Analysis of the costs of the basic care line for sickle cell disease in Brazilian children under 5 years of age

ABSTRACT Objective: To evaluate and estimate the cost of basic care in sickle cell disease (SCD) for patients under five years of age, within the scope of the Unified Health System (SUS) and to discuss the costs related to possible complications of the disease from the literature. Methods: The main management and conduct recommendations in the SCD up to five years of age, with healthy and baseline health status, were extracted from the Basic Guidelines of the Care Line in the SCD of the Ministry of Health. Systematic data regarding costs of medicines were extracted from the Medicine Market Regulation Chamber. The SUS Table of Procedures, Medicines and Orthotics, Prosthetics and Auxiliary Means of Movement Management System was the guide for the values of complementary exams, as well as for medical consultations. The values applied to calculate the vaccination schedule were extracted from the Pan American Health Organization, adopting the perspective of the SUS-paying costs. Results: The total cost obtained for basic care of SCD in children up to five years of age, including the use of antibiotic prophylaxis, immunizations and the performance of transcranial Doppler ultrasound in the prevention and early detection of cerebrovascular accidents was, on average, $1020.96. Conclusion: The cost-effectiveness of prophylaxis in SCD, up to five years of age, exceeds the expenses resulting from hospitalizations due to complications of the disease. The study of expenses associated with SCD could be used to establish public policies, improve prevention strategies and treat the symptoms and complications of the disease.

Immunotherapy for chronic hepatitis B / 临床肝胆病杂志

Although current direct anti-hepatitis B virus (HBV) drugs have good effects in controlling viral replication and limiting the progression to liver cirrhosis, there is still a long way to go in the treatment of chronic hepatitis B (CHB). Immune tolerance and immune dysfunction may be the two most important immunopathogenic factors. With reference to the development of new strategies and new drugs for anti-HBV immunotherapy and the latest research findings around the world, this article reviews the research advances in immunotherapy for CHB in recent years.

Research advances in cellular immunotherapy for primary hepatocellular carcinoma / 临床肝胆病杂志

The present therapy for primary hepatocellular carcinoma (HCC)consists of surgery as well as local radiotherapy and chemother-apy.However,the majority of patients are susceptible to recurrence after comprehensive treatment,and the overall treatment outcome is not ideal due to the lack of effective drugs and strategies.Increasing evidence has demonstrated that the immune system is closely related to the development,progression,metastasis,and recurrence of HCC.Thus,immune therapy,especially cellular immunotherapy,could regulate immune function and induce specific antitumor immunity to achieve the goal of controlling HCC and reducing its recurrence and metastasis, which has become an essential part in the comprehensive treatment of HCC.The findings in preclinical and clinical studies on cellular immu-notherapy for HCC data are reviewed,and the current problems are discussed.

In vitro induction of anterior gradient-2-specific cytotoxic T lymphocytes by dendritic cells transduced with recombinant adenoviruses as a potential therapy for colorectal cancer

Anterior gradient-2 (AGR2) promotes tumor growth, cell migration, and cellular transformation, and is one of the specific mRNA markers for circulating tumor cells in patients with gastrointestinal cancer. We investigated the feasibility of AGR2 as a potent antigen for tumor immunotherapy against colorectal cancer (CRC) cells using dendritic cells (DCs) transduced with a recombinant adenovirus harboring the AGR2 gene (AdAGR2). DCs transduced with a recombinant adenovirus encoding the AGR2 gene (AdAGR2/DCs) were characterized. These genetically-modified DCs expressed AGR2 mRNA as well as AGR2 protein at a multiplicity of infection of 1,000 without any significant alterations in DC viability and cytokine secretion (IL-10 and IL-12p70) compared with unmodified DCs as a control. In addition, AdAGR2 transduction did not impair DC maturation, but enhanced expression of HLA-DR, CD80, and CD86. AdAGR2/DCs augmented the number of IFN-gamma-secreting T-cells and elicited potent AGR2-specific cytotoxic T lymphocytes capable of lysing AGR2-expressing CRC cell lines. These results suggest that AGR2 act as a potentially important antigen for immunotherapy against CRC in clinical applications.

