RESUMO
Although lymphoid dendritic cells (DC) are thought to play an essential role in T cell activation, the initial physical interaction between antigen-bearing DC and antigen-specific T cells has never been directly observed in vivo under conditions where the specificity of the responding T cells for the relevant antigen could be unambiguously assessed. We used confocal microscopy to track the in vivo location of fluorescent dye-labeled DC and naive TCR transgenic CD4(+) T cells specific for an OVA peptide-I-Ad complex after adoptive transfer into syngeneic recipients. DC that were not exposed to the OVA peptide, homed to the paracortical regions of the lymph nodes but did not interact with the OVA peptide-specific T cells. In contrast, the OVA peptide-specific T cells formed large clusters around paracortical DC that were pulsed in vitro with the OVA peptide before injection. Interactions were also observed between paracortical DC of the recipient and OVA peptide-specific T cells after administration of intact OVA. Injection of OVA peptide-pulsed DC caused the specific T cells to produce IL-2 in vivo, proliferate, and differentiate into effector cells capable of causing a delayed-type hypersensitivity reaction. Surprisingly, by 48 h after injection, OVA peptide-pulsed, but not unpulsed DC disappeared from the lymph nodes of mice that contained the transferred TCR transgenic population. These results demonstrate that antigen-bearing DC directly interact with naive antigen-specific T cells within the T cell-rich regions of lymph nodes. This interaction results in T cell activation and disappearance of the DC.
Assuntos
Apresentação de Antígeno , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Animais , Feminino , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologiaRESUMO
Mature dendritic cells (DCs) are powerful antigen presenting cells that have the unique capacity to migrate to the T cell zone of draining lymph nodes after subcutaneous injection. Here we report that treatment of antigen-pulsed mature DCs with tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE), a TNF family member, before immunization enhances their adjuvant capacity and elicits improved T cell priming in vivo, such that both primary and memory T cell immune responses are enhanced. By enumerating migratory DCs in the draining lymph nodes and by studying their function in stimulating naive T cells, we show that one of the underlying mechanisms for enhanced T cell responses is an increase in the number of ex vivo antigen-pulsed DCs that are found in the T cell areas of lymph nodes. These results suggest that the longevity and abundance of mature DCs at the site of T cell priming influence the strength of the DC-initiated T cell immunity in situ. Our findings have the potential to improve DC-based immunotherapy; i.e., the active immunization of humans with autologous DCs that have been pulsed with clinically significant antigens ex vivo.
Assuntos
Proteínas de Transporte/farmacologia , Células Dendríticas/efeitos dos fármacos , Linfonodos/imunologia , Glicoproteínas de Membrana/farmacologia , Adjuvantes Imunológicos , Animais , Ligante de CD40 , Proteínas de Transporte/genética , Contagem de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Células Dendríticas/imunologia , Células Dendríticas/transplante , Fluoresceínas , Corantes Fluorescentes , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Imunização , Ativação Linfocitária , Glicoproteínas de Membrana/genética , Camundongos , Ligante RANK , Receptor Ativador de Fator Nuclear kappa-B , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Fatores de Tempo , Tuberculina , Fator de Necrose Tumoral alfa/genéticaRESUMO
Integrin-associated protein (CD47) is a broadly expressed protein that costimulates T cells, facilitates leukocyte migration, and inhibits macrophage scavenger function. To determine the role of CD47 in regulating alloresponses, CD47(+/+) or CD47(-/-) T cells were infused into irradiated or nonconditioned major histocompatibility complex disparate recipients. Graft-versus-host disease lethality was markedly reduced with CD47(-/-) T cells. Donor CD47(-/-) T cells failed to engraft in immunodeficient allogeneic recipients. CD47(-/-) marrow was unable to reconstitute heavily irradiated allogeneic or congenic immune-deficient CD47(+/+) recipients. These data suggested that CD47(-/-) T cells and marrow cells were cleared by the innate immune system. To address this hypothesis, dye-labeled CD47(-/-) and CD47(+/+) lymphocytes or marrow cells were infused in vivo and clearance was followed. Dye-labeled CD47(-/-) cells were engulfed by splenic dendritic cells and macrophages resulting in the clearance of virtually all CD47(-/-) lymphohematopoietic cells within 1 day after infusion. Host phagocyte-depleted CD47(+/+) recipients partially accepted allogeneic CD47(-/-) T cells. Thus, dendritic cells and macrophages clear lymphohematopoietic cells that have downregulated CD47 density. CD47 expression may be a critical indicator for determining whether lymphohematopoietic cells will survive or be cleared.
