Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Enfermedades Autoinmunes/terapia , Diabetes Mellitus Tipo 1/cirugía , Trasplante de Islotes Pancreáticos/fisiología , Enfermedades Pancreáticas/terapia , Receptores de Interleucina-2/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Trasplante de Islotes Pancreáticos/inmunología , Enfermedades Pancreáticas/inmunología , Ratas , Ratas Endogámicas BB , Recurrencia , Trasplante IsogénicoAsunto(s)
Trasplante de Islotes Pancreáticos/inmunología , Complejo Mayor de Histocompatibilidad , Animales , Células Presentadoras de Antígenos/inmunología , Diabetes Mellitus Experimental/cirugía , Supervivencia de Injerto , Leucocitos/inmunología , Masculino , Ratas , Ratas Endogámicas Lew , Ratas Endogámicas , Ratas Endogámicas WF , Trasplante HomólogoRESUMEN
Antigen presenting cells (APC) expressing MHC class II antigens have been attributed with stimulatory capacity for initiating islet allograft rejection (direct pathway). Therefore, we evaluated the effect of pretreating isolated islets with different monoclonal antibodies against MHC class II antigens and complement, with and without culture at 22 degrees C or 37 degrees C, on MHC class II antigen expression, on the allogeneic proliferative response in the mixed lymphocyte islet culture (MLIC) and on islet allograft survival in adult rats. Experiments were performed in two different strain combinations incompatible for MHC class II antigens and either incompatible or compatible for MHC class I antigens, in order to elucidate further the impact of class I antigens on islet allograft rejection. In terms of class II antigen suppression, pretreatment with anti-MHC class II antibodies together with complement and a 5-day (37 degrees C) culture period proved most effective. After this procedure 92.7% of the islets of LEW rats and 91.1% of the islets of LEW.1WR2 rats were negative for MHC class II antigens, as demonstrated by indirect immunofluorescence. Transfer of successfully pretreated islets to a MLIC in vitro test system provoked a significantly reduced allogeneic T-cell proliferative response in the case of additional MHC class I disparity (ratio 1.3 vs 4.7) and a response as low as that of a syngeneic setting when stimulator islets and allogeneic responder lymphocytes shared MHC class I antigens (ratio 1.0 vs 1.6).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Anticuerpos Monoclonales/farmacología , Supervivencia de Injerto/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Trasplante de Islotes Pancreáticos/inmunología , Islotes Pancreáticos/inmunología , Animales , Células Cultivadas , Haplotipos , Islotes Pancreáticos/citología , Islotes Pancreáticos/efectos de los fármacos , Activación de Linfocitos , Masculino , Ratas , Ratas Endogámicas Lew , Ratas Endogámicas , Linfocitos T/inmunología , Factores de Tiempo , Trasplante HomólogoRESUMEN
Pancreatic islet grafts transplanted into subjects with spontaneous autoimmune diabetes are threatened by two immune responses, allograft rejection and the recurrence of autoimmune insulitis. To examine the recurrent autoimmune response to transplanted islets it is necessary to exclude islet allograft rejection. The BB rat is a unique model of spontaneous diabetes with clinical and pathological characteristics identical or similar to those found in human insulin dependent diabetes mellitus (IDDM). In this study we demonstrate permanent acceptance of histocompatible islet grafts in chemically induced diabetes and a lack of intracolony tissue antigen rejection in our BB rat colony. Therefore the vigorous destruction of transplanted BB islets in the liver of spontaneously diabetic BB rats is due to recurrence of diabetes. This recurrence can be prevented by transplantation of islets under the renal capsule. This may be important for clinical application in IDDM, particularly with regard to host and donor tissue matching.
