RESUMEN
We performed a retrospective cohort study of 84 patients to determine the incidence and predictors of acute kidney injury after antibiotic-impregnated cement spacer (ACS) placement for infected total knee arthroplasties. Acute kidney injury was defined as a more than 50% rise in serum creatinine from a preoperative baseline to a level greater than 1.4 mg/dL within 90 days postoperatively. Total incidence was 17% (n = 14; 95% confidence interval [CI], 10%-26%), and acute kidney injury was significantly associated with ACS tobramycin dose as both a dichotomous variable (>4.8 g; odds ratio, 5.87; 95% CI, 1.43-24.19; P = .01) and linear variable (odds ratio, 1.24 for every 1-g increase; 95% CI, 1.00-1.52; P = .049). Routine monitoring of serum creatinine and measurement of serum aminoglycoside levels in response to a threshold creatinine rise may be warranted after the placement of an aminoglycoside-containing ACS.
Asunto(s)
Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/epidemiología , Antibacterianos/efectos adversos , Artroplastia de Reemplazo de Rodilla/instrumentación , Cementos para Huesos/efectos adversos , Prótesis de la Rodilla/efectos adversos , Infecciones Relacionadas con Prótesis/prevención & control , Lesión Renal Aguda/sangre , Anciano , Aminoglicósidos/efectos adversos , Aminoglicósidos/sangre , Aminoglicósidos/uso terapéutico , Antibacterianos/uso terapéutico , Artroplastia de Reemplazo de Rodilla/métodos , Estudios de Cohortes , Creatinina/sangre , Femenino , Humanos , Incidencia , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Infecciones Relacionadas con Prótesis/cirugía , Reoperación , Estudios Retrospectivos , Tobramicina/efectos adversos , Tobramicina/uso terapéuticoRESUMEN
Th17-driven immune responses contribute to the pathogenesis of many chronic inflammatory diseases. In this study, we investigated the role of IL-17 signaling in chronic gastric inflammation induced by Helicobacter pylori, a Gram-negative bacterium that persistently colonizes the human stomach. Wild-type C57BL/6 mice and mice lacking IL-17RA (IL-17RA(-/-)) were orogastrically infected with H. pylori. Differences in bacterial colonization density and gastric inflammation were not apparent at 1 mo postinfection, but by 3 mo postinfection, H. pylori colonization density was higher and mononuclear gastric inflammation more severe in infected IL-17RA(-/-) mice than in infected wild-type mice. A striking feature was a marked increase in gastric B cells, plasma cells, and lymphoid follicles, along with enhanced H. pylori-specific serum Ab responses, in infected IL-17RA(-/-) mice. Fewer gastric neutrophils and lower levels of neutrophil-recruiting chemokines were detected in infected IL-17RA(-/-) mice than in infected wild-type mice. Gastric IL-17a and IL-21 transcript levels were significantly higher in infected IL-17RA(-/-) mice than in infected wild-type mice or uninfected mice, which suggested that a negative feedback loop was impaired in the IL-17RA(-/-) mice. These results underscore an important role of IL-17RA signaling in regulating B cell recruitment. In contrast to many chronic inflammatory diseases in which IL-17RA signaling promotes an inflammatory response, IL-17RA signaling down-regulates the chronic mononuclear inflammation elicited by H. pylori infection.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Inhibición de Migración Celular/inmunología , Movimiento Celular/inmunología , Mucosa Gástrica/inmunología , Infecciones por Helicobacter/inmunología , Helicobacter pylori/inmunología , Receptores de Interleucina-17/fisiología , Transducción de Señal/inmunología , Animales , Subgrupos de Linfocitos B/metabolismo , Subgrupos de Linfocitos B/patología , Inhibición de Migración Celular/genética , Movimiento Celular/genética , Enfermedad Crónica , Modelos Animales de Enfermedad , Femenino , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Infecciones por Helicobacter/patología , Infecciones por Helicobacter/prevención & control , Helicobacter pylori/crecimiento & desarrollo , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/fisiología , Interleucina-17/biosíntesis , Interleucina-17/metabolismo , Interleucina-17/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Técnicas de Cultivo de Órganos , Receptores de Interleucina-17/deficiencia , Receptores de Interleucina-17/genética , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Information is limited on long-term outcomes after preemptive use of ganciclovir to control cytomegalovirus (CMV) infection in lung transplantation. METHODS: We studied 78 lung recipients who received antithymocyte globulin induction from 1994 to 2000. All patients received six months of oral acyclovir (800 mg TID). This was interrupted three wk post transplantation for a two-wk course of IV ganciclovir. Additional courses of ganciclovir were administered based on serial virological monitoring. CMV-mismatched patients (R-D+) also received four doses of CMV immunoglobulin between weeks 2 and 8. RESULTS: The one yr cumulative risk of CMV disease was 2% (1/61) in CMV seropositive (R+) patients, but was 37% (6/17) in R-D+ patients (p < 0.0001). Over 4.3 yr of follow-up, patients with CMV infection developed more chronic graft dysfunction caused by bronchiolitis obliterans or bronchiolitis obliterans syndrome than patients without CMV infection (p = 0.012). This effect was also apparent in the subgroup of R+ recipients (p = 0.043). Acute rejection and overall survival were not associated with CMV infection. CONCLUSIONS: The use of prophylactic acyclovir and short preemptive courses of ganciclovir effectively controlled CMV disease in R+ patients, but was a relative failure in R-D+ patients. CMV infection was significantly associated with chronic graft dysfunction, even in R+ recipients who had good control of CMV symptoms.
Asunto(s)
Antivirales/administración & dosificación , Infecciones por Citomegalovirus/prevención & control , Ganciclovir/administración & dosificación , Trasplante de Corazón-Pulmón , Aciclovir/administración & dosificación , Adolescente , Adulto , Anciano , Quimioprevención , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/transmisión , Funcionamiento Retardado del Injerto/virología , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Donantes de Tejidos , Adulto JovenRESUMEN
Recent evidence suggests that dysfunctional type II alveolar epithelial cells (AECs) contribute to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Based on the hypothesis that disease-causing mutations in surfactant protein C (SFTPC) provide an important paradigm for studying IPF, we investigated a potential mechanism of AEC dysfunction suggested to result from mutant SFTPC expression: induction of endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). We evaluated biopsies from 23 IPF patients (including 3 family members with L188Q SFTPC mutations, 10 individuals with familial interstitial pneumonia without SFTPC mutations, and 10 individuals with sporadic IPF) and sections from 10 control lungs. After demonstrating UPR activation in cultured A549 cells expressing mutant SFTPC, we identified prominent expression of UPR markers in AECs in the lungs of patients with SFTPC mutation-associated fibrosis. In individuals with familial interstitial pneumonia without SFTPC mutations and patients with sporadic IPF, we also found UPR activation selectively in AECs lining areas of fibrotic remodeling. Because herpesviruses are found frequently in IPF lungs and can induce ER stress, we investigated expression of viral proteins in lung biopsies. Herpesvirus protein expression was found in AECs from 15/23 IPF patients and colocalized with UPR markers in AECs from these patients. ER stress and UPR activation are found in the alveolar epithelium in patients with IPF and could contribute to disease progression. Activation of these pathways may result from altered surfactant protein processing or chronic herpesvirus infection.
