Genetics of graft-versus-host disease: The major histocompatibility complex

Graft-versus-host disease (GVHD) is a potentially life-threatening complication of allogeneic hematopoietic cell transplantation. Many genes are presumed to be involved in GVHD, but the best characterized genetic system is that of the human major histocompatibility complex (MHC) located on chromosome 6. Among the hundreds of genes located within the MHC region, the best known and characterized are the classical HLA genes, HLA-A, C, B, DRB1, DQB1, and DPB1. They play a fundamental role in T cell immune responses, and HLA-A, C, and B also function as ligands for the natural killer cell immunoglobulin-like receptors involved in innate immunity. This review highlights the state-of-the art in the field of histocompatibility and immunogenetics of the MHC with respect to genetic risk factors for GVHD.     

硼替佐米对HCT8细胞增殖、凋亡及黏附能力的影响

目的: 观察硼替佐米对HCT8细胞增殖、凋亡及黏附能力的影响.方法: 不同浓度梯度(12.5-200 nmol/L)的硼替佐米作用于HCT8细胞后, 用MTT检测细胞增殖抑制作用; 25 nmol/L的硼替佐米作用48 h后, 流式细胞仪检测细胞周期和凋亡率; Western blot检测E-cadherin、β-catenin、cyclinD1和NF-κB表达.结果: 硼替佐米对HCT8细胞的增殖抑制作用有时间和浓度的依赖性. 25 nmol/L的硼替佐米作用48 h诱导细胞的凋亡, 凋亡率为12.3%,显著高于对照组( P<0.05), 上调了E-cadherin和β-catenin蛋白的表达, 下降了NF-κB和cyclinD1蛋白的表达.结论: 硼替佐米可以抑制HCT8细胞的增殖,诱导细胞凋亡. 抑制NF-κB通路的激活有可能为其作用机制之一; 并有可能增加细胞之间的黏附, 降低肿瘤的远处转移.     

Compliance with yellow fever and measles vaccines in the revaccination program post-hematopoietic cell transplantation

Introduction

Measles, mumps, rubella, and even poliomyelitis outbreaks have recently perplexed infectious disease clinicians and epidemiologists globally due to the decline in vaccination coverage rates in children and adults. Measles and yellow fever (YF) have represented an increasing burden on the Brazilian public health system in recent decades. Both diseases are preventable by live-attenuated viral vaccines (LAVV), which have restricted use in hematopoietic cell transplant (HCT) recipients.

Methods

Autologous and allogeneic HCT recipients returning for regular appointments at the outpatient clinic were invited to participate in the study. Patients transplanted for at least 2 years and with a printed copy of the vaccination record were included.

Results

We assessed the vaccination records of 273 HCT recipients after the second year of HCT (193 allogeneic and 80 autologous) and observed lower compliance with the YF vaccine (58 patients, 21.2%) than with the measles vaccine (138 patients, 50.5%, p ≤ .0001). This is the largest published series of YF vaccination in HCT recipients so far. No severe adverse events occurred. Although expected, chronic graft-versus-host disease (GVHD) did not affect the compliance with measles (p = .08) or YF vaccination (p = .7). Indeed, more allogeneic recipients received measles vaccine in comparison with autologous patients (p < .0001), suggesting that chronic GVHD was not the main reason for not being vaccinated. Children and allogeneic HCT were more likely to receive measles vaccine. Time elapsed from HCT >5 years favored both measles and YF vaccination.

Conclusion

A better understanding of the reasons for low compliance with LAVV is necessary to overcome this problem.

     

Preclinical evaluation of an investigational 21-valent pneumococcal conjugate vaccine,V116, in adult-rhesus monkey,rabbit, and mouse models

Despite the widespread effectiveness of pneumococcal conjugate vaccines on the overall incidence of invasive pneumococcal disease, the global epidemiological landscape continues to be transformed by residual disease from non-vaccine serotypes, thus highlighting the need for vaccines with expanded disease coverage. To address these needs, we have developed V116, an investigational 21-valent non-adjuvanted pneumococcal conjugate vaccine (PCV), containing pneumococcal polysaccharides (PnPs) 3, 6A, 7F, 8, 9N, 10A, 11A, 12F, 15A, 16F, 17F, 19A, 20, 22F, 23A, 23B, 24F, 31, 33F, 35B, and a de-O-acetylated 15B (deOAc15B) individually conjugated to the nontoxic diphtheria toxoid CRM197 carrier protein. Preclinical studies evaluated the immunogenicity of V116 in adult monkeys, rabbits, and mice. Following one dose, V116 was found to be immunogenic in preclinical animal species and induced functional antibodies for all serotypes included in the vaccine, in addition to cross-reactive functional antibodies to serotypes 6C and 15B. In these preclinical animal studies, the increased valency of V116 did not result in serotype-specific antibody suppression when compared to lower valent vaccines V114 or PCV13. In addition, when compared with naïve controls, splenocytes from V116 to immunized animals demonstrated significant induction of CRM197-specific T cells in both IFN-γ and IL-4 ELISPOT assays, as well as Th1 and Th2 cytokine induction through in vitro stimulation assays, thus suggesting the ability of V116 to engage T cell dependent immune response pathways to aid in development of memory B cells. V116 also demonstrated significant protection in mice from intratracheal challenge with serotype 24F, a novel serotype not contained in any currently licensed vaccine.