Asunto(s)
Diabetes Mellitus Tipo 1/prevención & control , Trasplante de Islotes Pancreáticos/inmunología , Trasplante Heterotópico/inmunología , Animales , Enfermedades Autoinmunes/prevención & control , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/cirugía , Rechazo de Injerto , Hiperglucemia/metabolismo , Riñón , Nefrectomía , Vena Porta , Ratas , Ratas Endogámicas BBRESUMEN
Type 1, insulin-dependent diabetes mellitus is an autoimmune disease with destruction of beta-cells in islets of Langerhans by activated (antigen-positive) infiltrating mononuclear cells accompanied by serological immune phenomena. The pathological mechanism has not yet been clarified in detail, and some inversion in the proportion of epidermal antigen expression has recently been described in spontaneous diabetes. The BB rat is one of the animal models most closely resembling human type 1 diabetes of autoimmune origin. We compared the class I and class II antigen expression in the islets of Langerhans and in the skin of spontaneously diabetic (BBD) and normoglycaemic (BBND) BB rats in the prediabetic, diabetic and non-diabetic states. Class I and class II antigen expression increased significantly in the islets of BBD rats from prediabetes to diabetes and compared with non-diabetic controls. In the same period, the dermal antigen expression (class I and class II) did not decrease and was not lower in BBD than in BBND animals. These results do not support a loss of activated (antigen-positive) dermal cells at the onset of diabetes in the BB rat and do not show a clear correlation with the antigen expression in infiltrated islets of Langerhans.
Asunto(s)
Diabetes Mellitus Tipo 1/inmunología , Antígenos de Histocompatibilidad Clase II/análisis , Antígenos de Histocompatibilidad Clase I/análisis , Islotes Pancreáticos/inmunología , Páncreas/inmunología , Estado Prediabético/inmunología , Piel/inmunología , Envejecimiento , Animales , Diabetes Mellitus Tipo 1/patología , Islotes Pancreáticos/crecimiento & desarrollo , Islotes Pancreáticos/patología , Páncreas/crecimiento & desarrollo , Páncreas/patología , Estado Prediabético/patología , Ratas , Ratas Endogámicas BB , Piel/crecimiento & desarrollo , Piel/patologíaRESUMEN
To investigate whether the immunologic mechanisms of autoimmune pancreatic beta-cell destruction are MHC restricted, we examined the relative vulnerability of islet allografts from a panel of MHC-compatible and -incompatible donors to autoimmune damage after transplantation to spontaneously diabetic BB recipients. To circumvent a potentially confounding allograft response to the foreign islet graft, we utilized two strategies: (1) pretransplant in vitro culture of islets to delete intraislet APCs; and (2) induction of islet donor-specific immunologic tolerance in diabetes-prone BB rats. Experiments employing organ culture to prevent rejection demonstrated that MHC-incompatible grafts were significantly less vulnerable to autoimmunity than MHC-compatible grafts. In contrast, when we used the model of immunologic tolerance to exclude rejection, both MHC-compatible and -incompatible islet grafts were equally susceptible to autoimmune damage. The reason for this discrepancy has not been defined fully but may be related to our observation that tolerant BB animals exhibit increased peripheral blood NK-cell activity. NK cells are known to be cytotoxic to islets in vitro and could play a role in a non-MHC-restricted diabetogenic response in vivo. We conclude that both MHC-restricted and nonrestricted mechanisms are capable of contributing to anti-beta-cell autoimmunity in BB rats.
Asunto(s)
Autoinmunidad/fisiología , Trasplante de Islotes Pancreáticos/inmunología , Complejo Mayor de Histocompatibilidad/inmunología , Ratas Endogámicas BB/inmunología , Animales , Separación Celular , Quimera/inmunología , Diabetes Mellitus Experimental/cirugía , Femenino , Citometría de Flujo , Supervivencia de Injerto/inmunología , Tolerancia Inmunológica/inmunología , Células Asesinas Naturales/inmunología , Subgrupos Linfocitarios/inmunología , Masculino , Ratas , Ratas Endogámicas BN , Ratas Endogámicas Lew , Ratas Endogámicas WFAsunto(s)
Grasas de la Dieta/uso terapéutico , Aceites de Pescado/uso terapéutico , Trasplante de Islotes Pancreáticos , Islotes Pancreáticos/patología , Enfermedades Pancreáticas/prevención & control , Animales , Diabetes Mellitus Experimental/cirugía , Insulina/análisis , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Trasplante Isogénico/patologíaRESUMEN
A period of in vitro culture prior to transplantation has been shown to prolong the survival of many types of MHC-incompatible endocrine grafts. The effectiveness of this strategy has been attributed to a selective depletion of intragraft antigen-presenting cells. We report that in vitro culture at 24 degrees C results in a significantly better survival of rat isolated islet allografts than does culture at 37 degrees C. Using in vitro assays of APC activity, we were unable to detect differences in the quantity of residual intraislet APCs between 24 degrees C and 37 degrees C culture preparations. In contrast, islet endocrine cells cultured at 24 degrees C evidenced a reduced level of cell surface class I MHC antigen expression and were significantly less vulnerable to lysis in vitro by CTL. These findings suggest that culture at 24 degrees C produces islet alterations other than APC depletion, and that its beneficial effect on graft survival correlates with a reduction in endocrine cell class I MHC antigen expression.