Asunto(s)
Retículo Endoplásmico/fisiología , Infecciones por Herpesviridae/fisiopatología , Alveolos Pulmonares/ultraestructura , Fibrosis Pulmonar/fisiopatología , Proteína C Asociada a Surfactante Pulmonar/fisiología , Estrés Fisiológico/fisiopatología , Antígenos Virales/biosíntesis , Células Cultivadas , Proteínas de Unión al ADN/biosíntesis , Chaperón BiP del Retículo Endoplásmico , Glicoproteínas/biosíntesis , Proteínas de Choque Térmico/biosíntesis , Infecciones por Herpesviridae/complicaciones , Humanos , Inmunohistoquímica , Chaperonas Moleculares/biosíntesis , Proteínas Nucleares/biosíntesis , Pliegue de Proteína , Fibrosis Pulmonar/complicaciones , Proteína C Asociada a Surfactante Pulmonar/genética , Factores de Transcripción del Factor Regulador X , Factores de Transcripción , alfa-Manosidasa/biosíntesisRESUMEN
Pharmacologic antagonism of CCR5, a chemokine receptor expressed on macrophages and activated T cells, is an effective antiviral therapy in patients with macrophage-tropic HIV infection, but its efficacy in modulating inflammation and immunity is only just beginning to be investigated. In this regard, the recruitment of CCR5-bearing cells into clinical allografts is a hallmark of acute rejection and may anticipate chronic rejection, whereas conventionally immunosuppressed renal transplant patients homozygous for a nonfunctional Delta32 CCR5 receptor rarely exhibit late graft loss. Therefore, we explored the effects of a potent, highly selective CCR5 antagonist, Merck's compound 167 (CMPD 167), in an established cynomolgus monkey cardiac allograft model. Although perioperative stress responses (fever, diminished activity) and the recruitment of CCR5-bearing leukocytes into the graft were markedly attenuated, anti-CCR5 monotherapy only marginally prolonged allograft survival. In contrast, relative to cyclosporine A monotherapy, CMPD 167 with cyclosporine A delayed alloantibody production, suppressed cardiac allograft vasculopathy, and tended to further prolong graft survival. CCR5 therefore represents an attractive therapeutic target for attenuating postsurgical stress responses and favorably modulating pathogenic alloimmunity in primates, including man.
Asunto(s)
Antagonistas de los Receptores CCR5 , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Corazón/inmunología , Macrófagos/inmunología , Pirazoles/administración & dosificación , Linfocitos T/inmunología , Tolerancia al Trasplante/efectos de los fármacos , Valina/análogos & derivados , Animales , Formación de Anticuerpos/efectos de los fármacos , Formación de Anticuerpos/inmunología , Autoinmunidad/efectos de los fármacos , Autoinmunidad/inmunología , Ciclosporina/administración & dosificación , Modelos Animales de Enfermedad , Supervivencia de Injerto/inmunología , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Trasplante de Corazón/patología , Humanos , Inmunosupresores/administración & dosificación , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Isoanticuerpos/inmunología , Trasplante de Riñón/inmunología , Macaca fascicularis , Macrófagos/patología , Masculino , Estrés Fisiológico/tratamiento farmacológico , Estrés Fisiológico/inmunología , Estrés Fisiológico/patología , Linfocitos T/patología , Tolerancia al Trasplante/inmunología , Trasplante Homólogo , Valina/administración & dosificación , Enfermedades Vasculares/tratamiento farmacológico , Enfermedades Vasculares/inmunología , Enfermedades Vasculares/patologíaRESUMEN
Thymoglobulin (Genzyme, Cambridge, MA) is an antithymocyte globulin preparation used for induction immunosuppression therapy in solid organ transplantation. It is being utilized with increasing frequency in orthotopic liver transplantation (OLT) in an effort to minimize or delay the use of calcineurin inhibitors due to their inherent nephrotoxicity. Experience with thymoglobulin in OLT remains limited. We report a case of serum sickness in a patient who received thymoglobulin following OLT. The patient experienced intermittent fevers, polyarthralgia, and acute renal failure 9 days after completion of thymoglobulin administration. The patient's symptoms resolved rapidly and completely with a course of intravenous steroids. We review a set of diagnostic criteria for serum sickness and emphasize the importance of early recognition of the process. Early treatment of serum sickness with steroids or plasmapheresis is highly effective and can reduce unnecessary morbidity from this unusual sequela of induction immunosuppression with antithymocyte globulin.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Trasplante de Hígado , Enfermedad del Suero/etiología , Lesión Renal Aguda/etiología , Animales , Anticuerpos Monoclonales/uso terapéutico , Suero Antilinfocítico , Femenino , Glucocorticoides/administración & dosificación , Glucocorticoides/uso terapéutico , Humanos , Inyecciones Intravenosas , Metilprednisolona/administración & dosificación , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Conejos , Resultado del TratamientoRESUMEN
Cytomegalovirus encephalitis occurs rarely in transplant recipients. We describe a patient with cytomegalovirus ventriculoencephalitis who had a very high CSF viral load but a low peripheral blood viral load. No resistance mutations were present in cerebrospinal fluid viral DNA, whereas DNA from blood showed a resistance mutation in the UL54 gene but not in the UL97 gene. Viral replication was intense in the brain ependyma and periventricular areas without evidence of peripheral cytomegalovirus disease. The data provide evidence for compartmentalization of cytomegalovirus infection. Levels of ganciclovir and foscarnet in the cerebrospinal fluid may be inadequate for treatment, even for some drug-susceptible strains, and, together with periventricular replication, may explain the disparity between cerebrospinal fluid viral load and peripheral blood viral load.
