Role of HLA molecular mismatch in clinical practice

To date, traditional pre-transplant risk factors have failed to provide accurate risk stratification in transplantation. As a result, the practice of precision medicine remains elusive, resulting in a one-size-fits-all therapeutic approach for most patients. However, recent advancements in the understanding of HLA molecules at the molecular level have revitalized interest in HLA mismatch assessment. This review discusses HLA molecular mismatch as a potential prognostic and predictive biomarker available at the time of transplantation and answers some of the common questions and critiques of this approach. We highlight the retrospective data that supports single molecule risk categorization and explore the next steps required to evaluate its potential in clinical practice.     

原发性肾病综合征患者外周血淋巴细胞亚群、白介素2及其高亲和力受体表达的研究

目的　探讨原发性肾病综合征 ( PNS)患者发病期及缓解期的细胞免疫状态。方法　分别采用单克隆抗体致敏红细胞检测法、白介素 2 ( IL - 2 )生物活性检测法和受体的放射性配体结合法 ,对 39例 PNS患者及 2 5例正常对照的外周血淋巴细胞亚群、IL - 2活性及高亲和力白介素 2受体 ( IL - 2 R)的表达进行检测。结果　 PNS组2 2例发病期患者的 T淋巴细胞 ( CD3 )、辅助淋巴细胞 ( CD4)、抑制淋巴细胞 ( CD8)以及 IL - 2、IL - 2 R均显著低于对照组 ( P<0 .0 5 ) ;17例缓解期患者的 CD3 、CD4、IL - 2、IL - 2 R高于发病期组 ,但低于对照组 ,且与后两组的上述各项指标均有显著性差异 ( P<0 .0 5 )。结论　 PNS患者发病期细胞免疫功能低下 ,缓解期有所恢复 ,但仍未达正常水平。缓解期细胞免疫功能低下可能是 PNS易于复发的原因之一。     

Targeting NF-κB c-Rel in regulatory T cells to treat corneal transplantation rejection

The relevance of Tregs in the induction of tolerance against corneal allografts has been well established. Although it is well known that the conversion of Tregs into effector-like cells contributes to the loss of corneal immune privilege, the underlying mechanism is still not fully understood. Using heterologous penetrating keratoplasty model, we found that Tregs from corneal allograft rejected mice (inflam-Tregs) exhibit impaired function and characteristics of effector T cells. Further study showed that the expression of NF-κB c-Rel, a key mediator of effector T cell function, was significantly increased in inflam-Tregs. Mechanistic study revealed that elevated NF-κB c-Rel level in inflam-Tregs impaired Treg function through the promotion of inflammatory cytokine production and glycolysis. More importantly, we demonstrated that targeting NF-κB c-Rel was able to improve the immune suppressive function of inflam-Tregs in vitro and enhance the potential of them to suppress corneal transplantation rejection. Therefore, our current study identified NF-κB c-Rel as a key mediator of the conversion of Tregs into effector-like cells when under inflammatory environment.     

Exposure to formaldehyde and phenol during an anatomy dissecting course: sensitizing potency of formaldehyde in medical students

BACKGROUND: The sensitizing potency of formaldehyde and phenol during anatomy dissecting was investigated. The objective was to determine whether exposure induces specific IgE or IgG against formaldehyde-albumin or phenol-albumin. METHODS: In 27 medical students, specific IgE against formaldehyde-albumin by RAST plus ELISA and specific IgE against phenol-albumin by ELISA were assessed. In addition, specific IgG against formaldehyde-albumin was assessed in 23 students. Symptoms before and during dissecting were assessed, and indoor formaldehyde and phenol were measured. RESULTS: Mean indoor formaldehyde was 0.265 +/- 0.07 mg/m3, and mean indoor phenol was 4.65 +/- 2.96 mg/m3. Specific IgE/IgG against formaldehyde-albumin was not found at the beginning. Four students developed specific IgE against formaldehyde-albumin (RAST classes of > or =2.0), and all four also had specific IgE in the ELISA, but IgG against formaldehyde-albumin was not found. Specific IgE against phenol-albumin was not seen. Itch and paresthesia of the hands (P<0.00001), dizziness (P<0.008), burning eyes (P<0.01), headache, sneezing, epistaxis, gingival bleeding, oral or pharyngeal itch, and shortness of breath were experienced. CONCLUSIONS: Formaldehyde exposure during dissecting may induce specific IgE, but not IgG, against formaldehyde-albumin. Sensitization did not correlate with symptoms.     

