RESUMEN
Clinical outcomes after primary graft failure (PGF) remain poor. Here we present a large retrospective analysis (n=23,272) which investigates means to prevent PGF and early detection of patients at high risk. In patients with hematologic malignancies, who underwent their first myeloablative allogeneic hematopoietic cell transplantation, PGF was reported in 1278 (5.5%), and there was a marked difference in PGFs using peripheral blood stem cell compared with bone marrow grafts (2.5 vs 7.3%; P<0.001). A fourfold increase of PGF was observed in myeloproliferative disorders compared with acute leukemia (P<0.001). Other risk factors for PGF included recipient age <30, HLA mismatch, male recipients of female donor grafts, ABO incompatibility, busulfan/cyclophosphamide conditioning and cryopreservation. In bone marrow transplants, total nucleated cell doses ⩽2.4 × 10(8) per kg were associated with PGF (odds ratio 1.39; P<0.001). The use of tacrolimus-based immunosuppression and granulocyte colony-stimulating factor were associated with decreased PGF risk. These data, allow clinicians to do more informed choices with respect to graft source, donor selection, conditioning and immunosuppressive regimens to reduce the risk of PGF. Moreover, a novel risk score determined on day 21 post transplant may provide the rationale for an early request for additional hematopoietic stem cells.
Asunto(s)
Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Disfunción Primaria del Injerto/etiología , Acondicionamiento Pretrasplante/efectos adversos , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Estudios de Seguimiento , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/mortalidad , Humanos , Inmunosupresores/uso terapéutico , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Agonistas Mieloablativos/efectos adversos , Estadificación de Neoplasias , Disfunción Primaria del Injerto/tratamiento farmacológico , Disfunción Primaria del Injerto/mortalidad , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo , Adulto JovenAsunto(s)
Cistitis/terapia , Factor 7 de Crecimiento de Fibroblastos/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Hemorragia/terapia , Leucemia Mieloide Aguda/terapia , Proteínas Recombinantes/uso terapéutico , Antineoplásicos/uso terapéutico , Niño , Cistitis/etiología , Transfusión de Eritrocitos , Femenino , Hemorragia/etiología , Humanos , Oxígeno/uso terapéutico , Recurrencia , Trasplante Homólogo/efectos adversos , Resultado del TratamientoRESUMEN
We describe the first case, to our knowledge, of disseminated Mycobacterium bovis Bacillus Calmette-Guérin infection in a child with Bare Lymphocyte Syndrome type II after undergoing hematopoietic stem cell transplantation (HSCT). The patient presented 30 days post HSCT with fever and lymphadenitis. Lymph node, blood, and gastric aspirates were positive for M. bovis. The patient received a prolonged treatment course with a combination of isoniazid, levofloxacin, and ethambutol. Her course was further complicated by granulomatous lymphadenitis and otitis media associated with M. bovis that developed during immune suppression taper and immune reconstitution. Ultimately, the patient recovered fully, in association with restoration of immune function, and has completed 12 months of therapy.
Asunto(s)
Vacuna BCG/efectos adversos , Trasplante de Células Madre Hematopoyéticas , Infecciones por Mycobacterium/microbiología , Mycobacterium bovis , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Lactante , Infecciones por Mycobacterium/tratamiento farmacológico , Inmunodeficiencia Combinada Grave/complicaciones , Inmunodeficiencia Combinada Grave/terapiaRESUMEN
To assess the impact of spleen status on engraftment, and early morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT), we analyzed 9,683 myeloablative allograft recipients from 1990 to 2006; 472 had prior splenectomy (SP), 300 splenic irradiation (SI), 1,471 with splenomegaly (SM), and 7,440 with normal spleen (NS). Median times to neutrophil engraftment (NE) and platelet engraftment (PE) were 15 vs 18 days and 22 vs 24 days for the SP and NS groups, respectively (P<0.001). Hematopoietic recovery at day +100 was not different across all groups, however the odds ratio of days +14 and +21 NE and day +28 PE were 3.26, 2.25 and 1.28 for SP, and 0.56, 0.55, and 0.82 for SM groups compared to NS (P<0.001), respectively. Among patients with SM, use of peripheral blood grafts improved NE at day +21, and CD34+ cell dose >5.7 × 10(6)/kg improved PE at day+28. After adjusting variables by Cox regression, the incidence of GVHD and OS were not different among groups. SM is associated with delayed engraftment, whereas SP prior to HCT facilitates early engraftment without having an impact on survival.