The dendritic cells loaded with autologous tumor antigen in treatment of elderly patients with gastric cancer:a clinical efficacy and safety evaluation / 中华老年医学杂志

Objective To evaluate clinical safety and efficacy of autologous tissue antigens loaded dendritic cells (DC)in the treatment of elderly patients with gastric cancer.Methods Fresh tumor cells were isolated from surgical specimens in twenty patients with gastric cancer. Single cell suspensions were obtained and induced to apoptosis by heat shock. The apoptotic tumor cells were frozen before use.Peripheral blood mononuclear cells were isolated and cultured with recombinant human granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin-4 (IL-4).DCs were loaded with apoptotic tumor cells. The immunological and clinical responses were examined after the final vaccination. ResultsVaccination of dendritic cells was well tolerated and no toxicity was observed. The cytokine levels in serum such as IL-2(46 pg/mg vs 89 pg/mg), IL-12(44 pg/mg vs. 86 pg/mg) and IFN-γ(38 pg/mg vs.82 pg/mg) were increased after vaccinations as compared with pretherapy. DTH test were positive in five patients (5/10). The antigen special cells for CD8+/ IFN-γ+ were increased in five patients(5/10). The size of retroperitoneal lymph node of one patient was reduced. The tumor marker CEA level were decreased in five patients, stable in eight patient and increased in two patients.Conclusions Autologous DC vaccines loaded with autologous tumor antigens could improve function of non specific immunity and elicit specific T cells immunologic response and is one of safe and effective treatments for gastric cancer.

The clinical application of active immunotherapy in unexplained habitual abortion / 国际检验医学杂志

Objective To explore the relationship between the changes in cellular immunity and the causes of unexplained habitual abortion(UHA)as well as the mechanism of active immunotherapy on UHA patients.Methods T-lymphocyte and natural killer(NK)cell subsets(CD3+%,CD4+%,CD8+%,CD16+CD56+% and CD4+/CD8+ ratio)of peripheral blood were detected by applying flow cytometry and compared in 66 cases of UHA(UHA group,including 30 cases receiving active immunotherapy and 36 untreated UHA cases)and 30 cases of healthy fertile women(healthy control group).The re-pregnancy achievement ratio was compared between 30 treated UHA cases and 36 untreated UHA cases.Results The percentages of CD31+ and CD16+ CD56+ cells as well as CD4+/CD8+ ratio were significantly higher in UHA group than those of healthy control group(P＜0.050).As compared with those of untreated UHA subgroup,the percentages of CD3+ and CD16+ CD56+ cells as well as CD4+/CD8+ ratio were significantly lower(P＜0.050),while the re-pregnancy achievement ratio was higher(92.86% vs 05 29.03%,P＜0.001).Conclusion The changes in T-lymphocyte and NK cell subsets have something to do with occurrence of UHA.Active immunotherapy can regulate the cellular immune function and improve the re-pregnancy achievement ratio effectively.

Implicações da imunossenescência na vacinação de idosos: [revisão] / Implications of immunosenescence in vaccination of the elderly: [review]

A prevalência de indivíduos idosos em relação aos indivíduos jovens compreende um quadro comum na população mundial. Estima-se que, em 2050, cerca de 22% da população mundial será constituída por indivíduos idosos. No Brasil, o número de idosos (> 60 anos de idade) passou de 3 milhões em 1960 para 7 milhões em 1975 e 14 milhões em 2002 (um aumento de 500% em 40 anos), e estima-se que alcançará 32 milhões em 2020. Este fenômeno se deve ao advento de drogas antibacterianas, a vacinações em larga escala e a outros avanços no tratamento médico. Contudo, a eficácia de uma vacina depende, sobretudo, da habilidade dos indivíduos para exibir uma resposta imune adequada. Assim, esta revisão apresenta os principais efeitos da imunossenescência na resposta imune a uma vacina. Além disto, discute algumas estratégias que aumentam os níveis de proteção das imunizações neste grupo etário. A compreensão dos fatores envolvidos na geração de uma resposta imunológica durante a senescência e a introdução de estratégias que melhoram a eficácia de vacinas nos indivíduos idosos reduz a incidência e a severidade de doenças infecciosas, tendo forte impacto na qualidade de vida destes indivíduos.