Asunto(s)
Antígenos de Histocompatibilidad Clase I/inmunología , Trasplante de Islotes Pancreáticos , Animales , Células Presentadoras de Antígenos/inmunología , Células Cultivadas , Supervivencia de Injerto , Técnicas In Vitro , Islotes Pancreáticos/citología , Islotes Pancreáticos/inmunología , Complejo Mayor de Histocompatibilidad , Microscopía Electrónica , Ratas , Ratas Endogámicas , Linfocitos T Citotóxicos/inmunología , TemperaturaRESUMEN
Streptozotocin-diabetic BdII rats were treated daily with 20 mg/kg body weight gangliosides for ten days beginning two days before transplantation. This treatment did not prolong allograft survival of untreated Lewis islets. Culture treatment of isolated Lewis islets with gangliosides (100 micrograms/ml in RPMI 1640) for one day resulted in a significant reduction of MHC Ia antigen positive cells but not of class I antigens within the islets. Transplantation of the ganglioside pretreated islets into non-immunosuppressed BdII recipients prolonged allograft survival to 12 days only in one of five animals.
Asunto(s)
Diabetes Mellitus Experimental/inmunología , Gangliósidos/farmacología , Supervivencia de Injerto/efectos de los fármacos , Antígenos de Histocompatibilidad Clase II/análisis , Islotes Pancreáticos/inmunología , Animales , Diabetes Mellitus Experimental/cirugía , Islotes Pancreáticos/efectos de los fármacos , Trasplante de Islotes Pancreáticos , Ratas , Ratas Endogámicas Lew , Ratas Endogámicas , Trasplante HomólogoAsunto(s)
Enfermedades Autoinmunes/genética , Diabetes Mellitus Experimental/inmunología , Trasplante de Islotes Pancreáticos/inmunología , Animales , Enfermedades Autoinmunes/prevención & control , Diabetes Mellitus Experimental/genética , Inmunosupresores/uso terapéutico , Ratas , Ratas Endogámicas BB , RecurrenciaAsunto(s)
Supervivencia de Injerto/inmunología , Trasplante de Islotes Pancreáticos/inmunología , Trasplante Heterotópico/inmunología , Animales , Diabetes Mellitus Experimental/cirugía , Inmunocompetencia/inmunología , Riñón/inmunología , Vena Porta/inmunología , Ratas , Ratas Endogámicas BB , Ratas Endogámicas Lew , Ratas Endogámicas WF , Trasplante Heterotópico/métodosAsunto(s)
Supervivencia de Injerto/inmunología , Antígenos de Histocompatibilidad Clase II/análisis , Insulina/metabolismo , Trasplante de Islotes Pancreáticos/fisiología , Temperatura , Animales , Técnicas de Cultivo , Diabetes Mellitus Experimental/cirugía , Secreción de Insulina , Trasplante de Islotes Pancreáticos/inmunología , Preservación de Órganos/métodos , Ratas , Ratas Endogámicas Lew , Trasplante Homólogo/inmunologíaRESUMEN
Repeated low doses of streptozocin (STZ; 40 mg/kg, 5 injections/day) induce hyperglycemia in certain strains of mice after a latency of 1 wk. Omega-3 polyunsaturated fatty acids (omega 3FA) have been reported to suppress immune processes by blockade of the cyclooxygenase pathway of arachidonic acid metabolism. We investigated the effects of diets high in omega 3FA on the development of diabetes in the low-dose STZ-induced diabetes (LDSTZ-D) model. Male C57BL/6J mice were on a fish oil diet (FOD) as a source of omega 3FA 8 wk before STZ injection. Controls received laboratory chow only or a coconut oil diet (COD). Blood glucose levels in FOD mice were reduced (12.5 vs. 28 mM for COD mice, P less than .001) 60 days after STZ injection with a diet in which 20% of the calories were from fish oil. In FOD mice, immunohistology showed reduced numbers of class II antigen-expressing cells in pancreatic islets followed by a decreased extent of insulitis. FOD significantly decreased the number of Fc receptor-negative dendritic cells in cytospin preparations of islets isolated from diabetic mice. Interleukin 1-like activity of peritoneal exudate cell supernatants isolated from mice on FOD was reduced. FOD did not improve insulin secretion of isolated islets from LDSTZ-D mice. These data indicate a beneficial effect of FOD on the immune component of the mouse LDSTZ-D model.