Asunto(s)
Neoplasias Hematológicas/mortalidad , Trasplante de Células Madre Hematopoyéticas , Bazo/patología , Bazo/cirugía , Esplenectomía , Adolescente , Adulto , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/terapia , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Factores de TiempoRESUMEN
Hepatic dysfunction following hematopoietic stem cell transplantation (HSCT) is common, but making the correct diagnosis can be challenging. Liver biopsies can serve as an important diagnostic tool when the etiology cannot be clearly determined by laboratory data, physical examination, and imaging studies. We reviewed 12 consecutive pediatric patients (seven males, five females, age 9-23 years) who received allogeneic HSCT and underwent a laparoscopic-guided liver biopsy for hepatic dysfunction of unknown etiology from 1998 to 2005. Biopsies were performed using a single-port technique with a 16 or 18 gauge, spring-loaded biopsy gun. The time from HSCT to biopsy ranged from 31 days to 821 days (median 92 days). No intra- or postoperative complications were observed. The initial clinical diagnosis was confirmed in seven patients, whereas the initial working diagnosis was inaccurate in the remaining five patients. Our results suggest that laparoscopic-guided liver biopsy is an informative and safe procedure in pediatric HSCT recipients; this approach helped delineate the true cause of hepatic dysfunction and changed our therapeutic approach in approximately 40% of the patients reviewed. While the safety record at our institution appears promising, a larger multi-institutional study would be necessary to more accurately describe the overall efficacy of this procedure in pediatric HSCT patients.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Laparoscopía/métodos , Hepatopatías/diagnóstico , Adolescente , Adulto , Biopsia , Niño , Femenino , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/terapia , Humanos , Hígado/patología , Hígado/fisiopatología , Hepatopatías/etiología , Hepatopatías/patología , Masculino , Estudios Retrospectivos , Trasplante Homólogo , Resultado del TratamientoRESUMEN
Severe congenital neutropenia (SCN) is a hematologic condition characterized by arrested maturation of myelopoiesis at the promyelocyte stage of development. With appropriate treatment using recombinant human granulocyte-colony-stimulating factor (r-HuG-CSF), SCN patients are now surviving longer, but are at increased risk of developing myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML). Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but transplantation outcomes after malignant transformation are not well established. We report results for six patients with SCN who underwent HSCT for MDS or AML between 1997 and 2001 at two transplant centers. Two patients transplanted for MDS survived. Both of these patients were transplanted without being given induction chemotherapy. Four patients, who all received induction chemotherapy for AML prior to HSCT, died. Administering induction chemotherapy prior to HSCT resulted in significant morbidity. Rapid transplantation should be the goal for the SCN patient once the diagnosis of MDS/AML is established. SCN patients should be monitored carefully for progression to MDS in order to be treated with HSCT as soon as they have progressed and before developing AML. For SCN patients who progress to AML, HSCT should still be considered, even though the risks appear to be greater.
Asunto(s)
Transformación Celular Neoplásica , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide/terapia , Neutropenia/complicaciones , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Examen de la Médula Ósea , Niño , Preescolar , Progresión de la Enfermedad , Femenino , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Lactante , Cariotipificación , Leucemia Mieloide/etiología , Masculino , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/terapia , Neutropenia/congénito , Neutropenia/terapia , Estudios Retrospectivos , Tasa de Supervivencia , Acondicionamiento Pretrasplante , Resultado del TratamientoRESUMEN
Allogeneic hematopoietic stem cell transplantation (SCT) is an important therapeutic option for a number of malignant and nonmalignant conditions but the broader application of this treatment strategy is limited by several side effects. In particular, diffuse lung injury is a major complication of SCT that responds poorly to standard therapeutic approaches and significantly contributes to transplant-related morbidity and mortality. Historically, approximately 50% of all pneumonias seen after SCT have been secondary to infection, but the judicious use of broad-spectrum antimicrobial prophylaxis in recent years has tipped the balance of pulmonary complications from infectious to noninfectious causes. This mini review will discuss the definition, risk factors and pathogeneses of noninfectious lung injury that occurs early after allogeneic SCT.