The increase of the elderly population is a worldwide common phenomenon. According to some projections, in the year 2050 older people will be about 22% of the world population. In Brazil the number of elderly (> 60 years of age) increased from 3 million in 1960, and to 7 million by 1975 and 14 million by 2002 (an increase of 500% in just forty years); according to estimates, it will reach 32 million by 2020. This phenomenon is due to advent of antibacterial drugs, large-scale vaccinations and other advances of medical treatment. However, the vaccine efficacy depends on the ability of individuals to exhibit an adequate immune response. This review presents the main effects of immunosenescence in immune response to a vaccine. Furthermore, it discusses strategies that may counteract age-related defects in immune responses to vaccination. The understanding of how immunological memory is affected by ageing, and the introduction of strategies to ameliorate vaccine efficacy in the elderly, might reduce the incidence and the severity of infectious disease and have a strong impact on the quality of life of elderly individuals.

Anti-tumor immunostimulatory effect of heat-killed tumor cells

As a part of our ongoing search for a safe and efficient anti-tumor vaccine, we attempted to determine whether the molecular nature of certain tumor antigens would influence immune responses against tumor cells. As compared with freeze-thawed or formaldehyde-fixed tumor antigens, heat-denatured tumor antigens elicited profound anti-tumor immune responses and greatly inhibited the growth of live tumor cells. The heat-denatured tumor antigens induced a substantial increase in the anti-tumor CTL response in the absence of any adjuvant material. This response appears to be initiated by strong activation of the antigen-presenting cells, which may recognize heat-denatured protein antigens. Upon recognition of the heat-denatured tumor antigens, macrophages and dendritic cells were found to acutely upregulate the expression of co-stimulatory molecules such as B7.2, as well as the secretion of inflammatory cytokines such as IL-12 and TNF-alpha. The results of this study indicate that heat-denatured tumor extracts might elicit protective anti-tumor adaptive immune responses and also raise the possibility that a safe and efficient adjuvant-free tumor vaccine might be developed in conjunction with a dendritic cell-based tumor vaccine.

Increase of NKG2D ligands and sensitivity to NK cell-mediated cytotoxicity of tumor cells by heat shock and ionizing radiation

In this study, we have investigated if current cancer therapeutic modalities including hyperthermia and ionizing radiation can increase the expression of NKG2D ligands in human cancer cell lines. The expressions of NKG2D ligands were induced by both heat shock and ionizing radiation in various cell lines including KM12, NCI-H23, HeLa and A375 cells with peaks at 2 h and 9 h after treatment, respectively, although inducibility of each NKG2D ligand was various depending on cell lines. During the induction of NKG2D ligands, heat shock protein 70 was induced by heat shock but not by ionizing radiation. These results were followed by increased susceptibilities to NK cell-mediated cytolysis after treatment with heat shock and ionizing radiation. These results suggest that heat shock and ionizing radiation induce NKG2D ligands and consequently might lead to increased NK cell-mediated cytotoxicity in various cancer cells.

Antitumor immunity induced by tumor cells engineered to express a membrane-bound form of IL-2

Transduction of cytokine gene into tumor cells is a promising method of tumor therapy, but the value is limited by accompanying side effects. To focus antitumor immune response to tumor antigen-specific CTL, we developed an antitumor vaccine by transfecting modified IL-2 gene in a membrane-bound form (mbIL-2) into B16F10 melanoma cells. The mbIL-2 clone showed reduced tumorigenicity and metastatic ability, and inhibited metastasis and prolonged the survival of mice against B16F10 cells. The inhibition of B16F10 metastasis by mbIL-2 was accompanied by the increment of CD8+ T cells. The metastasis of mbIL-2 clone was significantly increased in the CD8+ T cell-depleted mice, but not in CD4+ T cell depleted mice. Spleen cells immunized with the mbIL-2 clone showed higher CTL activity towards B16F10 cells than those immunized with control cells. The size of CD8+ T cell population in the lung of mice injected with the mbIL-2 clone was markedly greater than that of mice injected with B16F10 cells, but there was no detectible change in CD4+ and CD8+ T cell populations of lymph nodes and spleen. These results suggest that when the mbIL-2 clone is introduced into the blood stream, it migrates mainly to lung and activates CD8+ T cells in situ, possibly by direct priming. Such a tumor vaccine may ameliorate the toxic side effects encountered with conventional cytokine gene therapy.