Competitive inhibition of the uptake of demethylphalloin by cholic acid in isolated hepatocytes

Summary Cholic acid inhibits the uptake of demethylphalloin (DMP), in a competitive manner. The bile acid increases the Michaelis constant but not V _max of the inward transport. The inhibition constant K _i for cholate was found to be 8 M. Cholate competes for the transport system but not for intracellular binding of phallotoxins. Various experimental data presented in this paper exclude an accumulation of phallotoxins in hepatocytes by intracellular binding only.Preincubation of hepatocytes with small concentrations of either (³H)-demethylphalloin or (¹⁴C)-cholate and subsequent treatment with high concentrations of the nonlabelled compounds reduces the intracellular concentration of both radioactive substrates. In accordance with earlier findings the above results suggest a common component needed for the transport of both phallotoxins and cholic acid.This work was supported by the Deutsche Forschungsgemeinschaft     

Impaired cytotoxicity of lymphocytes from patients with cancer.

We have investigated the ability of peripheral blood lymphocytes from 57 cancer patients and from 54 normal controls to exert cytotoxic activity in vitro on allogeneic target cells by using a residual tritiated proline assay. Phytohemagglutin was added to the cultures for potentiating the reaction. The cytotoxic potential of lymphocytes from cancer patients was significantly lower than that of healthy controls. Increased survival of target cells was found in numerous reactions with patients' lymphocytes, probably reflecting a "feeder" effect. The source of plasma used for testing, i.e., autologous or pooled normal homologous plasma, did not affect the strength of cytotoxicity reactions displayed by lymphocytes from either normal or cancer patients. A lower reactivity was generally seen in patients with metastatic disease than in patients with no evidence of distant spread.     

Effects of rosuvastatin on endothelial function in patients with familial combined hyperlipidaemia (FCH)

ABSTRACT

Objective: Although several studies have reported a positive effect of statins on endothelial vasoreactivity, most studies performed in subjects with type 2 diabetes mellitus report no effect at all. This lack of effect may be related to the existence of insulin resistance, or to insufficient lowering of atherogenic (apo)lipoproteins. Therefore, we tested in this study whether treatment of insulin resistant familial combined hyperlipidaemia (FCH) patients with a high dose (40?mg/day) of the potent rosuvastatin was able to improve endothelial function, without necessarily improving insulin sensitivity.

Research design and methods: In a double-blind randomised crossover study, 18 subjects with FCH (without evident cardiovascular disease, mean [standard deviation] age 54 [7] years) underwent a 4‐week run-in period after which they were randomised to treatment with placebo once daily for 12 weeks, followed by rosuvastatin 40?mg/day for 12 weeks or vice versa. Endothelial function was determined after 8 and 12 weeks of both treatment periods, respectively, by measurement of flow-mediated vasodilation (FMD) using high-resolution ultrasound and by measurement of vasodilator response to intrabrachial acetylcholine (Ach) by venous occlusion plethysmography (forearm blood flow [FBF]).

Results: Plasma levels of lipids, (apo)lipoproteins and high-sensitivity C‐reactive protein (hsCRP) improved significantly after rosuvastatin therapy compared to placebo. However, rosuvastatin had no effect on homeostasis model assessment (HOMA)-indices or on vasodilator responses to intra-brachial acetylcholine-infusion (FBF-ratio increased from a mean of 1.28 [SD: 0.46] to 5.82 [3.44] after rosuvastatin and from 1.33 [0.67] to 5.99 [3.89] after placebo, p = 0.35). Endothelium-dependent FMD was also unchanged (1.6% [3.1%] vs. 3.2% [3.5]%, p = 0.56 rosuvastatin vs. placebo, respectively).

Conclusion: In patients with FCH, a 12‐week treatment of rosuvastatin 40?mg/day did not improve endothelial function (either in large conduit vessels or in resistance vessels), despite significant improvements in plasma lipids, (apo)lipoproteins. and low-grade inflammation.     

Nitric Oxide: Biphasic Dose Responses

The capacity of nitric oxide (NO) to affect biphasic dose responses in pharmacological and toxicological systems was assessed. Numerous examples of such biphasic responses were documented, including osteoclast differentiation, various vascular responses, neutrophil migration, superoxide anion formation, exploratory behavior in rodents, vitamin D₃ levels in macrophages, human sperm motility and mobility, myocardial contraction, and other functions. The quantitative features of the dose response indicated a maximum stimulatory response usually less than twofold greater than the controls. While the stimulatory range was variable, ranging from ～2.5 to 500-fold, the majority was ≤10-fold. These findings indicate that biphasic dose-response relationships are common manifestations of the NO-induced effects.