Assuntos
Antígenos CD/metabolismo , Proteínas de Transporte/metabolismo , Transplante de Células , Células Dendríticas/metabolismo , Macrófagos/metabolismo , Receptores Imunológicos/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Células da Medula Óssea/imunologia , Antígeno CD47 , Proteínas de Transporte/genética , Proteínas de Transporte/imunologia , Regulação para Baixo , Doença Enxerto-Hospedeiro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos SCID , Modelos AnimaisRESUMO
Early events in the humoral immune response were visualized in lymph nodes by simultaneous tracking of antigen-specific CD4 T and B cells after immunization. The T cells were initially activated in the T cell areas when the B cells were still randomly dispersed in the B cell-rich follicles. Both populations then migrated to the edges of the follicles and interacted there, resulting in CD154-dependent B cell proliferation and germinal center formation. These results provide visual documentation of cognate T-B cell interactions and localize them to the follicular border.
Assuntos
Formação de Anticorpos , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfonodos/imunologia , Ativação Linfocitária , Transferência Adotiva , Animais , Apresentação de Antígeno , Linfócitos B/citologia , Linfócitos T CD4-Positivos/citologia , Ligante de CD40 , Movimento Celular , Células Dendríticas/imunologia , Centro Germinativo/imunologia , Imunização , Imunoglobulina M/análise , Linfonodos/citologia , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Plasmócitos/imunologiaRESUMO
Steroid-resistant FSGS and its recurrence posttransplantation are predominantly seen in children. We report on the largest pediatric transplant population for FSGS with similar numbers of azathioprine- and cyclosporine-treated patients analyzed for recurrence. Of 70 patients with idiopathic FSGS identified over the years 1974-1989, 49 progressed to end-stage renal disease and 28 received 42 transplants (17 live-related donors, 25 cadaveric). Seventeen patients each received one transplant, 9 patients each received two transplants, and one patient each received three and four transplants. The mean age at diagnosis of FSGS was 9.1 +/- 4.2 years, the mean duration of FSGS prior to reaching ESRD was 2.2 +/- 1.3 years, and the mean duration on dialysis prior to transplantation was 9.7 +/- 6.3 months. Primary nonfunction was observed in 2 transplants; in the remaining 40 transplants, 6 recurrences were noted (15%). Recurrences were noted in four AZA and prednisone (n = 22) and two CsA and prednisone (n = 18) recipients. Risk factors analyzed for recurrence included race, age at FSGS, histological and clinical severity of FSGS, classification of FSGS, duration of disease, interval on dialysis, multiple transplants, and HLA matching. Only age at onset of FSGS was predictive of recurrence. The incidence of recurrence was higher in children less than or equal to 6 years of age compared with those over 6 years (P less than .05). All 4 patients receiving AZA and prednisone went on to lose their grafts due to recurrence. Recurrent proteinuria in the 2 CsA and prednisone recipients was controlled by gradually increasing the CsA dose from 15 mg/kg/day to 27 and 35 mg/kg/day. Remission of the nephrotic syndrome was induced within 60 days in both patients. Presently, both grafts are functioning 24 and 16 months posttransplant with serum creatinines of 0.9 and 0.5 mg/dl, respectively. We conclude that recurrence is predominantly seen in very young children and occurs even under CsA immunosuppression. High-dose CsA may control the recurrent proteinuria--however, the long-term outcome of such intense therapy is not known.
