RESUMEN
Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Enfermedad Injerto contra Huésped/inmunología , Interleucinas/metabolismo , Intestino Delgado/inmunología , Células Madre/metabolismo , Animales , Trasplante de Médula Ósea/efectos adversos , Modelos Animales de Enfermedad , Citometría de Flujo , Enfermedad Injerto contra Huésped/mortalidad , Inmunohistoquímica , Interleucina-23/metabolismo , Interleucinas/genética , Interleucinas/inmunología , Intestino Delgado/citología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina/metabolismo , Interleucina-22RESUMEN
Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor that is well known for its role in regulating the cellular redox pathway. Although there is mounting evidence suggesting a critical role for Nrf2 in hematopoietic stem cells and innate leukocytes, little is known about its involvement in T-cell biology. In this study, we identified a novel role for Nrf2 in regulating alloreactive T-cell function during allogeneic hematopoietic cell transplantation (allo-HCT). We observed increased expression and nuclear translocation of Nrf2 upon T-cell activation in vitro, especially in CD4+ donor T cells after allo-HCT. Allo-HCT recipients of Nrf2 -/- donor T cells had significantly less acute graft-versus-host disease (GVHD)-induced mortality, morbidity, and pathology. This reduction in GVHD was associated with the persistence of Helios+ donor regulatory T cells in the allograft, as well as defective upregulation of the gut-homing receptor LPAM-1 on alloreactive CD8+ T cells. Additionally, Nrf2 -/- donor CD8+ T cells demonstrated intact cytotoxicity against allogeneic target cells. Tumor-bearing allo-HCT recipients of Nrf2 -/- donor T cells had overall improved survival as a result of preserved graft-versus-tumor activity and reduced GVHD activity. Our findings characterized a previously unrecognized role for Nrf2 in T-cell function, as well as revealed a novel therapeutic target to improve the outcomes of allo-HCT.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas , Activación de Linfocitos , Factor 2 Relacionado con NF-E2/inmunología , Neoplasias Experimentales/inmunología , Enfermedad Aguda , Aloinjertos , Animales , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/patología , Ratones , Ratones Noqueados , Factor 2 Relacionado con NF-E2/genética , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Neoplasias Experimentales/terapiaRESUMEN
Prostate cancer (PCa) is one of the most frequently diagnosed cancers among men. Many molecular changes have been detailed during PCa progression. The gene encoding the transcription factor ERG shows recurrent rearrangement, resulting in the overexpression of ERG in the majority of prostate cancers. Overexpression of ERG plays a critical role in prostate oncogenesis and development of metastatic disease. Among the downstream effectors of ERG, Frizzled family member FZD4 has been shown to be a target of ERG. Frizzled-8 (FZD8) has been shown to be involved in PCa bone metastasis. In the present study, we show that the expression of FZD8 is directly correlated with ERG expression in PCa. Furthermore, we show that ERG directly targets and activates FZD8 by binding to its promoter. This activation is specific to ETS transcription factor ERG and not ETV1. We propose that ERG overexpression in PCa leads to induction of Frizzled family member FZD8, which is known to activate the Wnt pathway. Taken together, these findings uncover a novel mechanism for PCa metastasis, and indicate that FZD8 may represent a potential therapeutic target for PCa.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Próstata/metabolismo , Neoplasias de la Próstata/genética , Receptores de Superficie Celular/genética , Línea Celular Tumoral , Progresión de la Enfermedad , Humanos , Masculino , Regiones Promotoras Genéticas , Próstata/patología , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Receptores de Superficie Celular/metabolismo , Regulador Transcripcional ERG/genética , Regulador Transcripcional ERG/metabolismoRESUMEN
IL-21 is a proinflammatory cytokine produced by Th17 cells. Abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL remain incompletely understood. In a murine MHC-mismatched BM transplantation model, we observed that IL-21 receptor knockout (IL-21R KO) donor T cells mediate decreased systemic and gastrointestinal GVHD in recipients of a transplant. This reduction in GVHD was associated with expansion of transplanted donor regulatory T cells and with tissue-specific modulation of Th-cell function. IL-21R KO and wild-type donor T cells showed equivalent alloactivation, but IL-21R KO T cells showed decreased infiltration and inflammatory cytokine production within the mesenteric lymph nodes. However, Th-cell cytokine production was maintained peripherally, and IL-21R KO T cells mediated equivalent immunity against A20 and P815 hematopoietic tumors. In summary, abrogation of IL-21 signaling in donor T cells leads to tissue-specific modulation of immunity, such that gastrointestinal GVHD is reduced, but peripheral T-cell function and GVL capacity are retained. IL-21 is thus an exciting target for therapeutic intervention and improvement of clinical transplantation outcomes.