Asunto(s)
Infecciones por Citomegalovirus/virología , Citomegalovirus/genética , ADN Viral/sangre , ADN Viral/líquido cefalorraquídeo , Encefalitis Viral/virología , Huésped Inmunocomprometido/inmunología , Trasplante de Células Madre de Sangre Periférica , Enfermedad Aguda , Antivirales/uso terapéutico , Encéfalo/virología , Citomegalovirus/aislamiento & purificación , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/líquido cefalorraquídeo , Infecciones por Citomegalovirus/tratamiento farmacológico , ADN Polimerasa Dirigida por ADN/genética , Farmacorresistencia Viral/genética , Encefalitis Viral/sangre , Encefalitis Viral/líquido cefalorraquídeo , Encefalitis Viral/tratamiento farmacológico , Humanos , Inmunosupresores/uso terapéutico , Leucemia Mieloide/inmunología , Leucemia Mieloide/terapia , Masculino , Persona de Mediana Edad , Mutación , Carga Viral , Proteínas Virales/genéticaRESUMEN
BACKGROUND: CD154 mediates key facets of humoral and cellular immunity to alloantigens, and is tolerogenic to influenza antigens in primates. Barriers to CD154-based tolerance induction for primate cardiac allografts have not previously been defined. METHODS: Heterotopic cardiac allograft outcomes in cynomolgus monkeys treated with a CD154 inhibitor, IDEC-131 (n=27), were compared to no treatment (n=4) or cyclosporine A (n=6). RESULTS: CD154 blockade significantly prolonged median allograft survival, from 6.2 (range 6, 7, n=4) days in untreated controls, to 39 (8,112, n=16) days with intensive monotherapy and 93 (>25, 386; n=3) days with added antithymocyte globulin (ATG), but did not yield tolerance. Alloantibody production was delayed but not prevented by IDEC-131 alone or with ATG, and was exacerbated by infusion of donor bone marrow (n=8). Expression of ICOS was prominent in graft infiltrating lymphocytes, and preceded elaboration of antidonor antibody and vasculopathy. CONCLUSION: CD154 monotherapy modulates primate cardiac alloimmunity, but does not readily induce tolerance. Targeting alternative costimulation pathways, including ICOS, may facilitate tolerance induction based on CD154 blockade.
