RESUMO
BACKGROUND.: Vaccination against Epstein-Barr virus (EBV), inducing an antibody response to the envelope glycoprotein gp350, might protect EBV-negative children with chronic kidney disease from lymphoproliferative disease after transplantation. METHODS.: A phase I trial recruited children with chronic kidney disease to two successive cohorts given three injections of 12.5 microg (n=6) and 25 microg (n=10) recombinant gp350/alhydrogel vaccine over 6 to 8 weeks. RESULTS.: One in each cohort acquired wild EBV before the week 28 evaluation. Both doses were similarly immunogenic, inducing an IgG response in all 13 evaluable patients. Neutralizing antibodies were detected in four recipients (1/4 in the 12.5 microg and 3/9 in the 25 microg cohort). Median time from first vaccination to transplantation was 24 weeks. Immune responses declined rapidly and were unlikely to affect posttransplant events. DISCUSSION.: The vaccine was immunogenic but a prolonged vaccine schedule up to time of transplantation or improved adjuvants are required in future trials to reduce posttransplant EBV load and risk of lymphoproliferative disease.
Assuntos
Herpesvirus Humano 4/imunologia , Falência Renal Crônica/imunologia , Transplante de Rim/imunologia , Glicoproteínas de Membrana/imunologia , Vacinas Sintéticas/toxicidade , Proteínas da Matriz Viral/imunologia , Vacinas Virais/toxicidade , Adolescente , Animais , Células CHO/imunologia , Criança , Pré-Escolar , Cricetinae , Cricetulus , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/efeitos dos fármacos , Lactente , Glicoproteínas de Membrana/genética , Proteínas da Matriz Viral/genéticaRESUMO
We present a case of post-transplantation Kaposi's sarcoma (KS) successfully treated by conversion to rapamycin. Clinical and histological resolution was observed within 6 months of commencing rapamycin. Also, vascular endothelial growth factor (VEGF) staining in the biopsy samples resolved following rapamycin therapy. Interestingly there was no expansion in cytotoxic T-lymphocyte (CTL) subsets observed during this period, as might be expected if this remission was due to immune reconstitution following reduction in immunosuppression. These data suggest that the resolution of tumour with rapamycin could be the result of the antiangiogenic, antiproliferative effects of rapamycin.
RESUMO
Reduction of immunosuppression (RIS) to allow development or recovery of Epstein-Barr virus (EBV) immunity can be used to treat EBV-associated posttransplant lymphoproliferative disease (PTLD). Quantification of EBV-specific immunity would help assessment of the efficacy of RIS therapy. Use of intracellular cytokine staining and analysis by flow cytometry to monitor functional EBV-specific T-cell immunity was evaluated in healthy volunteers. The technique was then used to monitor EBV immunity in nine renal transplant patients with PTLD during RIS. The number of interferon (IFN)-gamma producing CD8+ T cells specific for EBV increased distinctly before regression of EBV+ PTLD tumors occurred. The findings confirm the importance of IFN-gamma producing CD8+ T cells in controlling the malignant EBV-transformed B cells of PTLD. The assay effectively quantified EBV immunity during RIS in transplant patients with PTLD.
Assuntos
Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Herpesvirus Humano 4/imunologia , Imunoadsorventes/farmacologia , Interferon gama/biossíntese , Transtornos Linfoproliferativos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citocinas/biossíntese , Humanos , Transplante de Rim/efeitos adversos , Transtornos Linfoproliferativos/metabolismo , Transtornos Linfoproliferativos/cirurgia , Resultado do TratamentoRESUMO
We present the results of a multicenter clinical trial using Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) generated from EBV-seropositive blood donors to treat patients with EBV-positive posttransplantation lymphoproliferative disease (PTLD) on the basis of the best HLA match and specific in vitro cytotoxicity. Thirty-three PTLD patients who had failed on conventional therapy were enrolled. No adverse effects of CTL infusions were observed and the response rate (complete or partial) in 33 patients was 64% at 5 weeks and 52% at 6 months. Fourteen patients achieved a complete remission, 3 showed a partial response, and 16 had no response at 6 months (5 died before completing treatment). At 5 weeks, there was a significant trend toward better responses with higher numbers of CD4(+) cells in infused CTL lines (P = .001) that were maintained at 6 months (P = .001). Patients receiving CTLs with closer HLA matching responded better at 6 months (P = .048). Female patients responded better than male patients, but the differences were not statistically significant. Our results show that allogeneic CTLs are a safe and rapid therapy for PTLD, bypassing the need to grow CTLs for individual patients. The response rate in this poor prognosis patient group is encouraging.