Assuntos
Glomerulosclerose Segmentar e Focal/cirurgia , Transplante de Rim , Adolescente , Criança , Pré-Escolar , Colesterol/sangue , Ciclosporinas/administração & dosagem , Ciclosporinas/sangue , Feminino , Glomerulosclerose Segmentar e Focal/complicações , Glomerulosclerose Segmentar e Focal/terapia , Humanos , Masculino , Proteinúria/complicações , RecidivaRESUMO
Steroid therapy posttransplantation has been correlated with hyperlipidemia and hypertension. With improved graft survivals in the cyclosporine (CsA) era, post-tx hyperlipidemia and hypertension may place children at high risk for early atherosclerosis. Presently there are no large studies assessing the metabolic effects of steroid withdrawal in tx children. Thus, we report on the effect of prednisone withdrawal on blood pressure, weight, and serum lipid levels in children post-tx maintained on CsA alone. Pred taper is attempted in patients on CsA (6-7 mg/kg/day) with stable graft function and is extended over a 6-month period. Once a rejection is diagnosed pred is restarted and no future attempts to withdraw are made. BP, weight, and overnight fasting serum cholesterol (Schol) levels were measured 1 month prior to complete withdrawal (A), and after 6 months without pred (B). In patients requiring the restart of pred, subsequent measurements were obtained 6 months later (C). Of 74 tx children, 7 had primary nonfunction. Pred was successfully withdrawn in 49% (33) of the remaining 67. Of these patients, 42% (14/33) are still maintained off pred with stable renal function for a mean duration of 58.5 months (range 8-99 months). Nineteen patients had to be restarted on pred secondary to rejection between 7-36 months after withdrawal. Three of the patients subsequently lost their grafts to further rejection episodes. Univariate and multivariate analysis failed to identify clinical predictors of successful steroid withdrawal. The Schol at B, 171 +/- 5.4 mg/dl (mean +/- SEM) was lower (P < .001) than at A (249 +/- 10 mg/dl) or C (257 +/- 20 mg/dl). The systolic BP at B (108 +/- 2.8 mmHg) and diastolic BP at B (68 +/- 2.6 mmHg) were also lower (P < .001) than at A (122 +/- 3.2, 76 +/- 2.7 mmHg) or C (130 +/- 5, 80 +/- 3.2 mmHg), respectively. No difference in weight was noted. Lipid profile (total chol, triglyceride, HDL, VLDL, LDL) was measured in 10/14 patients off pred (mean age at sample 16.25 years) and was compared with 13 patients on pred (mean 15.5 years). Both the total chol (176 +/- 9.2, 265 +/- 8.3 mg/dl) and LDL (109 +/- 10, 167 +/- 9.2 mg/dl) were higher (P < .001) in the group on pred. Based on our findings of increased LDL and total chol, children on long-term pred therapy post-tx may be at increased risk for atherosclerotic disease.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Sobrevivência de Enxerto/efeitos dos fármacos , Transplante de Rim/fisiologia , Lipídeos/sangue , Prednisona/efeitos adversos , Síndrome de Abstinência a Substâncias/sangue , Adolescente , Criança , Pré-Escolar , Colesterol/sangue , LDL-Colesterol/sangue , Ciclosporina/uso terapêutico , Feminino , Humanos , Transplante de Rim/imunologia , Masculino , Fatores de TempoRESUMO
We have demonstrated earlier that the crosslinkage of the CD3/TCR complex with the CD2 antigen results in the proliferation of normal human T cells. The effect of this synergism was perceptible at the level of induction of the IL-2 gene, a process critical for T cell growth. To further understand the molecular and nuclear basis for this synergism, we have explored the induction of DNA-binding proteins in highly purified normal human T cells signaled via the CD3 and/or CD2 proteins. The effect of transmembrane signaling of T cells with ionomycin, and/or sn-1,2 dioctanoyl glycerol, was also determined. The emergence of nuclear binding proteins was investigated using interleukin-2 sequence specific oligonucleotide probes in the electrophoretic mobility shift assay. Our studies demonstrate for the first time that CD3 antigen-derived signals and CD2 antigen-derived signals are synergistic in inducing the emergence of transcription factors that bind to the NF-AT1, AP-1, and NF-kB sites located in the promoter/enhancer region of the IL-2 gene. Moreover, cyclosporine, at concentrations readily accomplished in clinical practice, was found to inhibit the emergence of these DNA-binding proteins in normal human T cells signaled via cell surface proteins implicated in antigen-dependent T cell activation and in T cells stimulated by mobilization of cellular calcium and activation of protein kinase C.