Asunto(s)
Ligando de CD40/inmunología , Trasplante de Corazón/inmunología , Animales , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Antígenos de Diferenciación de Linfocitos T/genética , Suero Antilinfocítico/administración & dosificación , Trasplante de Médula Ósea , Ciclosporina/farmacología , Femenino , Expresión Génica , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/inmunología , Trasplante de Corazón/patología , Inmunosupresores/farmacología , Proteína Coestimuladora de Linfocitos T Inducibles , Isoanticuerpos/biosíntesis , Macaca fascicularis , Masculino , Linfocitos T/inmunología , Donantes de Tejidos , Trasplante HomólogoRESUMEN
BACKGROUND: Members of the Src family of tyrosine kinases (SFKs) are requisite signaling molecules activated by multiple receptors during immune responses. Their expression and catalytic activity has not been characterized in allograft rejection in vivo. METHODS: We measured expression and catalytic activity of SFKs in MHC- mismatched murine cardiac allografts. We also examined the effects of a Src inhibitor (CGP77675) with or without anti-CD154 mAb on graft survival, histology, and expression and catalytic activity of SFKs within the grafts. RESULTS: In acutely rejecting allografts from untreated controls, total activity of Hck and Lyn increased 10-fold, predominantly reflecting increases in the amount of protein. Total activity of Lck increased only fourfold, reflecting small changes in both the amount of protein and specific activity. One dose of anti-CD154 plus CGP77675 markedly diminished cellular infiltration, but survival was only moderately prolonged despite inhibition of all SFKs in the rejected grafts. Two doses of anti-CD154 plus CGP77675 allowed permanent graft acceptance in 60% of recipients even after discontinuation of the inhibitor. Both rejected and long surviving grafts showed increased activity of all SFKs. Recipients that rejected their grafts showed serum alloantibody production, and grafts rejected during treatment demonstrated deposition of complement indicating the contribution of antibody to rejection. CONCLUSIONS: The myeloid and B cell Src family kinases, Hck and Lyn, rather than the T cell Src kinase Lck, show the greatest increase in expression and total activity in rejecting allografts. Both rejected and long-surviving grafts show significant increases in SFK expression and acitivity.
Asunto(s)
Ligando de CD40/efectos de los fármacos , Rechazo de Injerto/enzimología , Rechazo de Injerto/prevención & control , Supervivencia de Injerto , Trasplante de Corazón , Familia-src Quinasas/antagonistas & inhibidores , Animales , Anticuerpos/farmacología , Ligando de CD40/inmunología , Linfocitos T CD8-positivos/inmunología , Rechazo de Injerto/inmunología , Supervivencia de Injerto/efectos de los fármacos , Supervivencia de Injerto/inmunología , Corazón/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/farmacología , Pirroles/farmacología , Trasplante HomólogoRESUMEN
Immunity to autologous protein has not previously been described following nonhuman primate cardiac transplant. Native hearts and cardiac allografts from cynomolgus monkeys were assessed by immunohistology for vimentin, a highly conserved intermediate filament protein. IgM and IgG to vimentin were measured in serial sera from untreated (n = 4) or cyclosporine (CsA)-treated (n = 8, 2 with ATG) cardiac allograft recipients, and in groups treated with anti-CD154 antibody with (n = 6) or without ATG (n = 28). IgM or IgG reactive with vimentin was elaborated within 30 days with unmodified acute rejection (3/4) or in CsA-treated animals (5/6). CD154 blockade did not prevent anti-vimentin IgM (14/28) but tended to delay the IgG response during therapy (anti-CD154: 8/28, p = 0.10 vs. CsA; anti-CD154+ATG: 2/6). CAV and alloantibody were seen in 25 of 26 animals with grafts surviving over 30 days, including seven animals without increasing anti-vimentin antibody. Anti-vimentin antibodies and vascular complement deposition were found in rejected hearts. Acute and chronic alloimmunity disrupt modulation of autoreactivity to vimentin through pathways, which are resistant to CsA, but may be partially regulated by CD154.