Influences of active immunotherapy on T helper cell type 1 and 2 cytokines in women with unexplained habitual abortion / 中华妇产科杂志

Objective To investigate the influences of active immunotherapy on T helper cell (Th)1/Th2 type cytokines in women with unexplained habitual abortion(UHA) Methods A total of 55 patients with UHA were studied, including 30 cases after active immunotheraphy (AIT) and 25 cases without any therapy(NAIT). Fifteen cases of normal nonpregnant (NNP) women were selected as control group. Supernatants from trophoblast activated peripheral blood mononuclear cells (PBMC) of the three groups were tested by enzyme linked immunosorbent assay (ELISA) for interferon gamma (IFN ?), interleukin 2 (IL 2), IL 4, IL 10. Results (1) The levels of IL 2 and IFN ? in AIT group [(108?37) ng/L and (110 ?52) ng/L, respectively] were lower significantly than those in NAIT group[(223?85) ng/L and (326 ?92) ng/L, respectively]( P 0.05). (2) Twenty six women in AIT group got pregnant, but 8 women experienced pregnancy loss repeatedly whose IL 2?IFN ? levels were higher than those in other 18 women got successful pregnancy and IL 4,IL 10 levels lower than the latter. Conclusions UHA patients have Th1 type immunity to trophoblast and produce high level Th1 type cytokines which probably result in pregnancy loss. Active immunotheraphy could make a shift from Th1 to Th2 immunity, thus favoring the maintenance of pregnancy.

Study on changes of serum T helper cell type 1 and 2 cytokines after active immunotherapy in women with unexplained habitual abortion / 中华妇产科杂志

Objective To investigate the changes of serum T helper cell (TH)1/TH2 type cytokines after the active immunotherapy in unexplained habitual abortion (UHA) women. Methods Concentrations of interleukin (IL) 2, IL 12, interferon (IFN) ?, IL 4, IL 10 and transforming growth factor (TGF) ?1 were measured by enzyme linked immunosorbant assay (ELISA) method in sera from thirty three cases of unexplained habitual abortion (UHA) women before and after active immunotherapy. Thirty normal non pregnancy (NNP) women and thirty normal pregnancy (NP) women were taken as control. Results (1) Serum concentrations of IL 2 and IL 12 were higher significantly (P

A clinical study of autologous tumor vaccine in patients with malignant tumors / 解放军医学杂志

Objective To evaluate the clinical significance and the mechanism of immunotherapy with autologous tumor vaccine. Methods 400 patients with pathological diagnosis of malignant tumor were enrolled in this study. 5 days after operation, the patients received vaccination of autologous tumor vaccine every 2-3 days for 5 times. 3 days before and 7 days after administrations, the peripheral blood mononuclear cells (PBMC) were isolated to assay the alteration in the proportions of CD3,CD4,CD8,CD4/CD8, and NK cells. Meanwhile, serum IL-2 and IFN-? were measured. Results After active immunotherapy with autologous tumor vaccine, the proportions of CD4 and CD4/CD8 were significantly elevated, while the proportion of CD8 and NK showed no difference. All the patients tolerated the vaccine well without serious side effects, such as skin ulceration. Conclusion The autologous tumor vaccine can elicit specific cellular immune response, and may be a potential approach to treat the cancer.

Study on the mechanisms of T cell vaccination-induced survival prolongation of cardiac allograft in rats / 中华器官移植杂志

Objective To investigate the effect of T cell vaccination(TCV)on the survival time of cardiac allograft in rat.Methods Rat heterotopic cardiac transplantation was performed,Donor antigenprimed recipients' spleen cells were obtained bv 1/3 splenectomy for the preparation of TCV.TCV was then intraperitoneally into the abdominal cavity again.The survival time of cardiac allograft was observed.Results TCV could markedly prolonged rat cardiac allograft survival.T cell proliferation was increased and B cell proliferation was not affected in the vaccinated rats.The mixed lymphocyte reaction(MLR)was inhibited,The analysis of phenotypes on T cells showed that the number of CD8+ clones in vaccine cells and vaccinated rat spleen cells were increased.The antibody-mediated cytotoxicity was not affected by TCV.Conclusions TCV enhances the recipients' T cell-mediated immune response.The TCV-induced hyporeactivity to specific donor antigen is related to the induction of anti-idiotypic response and is not associated with humoral mechanisms.