Asunto(s)
Enfermedad Injerto contra Huésped/genética , Efecto Injerto vs Leucemia/genética , Inmunidad Innata/genética , Interleucinas/fisiología , Linfocitos T/metabolismo , Donantes de Tejidos , Animales , Técnicas de Silenciamiento del Gen , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/metabolismo , Humanos , Inmunidad Innata/fisiología , Subunidad alfa del Receptor de Interleucina-21/genética , Subunidad alfa del Receptor de Interleucina-21/metabolismo , Subunidad alfa del Receptor de Interleucina-21/fisiología , Interleucinas/genética , Interleucinas/metabolismo , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Especificidad de Órganos/genética , Especificidad de Órganos/inmunología , Transducción de Señal/genética , Linfocitos T/fisiología , Inmunología del TrasplanteRESUMEN
We have developed a dual bioluminescent reporter system allowing noninvasive, concomitant imaging of T-cell trafficking, expansion, and activation of nuclear factor of activated T cells (NFAT) in vivo. NFAT activation plays an important role in T-cell activation and T-cell development. Therefore we used this system to determine spatial-temporal activation patterns of (1) proliferating T lymphocytes during graft-versus-host disease (GVHD) and (2) T-cell precursors during T-cell development after allogeneic hematopoietic stem cell transplantation (HSCT). In the first days after HSCT, donor T cells migrated to the peripheral lymph nodes and the intestines, whereas the NFAT activation was dominant in the intestines, suggesting an important role for the intestines in the early stages of alloactivation during development of GVHD. After adoptive transfer of in vitro-derived T-cell receptor (TCR) H-Y transgenic T-cell precursors into B6 (H-2(b)) hosts of both sexes, NFAT signaling and development into CD4(+) or CD8(+) single-positive cells could only be detected in the thymus of female recipients indicating either absence of positive selection or prompt depletion of double-positive thymocytes in the male recipients. Because NFAT plays an important role in a wide range of cell types, our system could provide new insights into a variety of biologic processes.
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Movimiento Celular , Proliferación Celular , Células Precursoras de Linfocitos T/citología , Linfocitos T/citología , Células 3T3 , Traslado Adoptivo , Animales , Línea Celular , Línea Celular Tumoral , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/metabolismo , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Células Jurkat , Lentivirus/genética , Luciferasas/genética , Luciferasas/metabolismo , Luminiscencia , Mediciones Luminiscentes/métodos , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Factores de Transcripción NFATC/genética , Células Precursoras de Linfocitos T/metabolismo , Células Precursoras de Linfocitos T/trasplante , Regiones Promotoras Genéticas/genética , Linfocitos T/metabolismoRESUMEN
Alloreactive T cells are crucial for graft-versus-host disease (GVHD) pathophysiology, and modulating their trafficking patterns has been efficacious in ameliorating experimental disease. We report in this paper that P-selectin, a glycoprotein found on resting and inflamed endothelium, is important for donor alloreactive T cells trafficking into GVHD target organs, such as the intestines and skin. Compared with wild-type (WT) recipients of allogeneic bone marrow transplantation, P-selectin(-/-) recipients exhibit decreased GVHD mortality and decreased GVHD of the skin, liver, and small bowels. This was associated with diminished infiltration of alloactivated T cells into the Peyer's patches and small bowels, coupled with increased numbers of donor T cells in the spleen and secondary lymphoid organs (SLOs). Surprisingly, however, donor T cells deficient for P-selectin glycoprotein ligand 1, the most well described P-selectin ligand, mediated GVHD similar to WT T cells and accumulated in SLO and target organs in similar numbers as WT T cells. This suggests that P-selectin may be required for trafficking into inflamed tissues but not SLO and that donor T cells may use multiple P-selectin ligands apart from P-selectin glycoprotein ligand 1 to interact with P-selectin and traffic into inflamed tissues during GVHD. We conclude that targeting P-selectin may be a viable strategy for GVHD prophylaxis or treatment.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/terapia , Selectina-P/genética , Animales , Modelos Animales de Enfermedad , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Enfermedad Injerto contra Huésped/fisiopatología , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/fisiología , Ligandos , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Glicoproteínas de Membrana/deficiencia , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Selectina-P/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , Subgrupos de Linfocitos T/trasplante , Trasplante HomólogoRESUMEN