Assuntos
Antígenos de Diferenciação de Linfócitos T/fisiologia , Complexo CD3/fisiologia , Ciclosporina/antagonistas & inibidores , Proteínas de Ligação a DNA/fisiologia , Receptores Imunológicos/fisiologia , Sequência de Bases , Antígenos CD2 , Reagentes de Ligações Cruzadas/farmacologia , Humanos , Interleucina-2/genética , Dados de Sequência Molecular , NF-kappa B/fisiologia , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-jun/fisiologia , Transdução de Sinais , Linfócitos T/químicaRESUMO
Injection of soluble foreign antigen without an adjuvant induces a state of antigen-specific immunological unresponsiveness. We investigated the cellular mechanisms that underlie this form of peripheral tolerance by physically tracking a small population of ovalbumin (OVA) peptide/I-Ad-specific, CD4+ T cell receptor (TCR) transgenic T cells following adoptive transfer into normal recipients. Injection of OVA peptide in the absence of adjuvant caused the antigen-specific T cells to proliferate for a brief period after which most of the T cells disappeared. The remaining OVA-specific T cells had converted to a memory phenotype but were poorly responsive in vivo as evidenced by a failure to accumulate in the draining lymph nodes following immunization with OVA peptide in adjuvant. These surviving T cells possessed a long-lasting, but reversible, defect in Il-2 and TNF-alpha production and in vivo proliferation, but did not gain capacity to produce Th2-type cytokines or suppress the clonal expansion of T cells specific for another antigen. Therefore, some antigen-specific T cells survive this peripheral tolerance protocol but are functionally unresponsive due to an intrinsic activation defect.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Tolerância Imunológica , Interleucina-2/biossíntese , Fator de Necrose Tumoral alfa/biossíntese , Memória Imunológica , Modelos Imunológicos , Ovalbumina/imunologia , Fragmentos de Peptídeos/imunologiaRESUMO
To test the efficacy and toxicity of recombinant human growth hormone (rhGH, Protropin, Genentech), we reviewed our experience of its administration of rhGH to pediatric renal transplant recipients. Endogenous growth hormone (GH) levels were measured after stimulation with L-dopa and clonidine in growth retarded children whose height (ht) was greater than or equal to 2 standard deviations (SD) below the mean for age. Criteria for receiving rhGH were either subnormal GH levels (< 10 ng/ml) or a zero growth velocity over the preceding year despite normal GH levels after stimulation. The dose of rhGH administered subcutaneously was 0.1 mg/kg/day for 6 days/week. The efficacy of rhGH was evaluated using growth velocity index (GVI) and height standard deviation (Z) score. Catch-up growth was defined as an increase in Z score (delta Z) > or = 0.4. Twenty patients (17 with subnormal GH levels and 3 with normal GH levels but zero GVI) consented to rhGH treatment. Seventeen patients (14 males, 6 pubertal) have completed one year or more of rhGH therapy and are the subjects of this analysis. All 17 patients were receiving cyclosporine and 12 were receiving prednisone during rhGH therapy. Six of the 17 patients (35%) demonstrated catch-up growth (delta Z + 1.3 +/- 0.13). By regression analysis, the only factor noted to affect rhGH response was the concurrent use of prednisone. All five patients not receiving prednisone demonstrated catch-up growth compared to only 1 of 12 patients receiving prednisone (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Hormônio do Crescimento/antagonistas & inibidores , Hormônio do Crescimento/uso terapêutico , Transplante de Rim , Prednisona/uso terapêutico , Criança , Feminino , Glucose/metabolismo , Rejeição de Enxerto , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/etiologia , Hormônio do Crescimento/sangue , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Rim/efeitos dos fármacos , Masculino , Complicações Pós-Operatórias , Prednisona/efeitos adversos , Proteínas RecombinantesRESUMO