Induction of cytotoxic T lymphocytes from the hepatocellular carcinoma patients by using MAGE-3- gene-derived and HLA-A2-restricted peptide / 中国普通外科杂志

Objective To explore the possibility of immune therapy for hepatocellular carcinoma (HCC) with MAGE-3 antigen peptide (FLWGPRALV). Methods The expression of HLA-A2 in HCC patients were examined with microcytotoxicity assay .The mRNA of MAGE-3 genes in the tumor tissues were detected by RT-PCR, the CD8 positive T lympocytes were separated as effector cells with immunobeads from peripheral blood mononuclear cells (PBMCs) of those patients. The irradiated autologous CD8 negative PBMC were pulsed with MAGE-3 peptide as APC. Some effector cells were co-cultured with APC, and some not as the control. After 14 days′ culture with IL-2, the frequency of effector cells secreting IFN-? in response to MAGE-3 peptide were monitored by IFN-? secretion assay. The hepatocellular carcinoma cell line HLE was used as the target cells.ResultsNine HCC patients were HLA-A2 positive in 25 HCC patients, and 3 of them were MAGE-3 mRNA positive. After two weeks′ culture, the effector cells increased by 4-6 folds. The frequency of CD8 positive cells secreting IFN-? in response to MAGE-3 peptide was 22.0% in 3 MAGE-3 mRNA positive patients(n=3),and 0.5% in 6 negative patients( n=6) (?

Immunotherapeutic effects of dendritic cells vaccine pulsed with tumor cell lysate in mice with pancreatic carcinoma / 中国普通外科杂志

ObjectiveTo observe the immunotherapeutic effects of dendritic cells vaccine pulsed with tumor cell lysate on mice with pancreatic carcinoma. Methods Dendritic cells (MTSC4)were pulsed with tumor cells lysate. The immune preventative and immnotherapeutic effects of DC vaccines on mice with pancreatic carcinoma were assessed. Results After vaccination of the DC vaccines, mice remained tumor-free for at least 25 days in DCs vaccines group,but in other groups the subcutaneous implantation tumorigenesis were found beginning 3 to 9 days. CTL stimulated by DC vaccines effected cytolytic activity against pancreatic carcinoma cells. The survival period was obviously prolonged in DCs vaccines group (56?9)?d than in other groups (P

Clinical study on using anti-HBV therapeutic vaccine in the treatment of chronic HBV carriers / 解放军医学杂志

Objective To evaluate prove the clinical efficacy of anti HBV therapeutic vaccine in the treatment of chronic HBV carriers. Methods 600 patients diagnosed as chronic HBV carrier based on the criteria formulated by the National Conference of Viral Hepatitis in 1997 were enrolled for the study. The patients were randomly assigned into 2 groups. In the first group, 300 patients were given anti HBV therapeutic vaccine subcutaneously once a month, tagether with vitamin C 500mg p o. once a day for 12 months. Patients in the second group received normal saline 2 ml/month by subcutaneous injection and vitamin C 500mg/day p o. for 12months. There were no significant deferences in the age, sex, duration of the illness and the positive rate of serum HBV markers between the 2 groups. At the week 12, 24 and 48 after treatment, the patients were reexamined in the hospital. Serum HBsAg, HBeAg, HBV DNA, anti HBe, anti HBs and ALT were assayed before the treatment and at week 12, 24 and 48 during the course of the therapy. The efficacy of the treatment was evaluated on basis of the results of the assessment of parameters described above at week 48. After completion of the treatment, 208 patients in the treatment group and 196 cases in the control group were followed up for 12 months, and serum HBV markers were checked at the 12th month. The changes in HBV markers during the follow up study were analysed to evaluate the sustained effect after the therapy was ceased. Results The seronegative rates of serum HBsAg, HBeAg and HBV DNA in the treatment group were 14 7%, 32 0% and 37 3%, respectively, and they were significantly higher compared with the control group ( P