Keratinocyte growth factor (KGF), which is given exogenously to allogeneic bone marrow transplantation (allo-BMT) recipients, supports thymic epithelial cells and increases thymic output of naive T cells. Here, we demonstrate that this improved T-cell reconstitution leads to enhanced responses to DNA plasmid tumor vaccination. Tumor-bearing mice treated with KGF and DNA vaccination have improved long-term survival and decreased tumor burden after allo-BMT. When assayed before vaccination, KGF-treated allo-BMT recipients have increased numbers of peripheral T cells, including CD8(+) T cells with vaccine-recognition potential. In response to vaccination, KGF-treated allo-BMT recipients, compared with control subjects, generate increased numbers of tumor-specific CD8(+) cells, as well as increased numbers of CD8(+) cells producing interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha). We also found unanticipated benefits to antitumor immunity with the administration of KGF. KGF-treated allo-BMT recipients have an improved ratio of T effector cells to regulatory T cells, a larger fraction of effector cells that display a central memory phenotype, and effector cells that are derived from a broader T-cell-receptor repertoire. In conclusion, our data suggest that KGF can function as a potent vaccine adjuvant after allo-BMT through its effects on posttransplantation T-cell reconstitution.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Vacunas contra el Cáncer/inmunología , Factor 7 de Crecimiento de Fibroblastos/farmacología , Timo/efectos de los fármacos , Vacunas de ADN/inmunología , Animales , Trasplante de Médula Ósea/métodos , Trasplante de Médula Ósea/mortalidad , Antígenos CD4/metabolismo , Linfocitos T CD8-positivos/citología , División Celular/efectos de los fármacos , División Celular/inmunología , Femenino , Factores de Transcripción Forkhead/metabolismo , Memoria Inmunológica/efectos de los fármacos , Memoria Inmunológica/inmunología , Recuento de Linfocitos , Ratones , Ratones Endogámicos C57BL , Plásmidos , Tasa de Supervivencia , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo , Timo/citología , Timo/inmunología , Quimera por Trasplante , Trasplante HomólogoRESUMEN
Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estudios Retrospectivos , Trasplante AutólogoRESUMEN
Anti-PD-1 monoclonal antibodies yield high response rates in patients with relapsed/refractory classic Hodgkin lymphoma (cHL), but most patients will eventually progress. Allogeneic hematopoietic cell transplantation (alloHCT) after PD-1 blockade may be associated with increased toxicity, raising challenging questions about the role, timing, and optimal method of transplantation in this setting. To address these questions, we assembled a retrospective cohort of 209 cHL patients who underwent alloHCT after PD-1 blockade. With a median follow-up among survivors of 24 months, the 2-year cumulative incidences (CIs) of non-relapse mortality and relapse were 14 and 18%, respectively; the 2-year graft-versus-host disease (GVHD) and relapse-free survival (GRFS), progression-free survival (PFS), and overall survival were 47%, 69%, and 82%, respectively. The 180-day CI of grade 3-4 acute GVHD was 15%, while the 2-year CI of chronic GVHD was 34%. In multivariable analyses, a longer interval from PD-1 to alloHCT was associated with less frequent severe acute GVHD, while additional treatment between PD-1 and alloHCT was associated with a higher risk of relapse. Notably, post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis was associated with significant improvements in PFS and GRFS. While awaiting prospective clinical trials, PTCy-based GVHD prophylaxis may be considered the optimal transplantation strategy for this patient population.