With improved long-term graft survival after renal transplantation, cardiovascular mortality is emerging as the leading cause of death in adults and is also being reported in children. Chronic corticosteroid therapy is thought to be an important cause of post-transplant hyperlipidemia and hypertension. This study describes a steroid withdrawal protocol initiated to reduced cardiovascular risk factors in pediatric renal allograft recipients, reports on the rate of rejection observed and the use of an in vitro method to measure immunoresponsiveness and identify those patients who have not experienced a rejection episode. Thirty-six of 67 patients were able to discontinue prednisone and were maintained on cyclosporine alone. Twenty-two of the 36 patients experienced an acute rejection episode a mean of 14 months (range 1.5 to 36 months) after completion of the steroid taper. Ten of the 22 rejections occurred within 12 months after completion of the taper. Fourteen patients remain rejection free to date for a mean of 70.3 months (range 19 to 111 months) after withdrawal. Using the mixed lymphocyte culture reaction, we tested the hypothesis that steroid dependent recipients (SDR) will express donor antigen specific responsiveness and steroid independent recipients (SIR) will exhibit donor antigen-specific tolerance. Four of seven SDR were tolerant to donor specific antigens but responsive to unrelated controls, while five of six SIR were responsive to donor specific antigens. These unanticipated results highlight the complexity of allograft tolerance.
Assuntos
Rejeição de Enxerto , Transplante de Rim , Teste de Cultura Mista de Linfócitos , Prednisona/administração & dosagem , Pré-Escolar , Ciclosporina/uso terapêutico , Esquema de Medicação , Humanos , Cuidados Pós-Operatórios , Prednisona/uso terapêuticoAssuntos
Ciclosporinas/administração & dosagem , Transplante de Rim/efeitos adversos , Síndrome Nefrótica/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Pré-Escolar , Ciclosporinas/uso terapêutico , Humanos , Lactente , Masculino , Síndrome Nefrótica/etiologia , Recidiva , Fatores de RiscoRESUMO
In the cyclosporine era, reports on pediatric kidney transplant (KTx) patients with obstructive and reflux uropathy are limited by small numbers, short follow-up, and/or lack of control groups. Our single-center study evaluated long-term outcomes (patient and graft survival, urinary tract infections [UTIs], urologic complications) in a large cohort of KTx recipients (<20 years old). We matched our 117 study patients with obstructive and reflux uropathy with 117 controls whose KTx was needed for other reasons; all 234 underwent their KTx between April 25, 1984, and October 23, 2002. The mean age was 8.0 +/- 6.2 years; mean follow-up, 133 +/- 67 months. The urologic complication rate was higher in study patients (43%) than in controls (11%) (p < 0.0001), as was the UTI rate (45% vs. 2%; p < 0.0001). The metabolic acidosis and UTI rates were higher in study patients who did (vs. did not) undergo bladder augmentation (p < 0.0001). We found no significant difference between study patients and controls in patient or graft survival, acute or chronic rejection, or mean estimated glomerular filtration rates. Unique to our study is the finding of higher metabolic acidosis and UTI rates in study patients who underwent bladder augmentation.