Asunto(s)
Enfermedad Injerto contra Huésped/patología , Pulmón/patología , Trasplante de Células Madre/efectos adversos , Antibacterianos/uso terapéutico , Humanos , Lesión Pulmonar , Neumonía/etiología , Trasplante de Células Madre/mortalidad , Trasplante HomólogoRESUMEN
Acute graft-versus-host disease (GVHD) and leukemic relapse remain the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT). Recent studies have demonstrated that the loss of gastrointestinal tract integrity, and specifically the translocation of LPS into the systemic circulation, is critical to the induction of cytokine dysregulation that contributes to GVHD. Using a mouse BMT model, we studied the effects of direct LPS antagonism on GVHD severity and graft-versus-leukemia (GVL) activity. Administration of B975, a synthetic lipid-A analogue from day 0 to day +6, reduced serum TNF-alpha levels, decreased intestinal histopathology, and resulted in significantly improved survival and a reduction in clinical GVHD, compared with control-treated animals. Importantly, B975 had no effect on donor T cell responses to host antigens in vivo or in vitro. When mice received lethal doses of P815 tumor cells at the time of BMT, administration of B975 did not impair GVL activity and resulted in significantly improved leukemia-free survival. These findings reveal a critical role for LPS in the early inflammatory events contributing to GVHD and suggest that a new class of pharmacologic agents, LPS antagonists, may help to prevent GVHD while preserving T cell responses to host antigens and GVL activity.
Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Leucemia/efectos de los fármacos , Lípido A/farmacología , Lipopolisacáridos/antagonistas & inhibidores , Animales , Pruebas Inmunológicas de Citotoxicidad , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Intestinos/patología , Leucemia Experimental/prevención & control , Lípido A/análogos & derivados , Lípido A/uso terapéutico , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Tasa de Supervivencia , Trasplante Homólogo , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Idiopathic pneumonia syndrome (IPS) is a major complication of allogeneic bone marrow transplantation (BMT). We have shown that experimental IPS is associated with increased levels of LPS and TNF-alpha in the bronchoalveolar lavage (BAL) fluid. We hypothesized that the deleterious effects of these inflammatory mediators in the lung may be linked to gut injury that develops after BMT. To test this hypothesis, we used mouse strains that differ in their sensitivity to LPS as donors in an experimental BMT model. Lethally irradiated C3FeB6F(1) hosts received BMT from either LPS-sensitive or LPS-resistant donors. Five weeks after BMT, LPS-resistant BMT recipients had significantly less lung injury compared with recipients of LPS-sensitive BMT. This effect was associated with reductions in TNF-alpha secretion (both in vitro and in vivo), BAL fluid LPS levels, and intestinal injury. The relationship between TNF-alpha, gut toxicity, and lung injury was examined further by direct cytokine blockade in vivo; systemic neutralization of TNF-alpha resulted in a significant reduction in gut histopathology, BAL fluid LPS levels, and pulmonary dysfunction compared with control-treated animals. We conclude that donor resistance to endotoxin reduces IPS in this model by decreasing the translocation of LPS across the intestinal border and systemic and pulmonary TNF-alpha production. These data demonstrate a potential etiologic link between gut and lung damage after BMT and suggest that methods that reduce inflammatory responses to LPS, and specifically, those that protect the integrity of the gut mucosa, may be effective in reducing IPS after BMT.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Trasplante de Médula Ósea/patología , Tolerancia Inmunológica , Mucosa Intestinal/patología , Lipopolisacáridos/inmunología , Pulmón/patología , Neumonía/inmunología , Neumonía/prevención & control , Animales , Antígenos CD/administración & dosificación , Trasplante de Médula Ósea/efectos adversos , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Movimiento Celular/inmunología , Células Cultivadas , Regulación hacia Abajo/inmunología , Resistencia a Medicamentos , Femenino , Humanos , Inmunidad Innata , Fragmentos Fc de Inmunoglobulinas/administración & dosificación , Mucosa Intestinal/inmunología , Isoantígenos/inmunología , Lipopolisacáridos/antagonistas & inhibidores , Lipopolisacáridos/toxicidad , Pulmón/inmunología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Neumonía/patología , Receptores del Factor de Necrosis Tumoral/administración & dosificación , Receptores Tipo II del Factor de Necrosis Tumoral , Síndrome , Linfocitos T/inmunología , Linfocitos T/patología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
BACKGROUND: Idiopathic pneumonia syndrome (IPS) is a frequent and potentially fatal complication of bone marrow transplantation (BMT). We have previously shown that experimental IPS is associated with increased levels of lipopolysaccaride (LPS) and tumor necrosis factor-alpha (TNFalpha) in the bronchoalveolar lavage (BAL) fluid, and that administration of LPS to animals with extensive graft versus host exacerbated underlying lung injury (Blood 1996; 88: 3230). METHODS: Lethally irradiated CBA mice received BMT from allogeneic (B10.BR) or syngeneic (CBA) donors. The role of TNFalpha in the exacerbation of pulmonary toxicity caused by LPS injection and in the evolution of IPS after allogeneic BMT was examined by neutralizing TNFalpha after BMT using a soluble binding protein (rhTNFR:Fc). RESULTS: Five weeks after BMT, administration of rhTNFR:Fc dramatically reduced mortality and prevented the exacerbation of lung injury caused by LPS administration. This protective effect was associated with preservation of pulmonary function and with marked reductions of cells, neutrophils, and LPS in the BAL fluid of treated animals. TNFalpha neutralization from week 4 to 6 after allogeneic BMT effectively halted the progression of systemic GVHD and significantly reduced, but did not prevent lung injury that developed during the treatment period. CONCLUSIONS: We conclude that TNFalpha is central to early LPS induced toxicity in this model and is a significant, but not the exclusive contributor to the development of IPS after allogeneic BMT.