Asunto(s)
Resistencia a Antineoplásicos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Enfermedad de Hodgkin/terapia , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Recurrencia Local de Neoplasia/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Terapia Recuperativa , Adolescente , Adulto , Anciano , Femenino , Estudios de Seguimiento , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo , Adulto JovenRESUMEN
Patients undergoing allogeneic hematopoietic cell transplantation (HCT) are at risk for numerous acute and long-term complications from this procedure. Post-transplant diabetes mellitus (PTDM) is a common but under-recognized problem. Similar to graft-versus-host disease (GVHD), new-onset diabetes is characterized by immune dysregulation that can negatively impact transplant outcomes. This review will discuss the biology of IL-33/ST2 in acute GVHD and PTDM development, and how this cytokine axis could be leveraged for predicting and treating immuno-metabolic complications after transplant.
RESUMEN
PURPOSE: To assess the attitudes of medical students in India about participating in graduate medical education in the United States and other countries and in subsequent clinical practice in those countries. METHOD: A total of 240 students who were attending their final year at two medical schools in Bangalore, India, were surveyed during 2004. Surveys were completed by 166 (69%) of the students. RESULTS: Among the responding students, 98 (59%) thought of leaving India for further training abroad. Of those who wished to leave, 41 (42%) preferred the United States, 42 (43%) preferred the United Kingdom, and 9 (9%) preferred Canada, Australia or New Zealand. Only two students preferred the Middle East. Most who favored training in the United States indicated that they intended to remain after training, whereas fewer than 20% of those who favored training in the United Kingdom had such intentions. While more than 60% perceived greater professional opportunities in the United States than in India, approximately 75% were concerned that the United States had become less welcoming after the terrorist attacks of 9/11, and similar numbers were concerned about the examination administered by the Educational Commission on Foreign Medical Graduates. Conversely, the majority of respondents felt that opportunities for physicians in India were improving. CONCLUSIONS: While optimism about future medical careers in India is increasing, the interest of Indian medical students in training and subsequently practicing in the United States remains high.
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Actitud del Personal de Salud , Emigración e Inmigración/estadística & datos numéricos , Médicos Graduados Extranjeros/estadística & datos numéricos , Internado y Residencia , Estudiantes de Medicina/psicología , Recolección de Datos , Demografía , Emigración e Inmigración/legislación & jurisprudencia , Médicos Graduados Extranjeros/legislación & jurisprudencia , Humanos , India/etnología , Intención , Clase Social , Estados UnidosRESUMEN
Efforts to limit GVHD mediated by alloreactive donor T cells after allogeneic bone marrow transplantation are limited by a concomitant decrease in graft-versus-tumor (GVT) activity and increased possibilities of tumor relapse. Using a novel approach, we adoptively transferred conventional T cells expressing the transcription factor promyelocytic leukemia zinc finger (PLZF), which confers effector properties resembling invariant natural killer T cells, such as copious production of cytokines under suboptimal stimulation. PLZF expression in T-cell allografts attenuates expansion of alloreactive T cells, leading to lower GVHD. Intact alloreactivity-driven antitumor cytokine responses result in preserved GVT effects, leading to improved survival. Our findings suggest that therapy with PLZF-overexpressing T cells would result in overall improved outcomes due to less GVHD and intact GVT effects.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Tumor/inmunología , Factores de Transcripción de Tipo Kruppel/inmunología , Neoplasias Experimentales/inmunología , Linfocitos T/inmunología , Traslado Adoptivo , Animales , Trasplante de Médula Ósea , Citometría de Flujo , Enfermedad Injerto contra Huésped/inmunología , Activación de Linfocitos/inmunología , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Neoplasias Experimentales/terapia , Proteína de la Leucemia Promielocítica con Dedos de Zinc , Linfocitos T/trasplante , Trasplante HomólogoRESUMEN