Assuntos
Rejeição de Enxerto/epidemiologia , Transplante de Rim , Obstrução Ureteral/cirurgia , Obstrução do Colo da Bexiga Urinária/epidemiologia , Infecções Urinárias/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Obstrução do Colo da Bexiga Urinária/etiologia , Infecções Urinárias/etiologiaRESUMO
We used a defined model system to address the role of minor histocompatibility antigen-specific CD4+ T cells in chronic rejection. The coronary arteries of vascularized heart grafts expressing the model antigen ovalbumin developed intimal hyperplasia in normal recipients and those lacking CD8+ T cells but not in those lacking CD4+ T cells. Furthermore, purified ovalbumin-specific CD4+ T cells from T-cell antigen receptor transgenic mice caused intimal hyperplasia in ovalbumin-expressing heart grafts in lymphocyte-deficient mice. The graft antigen-specific CD4+ T cells only caused intimal hyperplasia when expressing CD154 and were found in the intima of the affected coronary arteries along with CD40+ cells, CD11c+ dendritic cells and CD11b+, Gr-1+ monocytes. These results show that minor histocompatibility antigen-specific CD4+ T cells are required to cause the classical vascular changes of chronic rejection. They are capable of doing so without contributions from other lymphocytes, and may cause intimal hyperplasia by using CD154 to stimulate other non-lymphoid cells in the intima.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Ligante de CD40/imunologia , Rejeição de Enxerto/imunologia , Transplante de Coração/imunologia , Túnica Íntima/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Doença Crônica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Camundongos Transgênicos , Receptores de Antígenos de Linfócitos T/genética , Túnica Íntima/patologiaRESUMO
The North American Pediatric Registry reports that from 1987 to 1989 blacks and Hispanic children accounted for 23% of all renal transplants performed but 38% of those performed for focal segmental glomerulosclerosis (FSGS). From these data, we infer that blacks and Hispanics form a disproportionate number of FSGS patients who progress to end-stage renal disease (ESRD) compared with white children. To explore this hypothesis we assessed our single-center experience of FSGS comparing black and Hispanic with white children. Of 177 black and Hispanic children followed in our clinic for idiopathic nephrotic syndrome (NS) between 1974 and 1989, 57 were diagnosed as having FSGS (group I). The mean age at onset of NS of these group I patients was 7.3 +/- 4.6 years and the mean duration of follow-up was 8.25 +/- 4.3 years. During the same period, 13 of 65 white patients (group II) with idiopathic NS were found to have FSGS. Their mean age (7.8 +/- 4.8 years) and duration of follow-up (8.8 +/- 4.8 years) were similar. Therapeutic modalities in the two groups were also similar. Of group I patients, 78% (42/54) reached ESRD compared with 33% (4/12) of group II patients (P less than 0.01). Life table analysis showed that 50% of black and Hispanic children will reach ESRD within 3 years of FSGS.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Glomerulosclerose Segmentar e Focal/etnologia , Síndrome Nefrótica/etnologia , Adolescente , População Negra , Boston/epidemiologia , Criança , Pré-Escolar , Colesterol/sangue , Creatinina/sangue , Feminino , Seguimentos , Hispânico ou Latino , Humanos , Incidência , Lactente , Falência Renal Crônica/etnologia , Transplante de Rim , Tábuas de Vida , Masculino , PrognósticoRESUMO
In order to identify possible markers of cyclosporin A (CSA) efficacy, the use of CSA (6 mg/kg) in 47 children with refractory nephrotic syndrome was reviewed. Response was defined as remission of proteinuria within 2 months. Before CSA administration, nonresponders (N = 13) were found to have more proteinuria (6 versus 3 g/24 h; P less than 0.03) and higher serum creatinine levels (0.9 versus 0.6 mg/dL; P less than 0.03) compared with responders (N = 34). Also, a markedly elevated serum cholesterol level (545 versus 312 mg/dL; P less than 0.001) was noted among nonresponders. Logistic regression analysis of all three parameters isolated serum cholesterol (P less than 0.01) as the only significant predictor of CSA nonresponsiveness. Discriminate analysis identified serum cholesterol to predict 97% of responders and 77% of nonresponders (P less than 0.0005) to conventional CSA doses. The CSA whole-blood trough HPLC levels were subtherapeutic among nonresponders (71 ng/mL) compared with responders (162 ng/mL) (P less than 0.001). Thus, a high serum cholesterol level may prevent the achievement of therapeutic CSA blood levels with conventional doses. On the basis of this, seven of the nonresponders were re-treated by titration of the CSA dose (10 to 14 mg/kg) with their serum cholesterol level. Their mean highest trough CSA level was 286 ng/mL. Five patients responded within 2 months. No elevation in serum creatinine or evidence of nephrotoxicity on repeat biopsy was seen after 2 months of therapy in all seven patients. It was concluded that severe hypercholesterolemia in nephrotic syndrome patients necessitates the titration of the CSA dose with the serum cholesterol level to achieve remission.
