine receptor/ligand interactions orchestrate the migration of cells to peripheral tissues such as the skin. We analysed chemokine receptor expression by acute myeloid leukaemic (AML) cells present in peripheral blood (n = 7), bone marrow (n = 6), or skin (n = 11) obtained from 15 paediatric AML patients with skin involvement and in 10 AML patients without skin involvement. High percentages of circulating CCR2(pos) AML cells were only detected in patients with extramedullary disease. Skin-residing AML cells displayed a different set of receptors in situ, namely: CCR5, CXCR4, CXCR7 and CX3CR1. These results suggest the involvement of different chemokine/chemokine receptor interactions in homing and retention of AML blasts in the skin.


Assuntos
Quimiocinas/análise , Leucemia Mieloide Aguda/patologia , Infiltração Leucêmica/patologia , Receptores de Quimiocinas/análise , Neoplasias Cutâneas/patologia , Adolescente , Receptor 1 de Quimiocina CX3C , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Receptores CCR2/análise , Receptores CCR5/análise , Receptores CXCR/análise , Receptores CXCR4/análise , Pele/química , Pele/patologia
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