Current strategies to suppress graft-versus-host disease (GVHD) also compromise graft-versus-tumor (GVT) responses. Furthermore, most experimental strategies to separate GVHD and GVT responses merely spare GVT function without actually enhancing it. We have previously shown that endogenously expressed TNF-related apoptosis-inducing ligand (TRAIL) is required for optimal GVT activity against certain malignancies in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In order to model a donor-derived cellular therapy, we genetically engineered T cells to overexpress TRAIL and adoptively transferred donor-type unsorted TRAIL+ T cells into mouse models of allo-HSCT. We found that murine TRAIL+ T cells induced apoptosis of alloreactive T cells, thereby reducing GVHD in a DR5-dependent manner. Furthermore, murine TRAIL+ T cells mediated enhanced in vitro and in vivo antilymphoma GVT response. Moreover, human TRAIL+ T cells mediated enhanced in vitro cytotoxicity against both human leukemia cell lines and against freshly isolated chronic lymphocytic leukemia (CLL) cells. Finally, as a model of off-the-shelf, donor-unrestricted antitumor cellular therapy, in vitro-generated TRAIL+ precursor T cells from third-party donors also mediated enhanced GVT response in the absence of GVHD. These data indicate that TRAIL-overexpressing donor T cells could potentially enhance the curative potential of allo-HSCT by increasing GVT response and suppressing GVHD.
Asunto(s)
Rechazo de Injerto/prevención & control , Enfermedad Injerto contra Huésped/inmunología , Linfocitos T/trasplante , Ligando Inductor de Apoptosis Relacionado con TNF/biosíntesis , Traslado Adoptivo , Animales , Células Presentadoras de Antígenos , Línea Celular Tumoral , Citotoxicidad Inmunológica , Rechazo de Injerto/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Células HEK293 , Humanos , Inmunoterapia Adoptiva , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/terapia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Linfocitos T/metabolismo , Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/fisiologíaRESUMEN
BACKGROUND: Allogeneic bone marrow transplantation (allo-BMT) is a potentially curative therapy for a variety of hematologic diseases, but benefits, including graft-versus-tumor (GVT) activity are limited by graft-versus-host-disease (GVHD). Carcinoembryonic antigen related cell adhesion molecule 1 (Ceacam1) is a transmembrane glycoprotein found on epithelium, T cells, and many tumors. It regulates a variety of physiologic and pathological processes such as tumor biology, leukocyte activation, and energy homeostasis. Previous studies suggest that Ceacam1 negatively regulates inflammation in inflammatory bowel disease models. METHODS: We studied Ceacam1 as a regulator of GVHD and GVT after allogeneic bone marrow transplantation (allo-BMT) in mouse models. In vivo, Ceacam1(-/-) T cells caused increased GVHD mortality and GVHD of the colon, and greater numbers of donor T cells were positive for activation markers (CD25(hi), CD62L(lo)). Additionally, Ceacam1(-/-) CD8 T cells had greater expression of the gut-trafficking integrin α(4)ß(7), though both CD4 and CD8 T cells were found increased numbers in the gut post-transplant. Ceacam1(-/-) recipients also experienced increased GVHD mortality and GVHD of the colon, and alloreactive T cells displayed increased activation. Additionally, Ceacam1(-/-) mice had increased mortality and decreased numbers of regenerating small intestinal crypts upon radiation exposure. Conversely, Ceacam1-overexpressing T cells caused attenuated target-organ and systemic GVHD, which correlated with decreased donor T cell numbers in target tissues, and mortality. Finally, graft-versus-tumor survival in a Ceacam1(+) lymphoma model was improved in animals receiving Ceacam1(-/-) vs. control T cells. CONCLUSIONS: We conclude that Ceacam1 regulates T cell activation, GVHD target organ damage, and numbers of donor T cells in lymphoid organs and GVHD target tissues. In recipients of allo-BMT, Ceacam1 may also regulate tissue radiosensitivity. Because of its expression on both the donor graft and host tissues, this suggests that targeting Ceacam1 may represent a potent strategy for the regulation of GVHD and GVT after allogeneic transplantation.
