Protection from insulin-dependent diabetes mellitus is linked to a peptide transporter gene

HLA class II association with insulin-dependent diabetes mellitus (IDDM) is well established but is still difficult to map to a particular locus. Polymorphism of the genes coding for transporter associated with antigen processing (TAP1 and TAP2), and located in the HLA class II region, was studied in 167 IDDM patients (116 adult-onset and 51 childhood-onset patients) and 98 normal controls using oligotyping after genomic amplification. A dominant protective effect was observed for theTAP2*0201 allele [relative risk (RR)=0.3, corrected probability (pc) < 0.001]. Conversely, susceptibility to IDDM was associated with apparent homozygosity for the TAP2*0101 allele (RR=3.4, pc < 0.001). Protection was independent from but additive to the protection conferred by the DRB1*02 DQB1*0602 haplotype (RR=0.06, pc<0.05), and antagonistic to the DRB1*03 DQB1*0201 and DRB1*04 DQB 1*0302 haplotypes predisposing effect (RR=1.1, not significant), arguing in favor of an absence of linkage disequilibrium between TAP2 and HLA class II genes. This was assessed by x² analysis. TAP1 allelic distribution was not different among diabetics and controls. A significant association was observed between the presence of TAP2*0101 and that of islet cell antibodies (p < 0.05). These data suggest that the TAP2 gene, which encodes protein required for delivery of antigen peptides to class I molecules in the endoplasmic reticulum, could modulate the autoimmune response leading to β cell destruction. From a practical point of view, they make the combined screening of HLA class II and TAP2 loci a highly valuable tool in IDDM prediction.     

Cell-mediated immunity to pancreatic islet cells in the non-obese diabetic (NOD) mouse: in vitro characterization and time course study

The non-obese diabetic (NOD) mouse is an animal model of insulin-dependent diabetes mellitus (IDDM), in which 80% of the females become diabetic after the age of 12 weeks. Using an in vitro assay we investigated the capacity of spleen lymphocytes from NOD mice to inhibit the insulin secretion of normal islet cells after stimulation by theophylline plus arginine. Spleen cells from diabetic NOD mice inhibited the insulin release of DBA/2 islet cells. Depletion experiments using monoclonal antibodies demonstrated that inhibitory cells belonged to the Lyt2 positive T lymphocyte subset. The phenomenon was not restricted by the MHC class I K region, shared by NOD and DBA/2 mice, since lymphocytes from diabetic NOD mice also inhibited the insulin secretion of normal Wistar rat islet cells. Inhibitory T cells were detected in overtly diabetic mice but also in non-diabetic females aged 5-11 weeks indicating that they are not secondary to metabolic disturbances and might contribute to their onset. Conversely they were not found in male NOD mice although some of these mice show insulitis. The presence of these inhibitory T cells might thus represent an early and sensitive marker of anti-islet cell-mediated autoimmunity.     

Increased incidence and unusual presentations of CMV disease in kidney transplant recipients after conversion to belatacept

Belatacept may increase cytomegalovirus (CMV) disease risk after conversion from CNI-based therapy. We analyzed CMV disease characteristics after belatacept conversion. Propensity score matching was used to compare CMV disease incidence in belatacept- and CNI-treated kidney transplant recipients (KTRs). CMV disease characteristics and risk factors under belatacept were analyzed. In total, 223 KTRs (median age [IQR] 59.2 years [45.4–68.5]) were converted to belatacept (median of 11.5 months [2.5–37.0] post-transplantation); 40/223 (17.9%) developed CMV disease. Independent risk factors included increased age (p = .0164), D+/R− CMV serostatus (p = .0220), and low eGFR at conversion (p = .0355). Among 181 belatacept-treated patients matched to 181 controls, 32/181 (17.7%) experienced CMV disease (vs. 5/181 controls [2.8%]). CMV disease cumulative incidences were 6.33 and 0.91/100 person-years (p-y) in belatacept and control groups, respectively. CMV disease risk was particularly high in elderly patients (converted >70 years) and those with eGFR <30 ml/min; cumulative incidences were 18.4 and 5.2/100 p-y, respectively. CMV diseases under belatacept were atypical, with late-onset disease (24/40 patients [60%]), high CMV seropositivity (27/40, 67%), increased severe and tissue-invasive disease rates (gastrointestinal involvement in 32/40 [80%]) and life-threatening diseases (4/40 [10%]). These findings should stimulate further research to secure the use of belatacept as a valuable rescue therapy in KTRs.     

Nosocomial infection and multidrug-resistant bacteria surveillance in intensive care units: a survey in France.

OBJECTIVES: To evaluate nosocomial infection (NI) surveillance strategies in French ICUs and to identify similar patterns defining subsets within which comparisons can be made. DESIGN: A questionnaire was sent to all French ICUs, and a random sample of nonresponders was interviewed. PARTICIPANTS: Three hundred ninety-five responder ICUs (69%) in France. RESULTS: In 282 ICUs (71%), a dedicated ICU staff member was responsible for infection control activities. The microbiology laboratory was usually in the hospital (90%) and computerized (94%) but issued regular hospital microbiology records in only 48% of cases. Patients receiving mechanical ventilation, central venous catheterization, and urinary catheterization were 90%, 79%, and 60%, respectively. Patients were screened for carriage of multidrug-resistant bacteria on admission and during the stay in 70% and 60% of ICUs, respectively, most often targeting MRSA. Quantitative cultures were used to diagnose ventilator-associated pneumonia (VAP) in 90% of ICUs, including distal specimens in 80% and bronchoscopy specimens in 60%. Quantitative central venous catheter (CVC)-segment cultures were used in 70% of ICUs. All CVCs were cultured routinely in 53% of the ICUs. Despite wide variations in infection control and surveillance strategies, multiple correspondence analysis identified 13 key points (4 structural variables and 9 variables concerning the diagnosis of VAP, the surveillance and diagnosis of catheter-related and urinary tract infections, and the mode of screening of MRSA carriers) that categorize the variability of French ICUs' approaches to NIs. CONCLUSION: This study revealed profound differences in NI surveillance strategies across ICUs, indicating a need for caution when using NI surveillance data for comparisons and benchmarking.