Asunto(s)
Trasplante de Médula Ósea , Síndrome de Dificultad Respiratoria/etiología , Síndrome de Dificultad Respiratoria/prevención & control , Factor de Necrosis Tumoral alfa/farmacología , Animales , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/inmunología , Femenino , Rechazo de Injerto , Enfermedad Injerto contra Huésped/prevención & control , Lipopolisacáridos , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/etiología , Ratones , Ratones Endogámicos CBA , Pruebas de Neutralización , Proteínas Recombinantes/uso terapéutico , Trasplante Homólogo/efectos adversos , Factor de Necrosis Tumoral alfa/uso terapéuticoRESUMEN
TNF-alpha is known to be an important mediator of tissue damage during allograft rejection and graft-vs-host disease (GVHD), but its role in supporting T cell responses to allogeneic Ags is unclear. We have studied this question by comparing normal mice with those lacking the p55 (p55 TNFR-/-) or p75 (p75 TNFR-/-) TNF-alpha receptors as donors in well-defined bone marrow transplant (BMT) models. Recipients of p55 TNFR-/- cells had significantly reduced mortality and morbidity from GVHD compared with the other two sources of T cells. In vitro, T cells lacking the p55 (but not the p75) TNF-alpha receptor exhibited decreased proliferation and production of Th1 cytokines in MLC. This defect was only partially restored by exogenous IL-2 and affected both CD4+ and CD8+ populations. CD8+ p55 TNFR-/- proliferation was impaired independently of IL-2 whereas CTL effector function was impaired in an IL-2-dependent fashion. Inhibition of TNF-alpha with TNFR:Fc in primary MLC also impaired the proliferation and Th1 differentiation of wild-type T cells. BMT mixing experiments demonstrated that the reduced ability of p55 TNFR-/- donor cells to induce GVHD was due to the absence of the p55 TNFR on T cells rather than bone marrow cells. These data highlight the importance of TNF-alpha in alloreactive T cell responses and suggest that inhibition of the T cell p55 TNF-alpha receptor may provide an additional useful therapeutic maneuver to inhibit alloreactive T cell responses following bone marrow and solid organ transplantation.