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Trasplante de Médula Ósea/inmunología , Antígeno Carcinoembrionario/metabolismo , Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Tumor/inmunología , Animales , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de la radiación , Polaridad Celular/efectos de la radiación , Proliferación Celular/efectos de la radiación , Citotoxicidad Inmunológica/efectos de la radiación , Células Dendríticas/inmunología , Células Dendríticas/efectos de la radiación , Enfermedad Injerto contra Huésped/complicaciones , Enfermedad Injerto contra Huésped/mortalidad , Efecto Injerto vs Tumor/efectos de la radiación , Humanos , Integrinas/metabolismo , Intestino Delgado/patología , Intestino Delgado/efectos de la radiación , Activación de Linfocitos/inmunología , Activación de Linfocitos/efectos de la radiación , Recuento de Linfocitos , Tejido Linfoide/citología , Tejido Linfoide/efectos de la radiación , Ratones , Especificidad de Órganos/inmunología , Especificidad de Órganos/efectos de la radiación , Traumatismos Experimentales por Radiación/complicaciones , Traumatismos Experimentales por Radiación/metabolismo , Traumatismos Experimentales por Radiación/patología , Radiación Ionizante , Trasplante HomólogoRESUMEN
Thymic graft-versus-host disease (tGVHD) can contribute to profound T cell deficiency and repertoire restriction after allogeneic BM transplantation (allo-BMT). However, the cellular mechanisms of tGVHD and interactions between donor alloreactive T cells and thymic tissues remain poorly defined. Using clinically relevant murine allo-BMT models, we show here that even minimal numbers of donor alloreactive T cells, which caused mild nonlethal systemic graft-versus-host disease, were sufficient to damage the thymus, delay T lineage reconstitution, and compromise donor peripheral T cell function. Furthermore, to mediate tGVHD, donor alloreactive T cells required trafficking molecules, including CCR9, L selectin, P selectin glycoprotein ligand-1, the integrin subunits alphaE and beta7, CCR2, and CXCR3, and costimulatory/inhibitory molecules, including Ox40 and carcinoembryonic antigen-associated cell adhesion molecule 1. We found that radiation in BMT conditioning regimens upregulated expression of the death receptors Fas and death receptor 5 (DR5) on thymic stromal cells (especially epithelium), while decreasing expression of the antiapoptotic regulator cellular caspase-8-like inhibitory protein. Donor alloreactive T cells used the cognate proteins FasL and TNF-related apoptosis-inducing ligand (TRAIL) (but not TNF or perforin) to mediate tGVHD, thereby damaging thymic stromal cells, cytoarchitecture, and function. Strategies that interfere with Fas/FasL and TRAIL/DR5 interactions may therefore represent a means to attenuate tGVHD and improve T cell reconstitution in allo-BMT recipients.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Proteína Ligando Fas/fisiología , Enfermedad Injerto contra Huésped/etiología , Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Timo/inmunología , Animales , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD/análisis , Movimiento Celular , Enfermedad Injerto contra Huésped/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores OX40/fisiología , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/agonistas , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/fisiología , Células del Estroma/fisiología , Linfocitos T/inmunología , Timo/citología , Trasplante HomólogoRESUMEN
Nucleotide-binding oligomerization domain 2 (NOD2) polymorphisms are independent risk factors for Crohn's disease and graft-versus-host disease (GVHD). In Crohn's disease, the proinflammatory state resulting from NOD2 mutations have been associated with a loss of antibacterial function of enterocytes such as paneth cells. NOD2 has not been studied in experimental allogeneic bone marrow transplantation (allo-BMT). Using chimeric recipients with NOD2(-/-) hematopoietic cells, we demonstrate that NOD2 deficiency in host hematopoietic cells exacerbates GVHD. We found that proliferation and activation of donor T cells was enhanced in NOD-deficient allo-BMT recipients, suggesting that NOD2 plays a role in the regulation of host antigen-presenting cells (APCs). Next, we used bone marrow chimeras in an experimental colitis model and observed again that NOD2 deficiency in the hematopoietic cells results in increased intestinal inflammation. We conclude that NOD2 regulates the development of GVHD through its inhibitory effect on host APC function.