RESUMEN
Recently, the keratinocyte IL-8/IL-8 receptor (IL-8R) pathway has been implicated in the pathogenesis of psoriasis, and there is evidence that the potent macrolide immune suppressant tacrolimus (formerly FK506) can inhibit this pathway in vitro. In this study, determination of the expression of cytokine mRNAs in lesional skin of patients with active disease by reverse transcriptase polymerase chain reaction revealed transcripts for IL-1 beta, tumour necrosis factor-alpha (TNF-alpha), IL-6, IL-8, IL-8R, IL-10, interferon-gamma (IFN-gamma), IL-2R and transforming growth factor-beta (TGF-beta), but not IL-2 or IL-4. IL-8 was the only cytokine expressed in affected skin of all patients but not in clinically normal skin of healthy subjects. In seven CD4+ T cell clones propagated from the lesional skin of an untreated psoriasis patient, IL-8 was expressed by the skin-derived T lymphocytes and not by feeder cells (irradiated autologous blood lymphocytes); IL-1 beta, IL-2, IL-6 and IL-10 were also expressed by some or all of the T cell clones. IL-8 mRNA was not detected in the skin of any patient after the start of systemic tacrolimus therapy; IL-1 beta, IL-6 and IFN-gamma transcripts were also reduced. By 12 weeks, the mean psoriasis area and severity index (PASI) had decreased from 18.8 to 3.8, a reduction of 80%. In the same post-treatment biopsies, however, message for IL-8R persisted. Estimation of circulating IL-8 levels by enzyme immunoassay showed that all patients with detectable IL-8 before treatment had decreased levels in response to treatment with tacrolimus; reductions in PASI scores were accompanied by decreases in IL-8 levels, that varied both in rate and extent. Partial relapse, which in a minority of patients followed the initial period of remission, and was precipitated by drug dose reduction, was accompanied by an increase in circulating IL-8. These findings add credence to the view that the IL-8/IL-8R autocrine/paracrine pathway may be important in the pathogenesis of psoriasis. They further suggest that interference with IL-8 production and/or that of other key chemokines may be an important mechanism underlying the therapeutic efficacy of tacrolimus, and other agents such as cyclosporin A, with similar molecular actions.
Asunto(s)
Interleucina-8/biosíntesis , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Receptores de Interleucina/biosíntesis , Linfocitos T/efectos de los fármacos , Tacrolimus/uso terapéutico , Adolescente , Adulto , Citocinas/biosíntesis , Citocinas/genética , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Interleucina-8/sangre , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Psoriasis/patología , ARN Mensajero/biosíntesis , Receptores de Interleucina-8A , Linfocitos T/inmunologíaAsunto(s)
Diabetes Mellitus Experimental/terapia , Trasplante de Islotes Pancreáticos/fisiología , Islotes Pancreáticos/citología , Animales , Glucemia/metabolismo , Separación Celular , Supervivencia Celular , Ditizona , Masculino , Ratones , Ratones Desnudos , Papio , Trasplante Heterólogo , Trasplante Heterotópico , Azul de TripanoRESUMEN
We have taken the opportunity of a clinical trial of the potential efficacy and safety of FK 506 (tacrolimus) in chronic progressive multiple sclerosis (MS) to examine the influence of this potent new immunosuppressant on circulating T-lymphocytes in an otherwise healthy non-transplant population. Peripheral blood levels of subsets of CD4+ T lymphocytes expressing the activation molecule interleukin-2 receptor (p55 alpha chain; CD25) or the CD45RA isoform were determined sequentially in 19 patients that were treated continuously with oral FK 506 (starting dose 0.15 mg/kg/day) for 12 months. No significant change in the proportion of circulating CD25+ CD4+ cells was observed over the study period in which the mean trough plasma FK 506 level rose from 0.3 +/- 0.2 to 0.5 +/- 0.4 ng/ml. There was also no significant effect of FK 506 on the percentage of CD45R+ CD4+ cells in the peripheral blood at 12 months compared with pretreatment values. Analysis of a subgroup of 7 patients, who showed a sustained reduction in CD25+ CD4+ cells and a reciprocal increase in CD45RA+ CD4+ cells for at least 6 months after start of treatment, did not reveal any difference in disability at one year compared with the treatment group as a whole. The side effects of FK 506 were mild and the overall degree of disability estimated by the mean Kurtzke expanded disability status scale (EDSS) score or the ambulation index did not deteriorate significantly in the 19 patients studied over the 12 months of FK 506 administration.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Antígenos Comunes de Leucocito/análisis , Esclerosis Múltiple/tratamiento farmacológico , Receptores de Interleucina-2/análisis , Tacrolimus/farmacología , Administración Oral , Adulto , Anciano , Linfocitos T CD4-Positivos/efectos de los fármacos , Fatiga/inducido químicamente , Trastornos de Alimentación y de la Ingestión de Alimentos/inducido químicamente , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/inmunología , Proyectos Piloto , Tacrolimus/efectos adversos , Tacrolimus/sangre , Temblor/inducido químicamenteAsunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Antígenos Comunes de Leucocito/análisis , Esclerosis Múltiple/inmunología , Receptores de Interleucina-2/análisis , Tacrolimus/uso terapéutico , Adulto , Relación CD4-CD8 , Linfocitos T CD4-Positivos/inmunología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológicoAsunto(s)