Assuntos
Infecções por Vírus Epstein-Barr/terapia , Herpesvirus Humano 4/imunologia , Transtornos Linfoproliferativos/terapia , Linfócitos T Citotóxicos/transplante , Adolescente , Adulto , Idoso , Anticorpos Antivirais/sangue , Estudos de Casos e Controles , Criança , Pré-Escolar , Infecções por Vírus Epstein-Barr/virologia , Feminino , Antígenos HLA/imunologia , Humanos , Imunoterapia , Imunoterapia Adotiva , Lactente , Transtornos Linfoproliferativos/virologia , Masculino , Pessoa de Meia-Idade , Transplante de Órgãos , Reação em Cadeia da Polimerase , Imunologia de Transplantes , Transplante HomólogoRESUMO
Adoptive immunotherapy using Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTL) generated ex vivo can be an effective treatment of EBV-positive posttransplantation lymphoproliferative disease (PTLD). We describe the establishment of a cryopreserved repository of allogeneic virus-specific CTL lines, to our knowledge the first of its kind in the world. CTL lines were grown by weekly stimulation with autologous EBV immortalized lymphoblastoid cell lines (LCLs) from 96 EBV-seropositive blood donors. Analysis of 60 CTL lines grown continuously for 7 to 10 weeks showed an average proportional weekly increase in cell numbers of 1.4, with an overall increase ranging from 1.1 to 83.4. The greatest increase occurred during the early culture period. After four rounds of stimulation, killing of autologous LCLs was generally high (mean 48%); however, most lines required 9 or 10 stimulations to reduce the killing of nonspecific targets. Overall, 79% of CTLs generated showed acceptable levels of specific killing. Phenotypically, the CTL lines consisted of TCRalpha beta+, CD8+ T cells (medians 97% and 90% respectively) with a minority population of CD4+ T cells (median 2%). Most cells expressed the activation and differentiation markers, HLA-DR, CD26, CD45RO, CD69, and CD150. Favorable results have been obtained in an open trial using partially HLA-matched, allogeneic CTLs from this bank to treat PTLD patients. This now represents a single resource that can provide therapeutic CTLs rapidly on a countrywide basis, superseding the time-consuming, expensive practice of generating autologous CTLs from each patient requiring treatment. Additionally, other patient groups, such as those with EBV-positive Hodgkin disease, may benefit from CTL treatment.
Assuntos
Armazenamento de Sangue/métodos , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/terapia , Imunoterapia/métodos , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Doadores de Sangue , Células Cultivadas , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/fisiologia , Humanos , Fenótipo , Linfócitos T Citotóxicos/efeitos da radiaçãoRESUMO
BACKGROUND: Epstein-Barr virus (EBV)-associated post-transplantation lymphoproliferative disease (PTLD) is a common, often fatal, complication of bone-marrow and solid-organ transplantation. Since tumour growth results from inadequate T-cell control of latent EBV, new immunotherapeutic approaches to treatment are being pioneered. METHODS: In a phase 1/2 trial, eight patients with progressive PTLD unresponsive to conventional treatment were given one to six infusions of partly HLA-matched allogeneic EBV-specific cytotoxic T lymphocytes (CTLs) from a frozen bank of CTLs derived from healthy blood donors. FINDINGS: Of the five patients who completed treatment, three had complete remission and two had no clinical response. One patient partly responded after two infusions. No graft-versus-host disease or allo-specific antibodies were detected, and graft function improved in three cases. Tumour responses were mainly seen in those with early, localised, polyclonal disease. EBV load in peripheral blood fell to undetectable levels in all patients who responded to treatment, but was more variable in those who did not. INTERPRETATION: Treatment of EBV-associated PTLD with partly HLA-matched CTLs grown from unrelated donors is effective. Spontaneous remission is very unlikely to account for tumour regression in our patients; however, a larger, controlled trial is needed to assess this treatment further. The frozen bank of allogeneic CTLs is less prohibitively labour intensive and expensive for wide scale use than treatment with autologous CTLs. Such banks could be established to treat other infectious and neoplastic diseases in many patients.