Asunto(s)
Formación de Anticuerpos , Trasplante de Corazón/métodos , Trasplante Homólogo/métodos , Vimentina/farmacología , Animales , Western Blotting , Ligando de CD40/biosíntesis , Núcleo Celular/metabolismo , Activación de Complemento , Complemento C4b/inmunología , Ciclosporina/farmacología , Citoplasma/metabolismo , Rechazo de Injerto , Supervivencia de Injerto , Humanos , Inmunoglobulina G/química , Inmunoglobulina M/química , Inmunohistoquímica , Inmunosupresores/farmacología , Vacunas contra la Influenza/farmacología , Isoanticuerpos/química , Macaca fascicularis , Miocardio/metabolismo , Miocardio/patología , Fragmentos de Péptidos/inmunología , Primates , Factores de Tiempo , Vimentina/química , Vimentina/inmunologíaAsunto(s)
Trasplante de Corazón , Complicaciones Posoperatorias/tratamiento farmacológico , Antiinfecciosos/farmacología , Antiinfecciosos/uso terapéutico , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Antihipertensivos/farmacología , Antihipertensivos/uso terapéutico , Depresión/complicaciones , Depresión/tratamiento farmacológico , Diabetes Mellitus/tratamiento farmacológico , Difosfonatos/farmacología , Difosfonatos/uso terapéutico , Interacciones Farmacológicas , Gota/complicaciones , Gota/tratamiento farmacológico , Cardiopatías/complicaciones , Cardiopatías/cirugía , Humanos , Hiperlipidemias/complicaciones , Hiperlipidemias/tratamiento farmacológico , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/farmacología , Hipolipemiantes/uso terapéutico , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Control de Infecciones , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/tratamiento farmacológico , Osteoporosis/complicaciones , Osteoporosis/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéuticoAsunto(s)
Trasplante de Corazón , Inmunosupresores/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Antiinfecciosos/efectos adversos , Antiinfecciosos/farmacocinética , Antidepresivos/efectos adversos , Antidepresivos/farmacocinética , Transporte Biológico , Biotransformación , Fármacos Cardiovasculares/efectos adversos , Fármacos Cardiovasculares/farmacocinética , Sistema Enzimático del Citocromo P-450/metabolismo , Interacciones Farmacológicas , Trasplante de Corazón/inmunología , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/clasificación , Inmunosupresores/uso terapéutico , Tasa de Depuración Metabólica , Inhibidores de Agregación Plaquetaria/efectos adversos , Inhibidores de Agregación Plaquetaria/farmacocinéticaAsunto(s)
Rechazo de Injerto/prevención & control , Trasplante de Corazón/inmunología , Inmunosupresores/uso terapéutico , Quimioterapia Combinada , Rechazo de Injerto/inmunología , Rechazo de Injerto/mortalidad , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Tasa de SupervivenciaAsunto(s)
Rechazo de Injerto/prevención & control , Trasplante de Corazón/efectos adversos , Inmunosupresores/uso terapéutico , Trasplante Homólogo/efectos adversos , Administración Oral , Corticoesteroides/administración & dosificación , Corticoesteroides/efectos adversos , Corticoesteroides/farmacología , Corticoesteroides/uso terapéutico , Antimetabolitos/administración & dosificación , Antimetabolitos/efectos adversos , Antimetabolitos/farmacología , Antimetabolitos/uso terapéutico , Azatioprina/administración & dosificación , Azatioprina/efectos adversos , Azatioprina/farmacología , Azatioprina/uso terapéutico , Inhibidores de la Calcineurina , Ensayos Clínicos como Asunto , Ciclosporina/administración & dosificación , Ciclosporina/efectos adversos , Ciclosporina/farmacología , Ciclosporina/uso terapéutico , Everolimus , Rechazo de Injerto/tratamiento farmacológico , Inhibidores de Crecimiento/administración & dosificación , Inhibidores de Crecimiento/efectos adversos , Inhibidores de Crecimiento/farmacología , Inhibidores de Crecimiento/uso terapéutico , Trasplante de Corazón/inmunología , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Inmunosupresores/farmacología , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/efectos adversos , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacología , Ácido Micofenólico/uso terapéutico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Quinasas/efectos de los fármacos , Sirolimus/administración & dosificación , Sirolimus/efectos adversos , Sirolimus/análogos & derivados , Sirolimus/farmacología , Sirolimus/uso terapéutico , Serina-Treonina Quinasas TOR , Tacrolimus/administración & dosificación , Tacrolimus/efectos adversos , Tacrolimus/farmacología , Tacrolimus/uso terapéuticoRESUMEN
Antibody-mediated rejection is well established for renal allografts but remains controversial for lung allografts. Cardinal features of antibody-mediated rejection in renal allografts include antibodies to donor human leukocyte antigen (HLA) and evidence for antibody action, such as complement activation demonstrated by C4d deposition. We report a lung allograft recipient with circulating antibodies to donor HLA who failed treatment for acute cellular rejection but responded to therapy for humoral rejection. To address the second criteria for antibody-mediated rejection, we determined whether complement activation could be detected by measuring C4d in bronchoalveolar lavage fluid (BALF) by ELISA. Airway allergen challenge of asthmatics activates the complement pathway; therefore, we used BALF from asthmatics pre- and post-allergen challenge to measure C4d. These controls demonstrated that ELISA could detect increases in C4d after allergen challenge. BALF from the index patient had elevated C4d concomitant with graft dysfunction and anti-donor HLA in the absence of infection. Analysis of BALF from 25 additional lung allograft recipients showed that C4d concentrations >100 ng/mL were correlated with anti-HLA antibodies (p = 0.006), but were also observed with infection and in asyptomatic patients. The findings support the occurrence of anti-HLA-mediated lung allograft rejection and suggest that C4d measurement in BALF may be useful in diagnosis.