Assuntos
Ciclosporina/administração & dosagem , Hipercolesterolemia/complicações , Síndrome Nefrótica/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Síndrome Nefrótica/complicaçõesRESUMO
With steady improvement in 1- and 5-year patient and graft survivals in the last decade, rehabilitation of the child is the major focus of the transplant physician. The notion that the elimination of the uremic milieu should enable children to grow has not been born out over time, and growth retardation continues to be a serious morbidity in many children despite a well-functioning renal allograft. In children with chronic renal failure prior to renal transplantation, recombinant human growth hormone (rhGH) has been recently shown in controlled trials to improve growth. The use of rhGH in children after renal transplantation is controversial, since uncontrolled studies have questioned its safety. Acute rejection and graft loss have been reported in children after the initiation of rhGH. This study analyzes the data regarding the safety and efficacy of rhGH in children after renal transplantation as presented in seven current published reports. The demographic characteristics of the patients, the dose and duration of rhGH therapy, the "growth" rates of the patients before and after rhGH therapy, renal function before and after rhGH therapy, and other possible complications are reviewed. Based on this analysis, suggestions for future studies are made.
Assuntos
Hormônio do Crescimento/fisiologia , Transplante de Rim/fisiologia , Criança , Crescimento/fisiologia , Hormônio do Crescimento/sangue , HumanosRESUMO
Idiopathic focal segmental glomerulosclerosis is a histologic diagnosis that usually presents as the nephrotic syndrome but, unlike minimal change disease, often leads to renal failure in children. Standard therapies used to treat the proteinuria are often futile, and thus patients are at risk for the multiple complications resulting from persistent, severe proteinuria. Eventually, end-stage renal failure ensues, and the possibility of the disease recurring in the transplanted renal allograft is worrisome. This report reviews the clinical features and outcomes of idiopathic focal segmental glomerulosclerosis in children, the response to newer treatment options, and new insights into understanding what factors may be involved in causing the disorder.
Assuntos
Glomerulosclerose Segmentar e Focal , Criança , Ciclosporina/uso terapêutico , Glomerulosclerose Segmentar e Focal/diagnóstico , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Glomerulosclerose Segmentar e Focal/fisiopatologia , Humanos , Falência Renal Crônica/etiologia , Transplante de Rim , Recidiva , Resultado do TratamentoRESUMO
TCR aggregation at the point of contact with an APC is thought to play an important role in T cell signal transduction. However, this potentially important phenomenon has never been documented during an immune response in vivo. Here we used immunohistology to show that the TCR on naive Ag-specific CD4 T cells in the lymph nodes of mice injected with Ag redistributed to one side of the cell. In cases where the APC could be identified, the TCR was concentrated on the side of the T cell facing the APC. In those T cells that produced IL-2, the TCR and IL-2 localized to the same side of the cell. In vivo IL-2 production depended on costimulatory signaling through CD28, whereas TCR redistribution did not. These results show that Ag-stimulated CD4 T cells produce IL-2 in a polarized fashion and undergo CD28-independent TCR redistribution in vivo.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Polaridade Celular/imunologia , Interleucina-2/biossíntese , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos/administração & dosagem , Antígenos CD28/genética , Linfócitos T CD4-Positivos/imunologia , Comunicação Celular/genética , Comunicação Celular/imunologia , Polaridade Celular/genética , Epitopos de Linfócito T/imunologia , Injeções Subcutâneas , Interfase/genética , Interfase/imunologia , Linfonodos/citologia , Linfonodos/imunologia , Linfonodos/metabolismo , Linfocinas/biossíntese , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Camundongos Transgênicos , Ovalbumina/administração & dosagem , Receptores de Antígenos de Linfócitos T/genéticaRESUMO