Asunto(s)
Antígenos CD/fisiología , Isoantígenos/inmunología , Activación de Linfocitos , Receptores del Factor de Necrosis Tumoral/fisiología , Linfocitos T/inmunología , Adyuvantes Inmunológicos/fisiología , Animales , Antígenos CD/genética , Antígenos CD/metabolismo , Células de la Médula Ósea/inmunología , Trasplante de Médula Ósea/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Femenino , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Activación de Linfocitos/genética , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Subgrupos de Linfocitos T/trasplante , Linfocitos T/metabolismo , Células TH1/citología , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
We demonstrate an increase in graft-versus-host disease (GVHD) after experimental bone marrow transplant (BMT) when cyclophosphamide (Cy) is added to an otherwise well-tolerated dose (900 cGy) of total body irradiation (TBI). Donor T cell expansion on day +13 was increased after conditioning with Cy/TBI compared with Cy or TBI alone, although cytotoxic T lymphocyte (CTL) function was not altered. Histological analysis of the gastrointestinal tract demonstrated synergistic damage by Cy/TBI and allogeneic donor cells, which permitted increased translocation of LPS into the systemic circulation. TNF-alpha and IL-1 production in response to LPS was increased in BMT recipients after Cy/TBI conditioning. Neutralization of IL-1 significantly reduced serum LPS levels and GVHD mortality, but it did not affect donor CTL activity. By contrast, neutralization of TNF-alpha did not prevent GVHD mortality but did impair CTL activity after BMT. When P815 leukemia cells were added to the bone marrow inoculum, allogeneic BMT recipients given the TNF-alpha inhibitor relapsed at a significantly faster rate than those given the IL-1 inhibitor. To confirm that the role of TNF-alpha in graft versus leukemia (GVL) was due to effects on donor T cells, cohorts of animals were transplanted with T cells from either wild-type mice or p55 TNF-alpha receptor-deficient mice. Recipients of TNF-alpha p55 receptor-deficient T cells demonstrated a significant impairment in donor CTL activity after BMT and an increased rate of leukemic relapse compared with recipients of wild-type T cells. These data highlight the importance of conditioning in GVHD pathophysiology, and demonstrate that TNF-alpha is critical to GVL mediated by donor T cells, whereas IL-1 is not.
Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Interleucina-1/inmunología , Factor de Necrosis Tumoral alfa/inmunología , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Trasplante de Médula Ósea/efectos adversos , Trasplante de Médula Ósea/inmunología , Ciclofosfamida/farmacología , Sistema Digestivo/lesiones , Femenino , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Reacción Injerto-Huésped/efectos de los fármacos , Reacción Injerto-Huésped/inmunología , Interleucina-1/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral , Linfocitos T Citotóxicos/inmunología , Acondicionamiento Pretrasplante , Trasplante Homólogo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Irradiación Corporal TotalRESUMEN
We recently showed that IL-11 prevents lethal graft-versus-host disease (GVHD) in a murine bone marrow transplantation (BMT) model of GVHD directed against MHC and minor antigens. In this study, we have investigated whether IL-11 can maintain a graft-versus-leukemia (GVL) effect. Lethally irradiated B6D2F1 mice were transplanted with either T cell-depleted (TCD) bone marrow (BM) alone or with BM and splenic T cells from allogeneic B6 donors. Animals also received host-type P815 mastocytoma cells at the time of BMT. Recipients were injected subcutaneously with recombinant human IL-11 or control diluent twice daily, from 2 days before BMT to 7 days after BMT. TCD recipients all died from leukemia by day 23. All control- and IL-11-treated allogeneic animals effectively rejected their leukemia, but IL-11 also reduced GVHD-related mortality. Examination of the cellular mechanisms of GVL and GVHD in this system showed that IL-11 selectively inhibited CD4-mediated GVHD, while retaining both CD4- and CD8-mediated GVL. In addition, IL-11 treatment did not affect cytolytic effector functions of T cells after BMT either in vivo or in vitro. Studies with perforin-deficient donor T cells demonstrated that the GVL effect was perforin dependent. These data demonstrated that IL-11 can significantly reduce CD4-dependent GVHD without impairing cytolytic function or subsequent GVL activity of CD8(+) T cells. Brief treatment with IL-11 shortly after BMT may therefore represent a novel strategy for separating GVHD and GVL.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Enfermedad Injerto contra Huésped/inmunología , Efecto Injerto vs Tumor/inmunología , Interleucina-11/fisiología , Animales , Trasplante de Médula Ósea/efectos adversos , Antígenos CD4/fisiología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Citotoxicidad Inmunológica/efectos de los fármacos , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/terapia , Humanos , Inmunosupresores/uso terapéutico , Interleucina-11/uso terapéutico , Leucemia Experimental/inmunología , Leucemia Experimental/terapia , Glicoproteínas de Membrana/fisiología , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Perforina , Proteínas Citotóxicas Formadoras de Poros , Sarcoma Experimental/inmunología , Sarcoma Experimental/terapia , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Células Tumorales Cultivadas , Receptor fas/fisiologíaRESUMEN
The major obstacles to successful outcome after allogeneic bone marrow transplantation (BMT) for leukemia remain graft-versus-host disease (GVHD) and leukemic relapse. Improved survival after BMT therefore requires more effective GVHD prophylaxis that does not impair graft-versus-leukemia (GVL) effects. We studied the administration of human recombinant keratinocyte growth factor (KGF) in a well- characterized murine BMT model for its effects on GVHD. KGF administration from day -3 to +7 significantly reduced GVHD mortality and the severity of GVHD in the gastrointestinal (GI) tract, reducing serum lipopolysaccharide (LPS) and tumor necrosis factor (TNF)alpha levels, but preserving donor T-cell responses (cytotoxic T lymphocyte [CTL] activity, proliferation, and interleukin [IL]-2 production) to host antigens. When mice received lethal doses of P815 leukemia cells at the time of BMT, KGF treatment significantly decreased acute GVHD compared with control-treated allogeneic mice and resulted in a significantly improved leukemia-free survival (42% v 4%, P <.001). KGF administration thus offers a novel approach to the separation of GVL effects from GVHD.