Asunto(s)
Asma/metabolismo , Líquido del Lavado Bronquioalveolar/inmunología , Complemento C4b/biosíntesis , Trasplante de Pulmón/métodos , Fragmentos de Péptidos/biosíntesis , Anticuerpos , Asma/patología , Biopsia , Activación de Complemento , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Rechazo de Injerto , Supervivencia de Injerto , Antígenos HLA/química , Humanos , Hipoxia , Inmunoglobulinas Intravenosas/química , Isoanticuerpos , Pulmón/patología , Trasplante de Pulmón/inmunología , Masculino , Persona de Mediana Edad , Plasma/metabolismo , Tórax/patología , Factores de Tiempo , Donantes de Tejidos , Tomografía Computarizada por Rayos X , Trasplante HomólogoRESUMEN
Fibroblast growth factor receptors are expressed by some T cells, and provide costimulation for these cells. Such receptors allow T cells to respond to fibroblast growth factors expressed in response to injury and inflammation and may provide a mechanism for 'context-dependent' responses to antigens within the local microenvironment. The mechanisms by which fibroblast growth factor receptors might interact with the TCR signalling pathway are not defined. Here we show that the TCR and fibroblast growth factor receptors co-localize during combined stimulation. Signalling via fibroblast growth factor receptors alone results in phosphorylation of Lck and induces nuclear translocation of nuclear factors of activated T cells. Combined stimulation via fibroblast growth factor receptors and the TCR synergistically enhances the activation of nuclear factors of activated T cells. The results suggest that peptide growth factors produced at sites of injury and inflammation can contribute to the outcome of T-cell encounters with antigen.
Asunto(s)
Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/inmunología , Linfocitos T/inmunología , Transporte Activo de Núcleo Celular/efectos de los fármacos , Anticuerpos Monoclonales/farmacología , Complejo CD3/inmunología , Membrana Celular/metabolismo , Factores de Crecimiento de Fibroblastos/farmacología , Humanos , Células Jurkat , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/efectos de los fármacos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Factores de Transcripción NFATC/metabolismo , Fosforilación/efectos de los fármacos , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/análisis , Linfocitos T/citologíaRESUMEN
Current methods of immunosuppression for the purposes of allowing solid organ transplantation in humans are broadly inhibitory and thus are associated with an increased risk of opportunistic infections and neoplasia. We have shown previously that a selective blockade of CD40-CD154 interactions during heart transplantation in cynomolgus macaques significantly delays immune-mediated graft injury. Here, we determined the effect of anti-CD154 mAb therapy on primate serologic responses to immunization with influenza virus hemagglutinin (HA), a T-cell-dependent Ag. We found that CD154 blockade attenuated primary and secondary serum Ab responses of IgM and IgG isotypes to influenza, even when anti-CD154 treatment was discontinued prior to reimmunization. These findings show that in primates CD40-CD154 interactions are necessary for both primary and secondary Ab responses to viral Ags. Furthermore, the data suggest that viral Ag stimulation of primates in the absence of CD154 stimulation may have a tolerizing effect on that Ag.