We report here the cases of 15 children in whom nephrotic syndrome developed, from among 164 children (55% male, 90% black) followed in our acquired immunodeficiency syndrome clinic from 1984 through 1990. Mean age at onset of nephrotic syndrome was 4.9 +/- 2.6 years. Fourteen patients were black and one was Hispanic. Seventy-three percent of our patients with nephrotic syndrome were girls. The mean duration of clinical acquired immunodeficiency syndrome before development of nephrotic syndrome was 1.7 +/- 1.1 years. In eight patients, nephrotic syndrome appeared between 3 and 11 months after intravenous infusions of immune globulin or albumin were administered as part of a research protocol; this incidence (8/47) was higher than the incidence of nephrotic syndrome among those who did not receive intravenous infusions (7/117, p less than 0.05). Tissue for histologic examination was available for 80% of the patients, and histologic examination demonstrated mesangial hypercellularity (5 patients), focal segmental glomerulosclerosis (4 patients), minimal change disease (2 patients), and IgM nephropathy (1 patient). Deposition of one or more immunoglobulins was noted in all but one patient studied with immunofluorescence. Corresponding electron-dense deposits were seen by electron microscopy in 78% of specimens. Prednisone did not induce a remission of nephrotic syndrome in the 13 patients treated, whereas cyclosporine did so in the 3 patients to whom it was administered. Five patients were in the end stage of renal disease within 8 months. Successful maintenance peritoneal dialysis was performed in three patients, but 80% of patients have died of human immunodeficiency virus-related complications; one patient was lost to follow-up. We conclude that immune-complex deposition is consistently seen in children with human immunodeficiency virus-associated nephrotic syndrome. This nephrotic syndrome is resistant to steroid therapy, but we observed a remission of the proteinuria with cyclosporine therapy in three patients. For patients with end-stage renal disease, maintenance peritoneal dialysis may improve the quality of life.
Assuntos
Síndrome da Imunodeficiência Adquirida/complicações , Síndrome Nefrótica/complicações , Síndrome da Imunodeficiência Adquirida/terapia , Adolescente , Albuminas/efeitos adversos , Criança , Pré-Escolar , Método Duplo-Cego , Edema/patologia , Feminino , Soropositividade para HIV , Humanos , Imunização Passiva/efeitos adversos , Imunoglobulinas/administração & dosagem , Lactente , Masculino , Síndrome Nefrótica/sangue , Síndrome Nefrótica/patologia , Síndrome Nefrótica/urina , Prognóstico , Proteinúria/urina , Albumina Sérica/análise , Taxa de SobrevidaRESUMO
Short-term cyclosporine (CsA) has been shown to reduce the proteinuria in refractory nephrotic syndrome, but the effect on disease progression has not been evaluated. This study was undertaken to evaluate whether maintenance CsA therapy in steroid-resistant focal segmental glomerulosclerosis (FSGS) will prevent progression to ESRD. Twenty-one black and Hispanic children (mean age, 8.4 +/- 4.5 yr) with biopsy-proven, steroid/cyclophosphamide-resistant FSGS were treated with CsA (initiated at 6 mg/kg per day and titrated to the serum cholesterol level to achieve a response). The mean CsA dose was 7 (4 to 20) mg/kg per day, the duration of CsA therapy was 27.5 (3 to 97) months, and the duration of follow-up was 8.5 +/- 4.7 yr. At the end of CsA therapy, the mean (+/- SE) proteinuria fell from 6.2 +/- 0.2 to 2.0 +/- 0.1 g/24 h (P < 0.001), the mean albumin rose from 1.95 +/- 0.04 to 3.41 +/- 0.04 g/dL (P < 0.001), the mean cholesterol decreased from 472 +/- 12.7 to 257 +/- 5.3 mg/dL (P < 0.005), and the mean creatinine rose from 0.79 +/- 0.02 to 1.16 +/- 0.03 mg/dL (P < 0.005). Seven children continue to receive maintenance CsA therapy, and 14 patients have had CsA stopped: 6 for an increase in serum creatinine and/or continued proteinuria, 5 for sustained remission, 2 for noncompliance, and 1 for pregnancy. Five (24%) of the 21 patients progressed to ESRD.(ABSTRACT TRUNCATED AT 250 WORDS)