Asunto(s)
Factores de Crecimiento de Fibroblastos , Enfermedad Injerto contra Huésped/prevención & control , Efecto Injerto vs Tumor/efectos de los fármacos , Sustancias de Crecimiento/uso terapéutico , Animales , Trasplante de Médula Ósea/efectos adversos , Evaluación Preclínica de Medicamentos , Ensayo de Inmunoadsorción Enzimática , Células Epiteliales/efectos de los fármacos , Células Epiteliales/efectos de la radiación , Femenino , Factor 10 de Crecimiento de Fibroblastos , Factor 7 de Crecimiento de Fibroblastos , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Sustancias de Crecimiento/farmacología , Humanos , Interleucina-2/biosíntesis , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/efectos de la radiación , Leucemia Experimental/terapia , Lipopolisacáridos/sangre , Ratones , Ratones Endogámicos C57BL , Quimera por Radiación , Traumatismos Experimentales por Radiación/tratamiento farmacológico , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico , Linfocitos T Citotóxicos/inmunología , Trasplante Homólogo/efectos adversos , Factor de Necrosis Tumoral alfa/análisisRESUMEN
BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is known to be a critical effector molecule in the pathogenesis of graft-versus-host disease (GVHD), and elevated levels during bone marrow transplantation (BMT) conditioning are associated with more severe GVHD. Many patients receive chemotherapy prior to BMT, but its effect on subsequent toxicities is controversial. METHODS: We studied the effect of prior chemotherapy on GVHD severity and inflammatory cytokine generation in a well-established murine model of allogeneic BMT (B6-->B6D2F1). RESULTS: Three weeks after a single dose of cyclophosphamide, bone marrow and splenic cellularity was reduced by 50% and the production of TNF-alpha to LPS stimulation by macrophages was also markedly impaired (both before and after total body irradiation). Allogeneic BMT recipients previously treated with cyclophosphamide had significantly less GVHD and improved survival relative to recipients previously pretreated with diluent only. This survival advantage was associated with reduced systemic levels of both TNF-alpha and interleukin-1beta 7 days after BMT. This reduction occurred despite equivalent serum levels of lipopolysaccharide, consistent with the reductions in TNF-alpha and interleukin-1beta production by host macrophages after cyclophosphamide pretreatment. CONCLUSIONS: These data support the notion that patients entering BMT conditioning without prior cytotoxic treatment (e.g., patients with chronic myeloid leukemia) may be at increased risk of posttransplant complications associated with excessive inflammatory cytokine production.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Citocinas/biosíntesis , Enfermedad Injerto contra Huésped/prevención & control , Acondicionamiento Pretrasplante , Enfermedad Aguda , Animales , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/etiología , Humanos , Interleucina-1/sangre , Ratones , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Minimization of graft-versus-host disease (GVHD) with preservation of the graft-versus-leukemia (GVL) effect is a crucial step to improve the overall survival of allogeneic bone marrow transplantation (BMT) for patients with hematological malignancies. We and other investigators have shown that granulocyte colony-stimulating factor (G-CSF)-mobilized allogeneic peripheral stem cell transplantation (PBSCT) reduces the severity of acute GVHD in murine models. In this study, we investigated whether G-CSF-mobilized PBSC maintain their GVL effect in a murine allogeneic transplant model (B6 --> B6D2F1). B6 mice (H-2(b)) were injected subcutaneously with human G-CSF (100 micrograms/kg/d) for 6 days and their splenocytes were harvested on day 7 as a source of PBSC. G-CSF mobilization dramatically improved transplant survival compared with nonmobilized controls (95% v 0%, P <.001). Systemic levels of lipopolysaccharide and tumor necrosis factor-alpha were markedly reduced in recipients of allogeneic G-CSF-mobilized donors, but cytolytic T lymphocyte (CTL) activity against host tumor target cells p815 was retained in those recipients. When leukemia was induced in recipients by coinjection of p815 tumor cells (H-2(d)) at the time of transplantation, all surviving recipients of G-CSF-mobilized B6 donors were leukemia-free at day 70 after transplant, whereas all mice who received T-cell-depleted (TCD) splenocytes from G-CSF-mobilized B6 donors died of leukemia. When splenocytes from G-CSF-mobilized perforin-deficient (pfp-/-) mice were used for transplantation, 90% of recipients died of leukemia, demonstrating that perforin is a crucial pathway mediating GVL effects after G-CSF-mobilized PBSCT. These data illustrate that G-CSF-mobilized allogeneic PBSCT separate GVL from GVHD by preserving perforin-dependent donor CTL activity while reducing systemic inflammation.