Moléculas de Adhesión Celular/análisis , Citocinas/genética , Psoriasis/tratamiento farmacológico , Piel/metabolismo , Tacrolimus/uso terapéutico , Adulto , Selectina E , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Molécula 1 de Adhesión Intercelular , Masculino , Persona de Mediana Edad , Psoriasis/metabolismo , Tacrolimus/farmacologíaRESUMEN
An increased frequency of kidney rejection has been reported in diabetic patients who have simultaneous pancreas and kidney transplantation compared with patients who have a kidney transplant alone. Kidney graft outcome is similar in the two groups. The mechanism for increased kidney graft rejection with a simultaneous pancreas graft is not clear. It is ascribed to the immunogenicity of the exocrine pancreas that initiates migration of activated cells from the peripheral blood that are entrapped in the kidney. Since the volume of the transplanted tissue is less in islet transplantation (usually < 2 ml) than in pancreas transplantation, one might not expect an increased frequency of kidney rejection in islet cell recipients. We looked at biopsy-proven kidney rejection episodes in patients who had combined kidney and islet transplants and compared this with the frequency of rejection in diabetic and nondiabetic patients who underwent a kidney transplant alone under the same immunosuppression. Diabetic patients who had kidney islet transplants (n = 9) had a higher frequency of rejection (100%) compared with diabetic patients (n = 107, 55.1%) and nondiabetic patients (n = 327, 65%) who had a kidney transplant alone. The 1-year graft and patient survival rates were not different among the groups. Although the number of patients is small, it would appear that transplantation of a low volume of islet cells with high purity can lead to an increased frequency of kidney rejection. This is unlikely to be explained solely on the basis of fewer antigen matches in these recipients but may reflect the inherent immunogenicity of the purified islet preparations. Alternatively, there may be an effect of their direct infusion into the portal vein.
Asunto(s)
Diabetes Mellitus/cirugía , Trasplante de Islotes Pancreáticos , Trasplante de Riñón/inmunología , Corticoesteroides/uso terapéutico , Adulto , Análisis de Varianza , Creatinina/sangre , Femenino , Rechazo de Injerto/tratamiento farmacológico , Supervivencia de Injerto , Humanos , MasculinoAsunto(s)
Diabetes Mellitus Tipo 1/cirugía , Nefropatías Diabéticas/cirugía , Supervivencia de Injerto/fisiología , Trasplante de Islotes Pancreáticos/fisiología , Trasplante de Riñón/fisiología , Adulto , Humanos , Trasplante de Islotes Pancreáticos/inmunología , Trasplante de Riñón/inmunología , Vena Porta , Tacrolimus/uso terapéuticoRESUMEN
FK 506 is a new immunosuppressive agent with a similar molecular action to cyclosporin A. We have investigated immunohistochemical changes in lesional biopsies of seven patients with severe recalcitrant chronic plaque psoriasis receiving systemic FK 506 therapy. Within 4 weeks of start of treatment, there was a striking reduction in psoriasis area and severity index (mean reduction 87.4%), accompanied by marked reductions in dermal and epidermal CD4+ and CD8+ cells. Investigation of biopsies obtained 4-8 weeks after start of treatment revealed a significant fall in the numbers of activated mononuclear cells expressing CD25 (IL-2 receptor alpha-chain), HLA-DR, or CD11a (lymphocyte function-associated antigen-1, LFA-1 alpha chain). In contrast, the number of epidermal CD1+ (Langerhans) cells increased in response to FK 506 therapy. Study of leukocyte adhesion-related epitopes in active disease revealed strong expression of CD54 (intercellular adhesion molecule-1, ICAM-1) and E-selectin (previously known as endothelial leukocyte adhesion molecule-1) both on microvascular endothelial cells and of ICAM-1 on infiltrating mononuclear cells; ICAM-1 was also expressed weakly on epidermal keratinocytes. Vascular cell adhesion molecule-1 (VCAM-1) was either absent or expressed rarely on vascular endothelium. In response to FK 506 treatment, both ICAM-1 and E-selectin expression on blood vessels was reduced consistently but nevertheless persisted, even in individuals exhibiting total clearance of psoriatic lesions.(ABSTRACT TRUNCATED AT 250 WORDS)