Asunto(s)
Diabetes Mellitus Experimental/inmunología , Grasas de la Dieta/farmacología , Ácidos Grasos Omega-3/farmacología , Aceites de Pescado/farmacología , Alimentos Fortificados , Hiperglucemia/inmunología , Activación de Macrófagos/efectos de los fármacos , Animales , Suero Antilinfocítico/inmunología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Grasas de la Dieta/administración & dosificación , Ácidos Grasos Omega-3/administración & dosificación , Aceites de Pescado/administración & dosificación , Glucosa/metabolismo , Hiperglucemia/inducido químicamente , Hiperglucemia/metabolismo , Hiperglucemia/patología , Inmunidad Celular/efectos de los fármacos , Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Páncreas/patología , EstreptozocinaAsunto(s)
Diabetes Mellitus Experimental/cirugía , Rechazo de Injerto , Trasplante de Islotes Pancreáticos , Animales , Células Cultivadas , Hiperglucemia/etiología , Terapia de Inmunosupresión , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Riñón , Hígado , Masculino , Complicaciones Posoperatorias/etiología , Cuidados Preoperatorios , Ratas , Ratas Endogámicas LewAsunto(s)
Enfermedades Autoinmunes/inmunología , Diabetes Mellitus Experimental/inmunología , Trasplante de Islotes Pancreáticos , Animales , Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/patología , Células Cultivadas , Diabetes Mellitus Experimental/etiología , Diabetes Mellitus Experimental/patología , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/patología , Ratones , Ratones Endogámicos C57BL , EstreptozocinaRESUMEN
This article is concerned with suppression of the development of diabetes experimentally induced by multiple injections of subdiabetogenic doses of streptozotocin (4 x 45 mg/kg/d) in mice (CD 1 and C57B16). Streptozotocin injections were followed by hyperglycemia and mononuclear cell infiltration of islets (insulitis). Ciamexon is a new immuno-modulating agent with promising effects in experimental models of autoimmune diseases and practically no toxic side effects. When Ciamexon was given before streptozotocin treatment blood glucose levels in the parenteral glucose tolerance test were suppressed in a dose dependent way. 60 days after streptozotocin application the percentage of islets showing insulitis or even necrosis was reduced in the Ciamexon treated group compared to the streptozotocin only group. In contrast, Cyclosporin A had a detrimental effect on diabetes in this model although blood levels were proved to be in the therapeutic range. From these results we conclude that Ciamexon should be tested for its effect in human type I diabetes.
Asunto(s)
Aziridinas/farmacología , Azirinas/farmacología , Ciclosporinas/farmacología , Diabetes Mellitus Experimental/prevención & control , Adyuvantes Inmunológicos , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/patología , Islotes Pancreáticos/patología , Ratones , Ratones Endogámicos C57BLAsunto(s)
Diabetes Mellitus Experimental/cirugía , Supervivencia de Injerto/fisiología , Trasplante de Islotes Pancreáticos , Animales , Separación Celular/métodos , Islotes Pancreáticos/citología , Ratas , Ratas Endogámicas BB , Ratas Endogámicas WF , Ensayo de Capsula Subrrenal , Trasplante Heterotópico , Trasplante HomólogoRESUMEN
Pancreatic endocrine cells normally express only Class I gene products of the major histocompatibility complex (MHC). Recently it has been shown that in both patients with recent onset type I diabetes and acutely diabetic BB rats, residual islet beta cells express Class II MHC antigens. In an attempt to define a potential inducer of this aberrant Class II antigen expression, we have investigated the effect of in vitro incubation of rat isolated pancreatic islets with the lymphokine gamma interferon (IFN-gamma) on MHC antigen expression. Our results demonstrate that in vitro exposure to IFN-gamma induces novel expression of Class II antigens on the surface of rat islet endocrine cells and increases the level of pre-existing Class I antigen expression.