Asunto(s)
Efecto Injerto vs Tumor , Factor Estimulante de Colonias de Granulocitos/farmacología , Trasplante de Células Madre Hematopoyéticas , Animales , Citocinas/sangre , Femenino , Enfermedad Injerto contra Huésped/prevención & control , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Inmunoterapia , Leucemia Experimental/inmunología , Leucemia Experimental/terapia , Lipopolisacáridos/sangre , Glicoproteínas de Membrana/fisiología , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Perforina , Proteínas Citotóxicas Formadoras de Poros , Proteínas Recombinantes , Bazo/citología , Linfocitos T Citotóxicos/inmunología , Trasplante Homólogo , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Donor T cell responses to host alloantigen are known predictors for graft-versus-host disease (GVHD); however, the effect of donor responsiveness to an inflammatory stimulus such as lipopolysaccharide (LPS) on GVHD severity has not been investigated. To examine this, we used mouse strains that differ in their sensitivity to LPS as donors in an experimental bone marrow transplant (BMT) system. Lethally irradiated (C3FeB6)F1 hosts received BMT from either LPS-sensitive (LPS-s) C3Heb/Fej, or LPS-resistant (LPS-r) C3H/ Hej donors. Mice receiving LPS-r BMT developed significantly less GVHD as measured by mortality and clinical score compared with recipients of LPS-s BMT, a finding that was associated with significant decreases in intestinal histopathology and serum LPS and TNF-alpha levels. When donor T cell responses to host antigens were measured, no differences in proliferation, serum IFN-gamma levels, splenic T cell expansion, or CTL activity were observed after LPS-r or LPS-s BMT. Systemic neutralization of TNF-alpha from day -2 to +6 resulted in decreased intestinal pathology, and serum LPS levels and increased survival after BMT compared with control mice receiving Ig. We conclude that donor resistance to endotoxin reduces the development of acute GVHD by attenuating early intestinal damage mediated by TNFalpha. These data suggest that the responsiveness of donor accessory cells to LPS may be an important risk factor for acute GVHD severity independent of T cell responses to host antigens.
Asunto(s)
Enfermedad Injerto contra Huésped/inmunología , Lipopolisacáridos/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Trasplante de Médula Ósea/inmunología , Citocinas/metabolismo , Sistema Digestivo/efectos de los fármacos , Sistema Digestivo/patología , Ensayo de Inmunoadsorción Enzimática , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Inmunofenotipificación , Lipopolisacáridos/sangre , Macrófagos/efectos de los fármacos , Macrófagos/fisiología , Ratones , Ratones Endogámicos C3H , Pronóstico , Bazo/metabolismo , Linfocitos T/efectos de los fármacos , Linfocitos T/fisiología , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
Noninfectious lung injury is common after allogeneic bone marrow transplantation (BMT), but its association with acute graft-versus-host disease (GVHD) is unclear. Using a murine BMT system where donor and host differ by multiple minor histocompatibility (H) antigens, we investigated the nature of lung injury and its relationship both to systemic GVHD and host-reactive donor T cells. Lethally irradiated CBA hosts received syngeneic BMT or allogeneic (B10.BR) T-cell-depleted (TCD) bone marrow (BM) with and without the addition of T cells. Six weeks after BMT, significant pulmonary histopathology was observed in animals receiving allogeneic BMT compared with syngeneic controls. Lung damage was greater in mice that received allogeneic T cells and developed GVHD, but it was also detectable after TCD BMT when signs of clinical and histologic acute GVHD were absent. In each setting, lung injury was associated with significant alterations in pulmonary function. Mature, donor (Vbeta6(+) and Vbeta3(+)) T cells were significantly increased in the broncho-alveolar lavage (BAL) fluid of all allogeneic BMT recipients compared with syngeneic controls, and these cells proliferated and produced interferon-gamma (IFN-gamma) to host antigens in vitro. These in vitro responses correlated with increased IFN-gamma and tumor necrosis factor-alpha (TNF-alpha) in the BAL fluid. We conclude that alloreactive donor lymphocytes are associated with lung injury in this allogeneic BMT model. The expansion of these cells in the BAL fluid and their ability to respond to host antigens even when systemic tolerance has been established (ie, the absence of clinical GVHD) suggest that the lung may serve as a sanctuary site for these host reactive donor T cells. These findings may have important implications with regard to the evaluation and treatment of pulmonary dysfunction after allogeneic BMT even when clinical GVHD is absent.
Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Enfermedades Pulmonares/etiología , Linfocitos T/inmunología , Trasplante Homólogo/efectos adversos , Animales , Líquido del Lavado Bronquioalveolar/química , Femenino , Histocompatibilidad , Interferón gamma/análisis , Pulmón/inmunología , Pulmón/patología , Rendimiento Pulmonar , Enfermedades Pulmonares/inmunología , Enfermedades Pulmonares/patología , Depleción Linfocítica , Ratones , Ratones Endogámicos CBA , Antígenos de Histocompatibilidad Menor/inmunología , Quimera por Radiación , Factor de Necrosis Tumoral alfa/análisisRESUMEN
Administration of IL-11 prevented lethal graft-versus-host disease (GVHD) in a murine bone marrow transplant (BMT) model (B6 --> B6D2F1) across MHC and minor H antigen barriers (survival at day 50: 90 vs 20%, P < 0.001). Surpisingly, IL-11 administration polarized the donor T cell cytokine responses to host antigen after BMT with a 50% reduction in IFNgamma and IL-2 secretion and a 10-fold increase in IL-4. This polarization of T cell responses was associated with reduced IFNgamma serum levels and decreased IL-12 production in mixed lymphocyte cultures (MLC). In addition, IL-11 prevented small bowel damage and reduced serum endotoxin levels by 80%. Treatment with IL-11 also reduced TNFalpha serum levels and suppressed TNFalpha secretion by macrophages to LPS stimulation in vitro. IL-11 thus decreased GVHD morbidity and mortality by three mechanisms: (a) polarization of donor T cells; (b) protection of the small bowel; and (c) suppression of inflammatory cytokines such as TNFalpha. We conclude that brief treatment with IL-11 may represent a novel strategy to prevent T cell-mediated inflammatory processes such as GVHD.
Asunto(s)
Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped/prevención & control , Interleucina-11/farmacología , Linfocitos T/efectos de los fármacos , Enfermedad Aguda , Animales , Polaridad Celular , Células Cultivadas , Femenino , Interferón gamma/sangre , Interleucina-12/biosíntesis , Intestino Delgado/efectos de los fármacos , Lipopolisacáridos/sangre , Ratones , Ratones Endogámicos C57BL , Trasplante Homólogo , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The influence of bone marrow transplantation (BMT) conditioning regimens on the incidence and severity of graft-versus-host disease (GVHD) has been suggested in clinical BMT. Using murine BMT models, we show here an increase in GVHD severity in several donor-recipient strain combinations after intensification of the conditioning regimen by increasing the total body irradiation (TBI) dose from 900 cGy to 1,300 cGy. Increased GVHD was mediated by systemic increases in tumor necrosis factor alpha (TNF alpha). Histologic analysis of gastrointestinal tracts showed synergistic damage by increased TBI and allogeneic donor cells that permitted increased translocation of lipopolysacharide (LPS) into the systemic circulation. In vitro, LPS triggered excess TNF alpha from macrophages primed by the GVH reaction. In addition, macrophages isolated within 4 hours of conditioning were primed in proportion to the TBI dose itself to secrete TNF alpha. Thus, the higher TBI dose increased macrophage priming and increased gut damage after allogeneic BMT, causing higher systemic levels of inflammatory cytokines and subsequent severe GVHD. These data highlight the importance of conditioning in GVHD pathophysiology and suggest that interventions to prevent LPS stimulation of primed macrophages may limit the severity of GVHD after intensive conditioning for allogeneic BMT.