Asunto(s)
Formación de Anticuerpos/inmunología , Ligando de CD40/metabolismo , Infecciones por Orthomyxoviridae/inmunología , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales Humanizados , Ligando de CD40/inmunología , Femenino , Macaca fascicularis , Masculino , Vacunas/inmunologíaRESUMEN
Activated fibroblast growth factor receptor 1 (FGFR1) propagates FGF signals through multiple intracellular pathways via intermediates FRS2, PLCgamma, and Ras. Conflicting reports exist concerning the interaction between FGFR1 and Src family kinases. To address the role of c-Src in FGFR1 signaling, we compared proliferative responses of murine embryonic fibroblasts (MEF) deficient in c-Src, Yes, and Fyn to MEF expressing either endogenous levels or overexpressing c-Src. MEF with endogenous c-Src had significantly greater FGF-induced DNA synthesis and proliferation than cells lacking or overexpressing c-Src. This was related directly to c-Src expression by analysis of c-Src-deficient cells transfected with and sorted for varying levels of a c-Src expression vector. This suggests an "optimal" quantity of c-Src expression for FGF-induced proliferation. To determine if this was a general phenomenon for growth factor signaling pathways utilizing c-Src, responses to epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and lysophosphatidic acid (LPA) were examined. As for FGF, responses to EGF were clearly inhibited when c-Src was absent or overexpressed. In contrast, varying levels of c-Src had little effect on responses to PDGF or LPA. The data show that mitogenic pathways activated by FGF-1 and EGF are regulated by c-Src protein levels and appear to differ significantly from those activated by PDGF and LPA.
Asunto(s)
Factor 1 de Crecimiento de Fibroblastos/farmacología , Fibroblastos/citología , Genes src/fisiología , Animales , División Celular/efectos de los fármacos , División Celular/fisiología , Línea Celular , Fibroblastos/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Ratones , Factor de Crecimiento Derivado de Plaquetas/farmacologíaRESUMEN
Methylation of bacterial DNA can regulate microbial growth and virulence. Expression of hpyIM, a conserved methyltransferase of the gastric pathogen Helicobacter pylori, was quantitated in gastric biopsy specimens from 41 H. pylori-infected patients and during growth in vitro, by quantitative reverse transcriptase-polymerase chain reaction and/or RNA slot-blot analysis, to determine whether levels of transcription were associated with pathologic outcome, as based on both severity of gastritis and inflammatory cytokine levels, or were regulated by bacterial growth phase. The effects that hpyIM inactivation has on bacterial morphology were determined by electron microscopy. Expression of hpyIM varied dramatically within colonized gastric tissue, and levels were not related to either colonization density, severity of inflammation, mucosal IL-8 concentrations, or clinical disease. In vitro, hpyIM expression was higher during log-phase growth and was required for normal bacterial morphology, suggesting that hpyIM expression may be growth-phase regulated within the gastric niche.
Asunto(s)
Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Regulación Bacteriana de la Expresión Génica , Infecciones por Helicobacter/patología , Helicobacter pylori/enzimología , Helicobacter pylori/crecimiento & desarrollo , Metiltransferasas/genética , Genes Bacterianos/genética , Infecciones por Helicobacter/microbiología , Helicobacter pylori/genética , Helicobacter pylori/ultraestructura , Humanos , Immunoblotting , Inflamación/microbiología , Metiltransferasas/biosíntesis , Metiltransferasas/metabolismo , ARN Bacteriano/análisis , ARN Bacteriano/genética , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: Successful management of an ABO-mismatched lung allograft recipient has not previously been described. METHODS: Because of a clerical error, a 67-year-old blood type B patient with idiopathic pulmonary fibrosis received a left single-lung allograft from a blood type A donor. Cyclophosphamide was added to immunosuppression with anti-thymocyte globulin induction, cyclosporine, mycophenolate mofetil, and prednisone. When increasing anti-A antibody titers were detected, antigen-specific immunoadsorption, anti-CD20 monoclonal antibody, and recombinant soluble complement receptor type 1 (TP10) were administered. RESULTS: Rising anti-A antibody titers were reduced acutely by immunoadsorption, and remained low during long-term follow-up. Humoral injury to the graft was not detected. Acute cellular rejection and multiple complications were successfully managed. Three years after transplantation the patient is clinically well on stable maintenance immunosuppression and prophylactic photochemotherapy. CONCLUSIONS: Modulation of anti-A antibody, preserved graft function, and a favorable patient outcome can be achieved for an ABO-mismatched lung allograft.