The Blood of Healthy Individuals Exhibits CD8 T Cells with a Highly Altered TCR Vb Repertoire but with an Unmodified Phenotype

CD8 T cell clonal expansions (TCE) have been observed in elderly, healthy individuals as well in old mice, and have been associated with the ageing process. Both chronic latent and non-persistent viral infections have been proposed to drive the development of distinct non-functional and functional TCE respectively. Biases in TCR Vβ repertoire diversity are also recurrently observed in patients that have undergone strong immune challenge, and are preferentially observed in the CD8 compartment. Healthy adults can also exhibit CD8 T cells with strong alterations of their CDR3 length distribution. Surprisingly, no specific investigations have been conducted to analyze the CD8 T cell repertoire in normal adults, to determine if such alterations in TCR Vβ repertoire share the features of TCE. In this study, we characterized the phenotype and function of the CD8 population in healthy individuals of 25–52 years of age. All but one of the EBV-positive HLA-B8 healthy volunteers that were studied were CMV-negative. Using a specific unsupervised statistical method, we identified Vβ families with altered CDR3 length distribution and increased TCR Vβ/HPRT transcript ratios in all individuals tested. The increase in TCR Vβ/HPRT transcript ratio was more frequently associated with an increase in the percentage of the corresponding Vβ+ T cells than with an absence of modification of their percentage. However, in contrast with the previously described TCE, these CD8+ T cells were not preferentially found in the memory CD8 subset, they exhibited normal effector functions (cytokine secretion and cytotoxic molecule expression) and they were not reactive to a pool of EBV/CMV/Flu virus peptides. Taken together, the combined analysis of transcripts and proteins of the TCR Vβ repertoire led to the identification of different types of CD8+ T cell clone expansion or contraction in healthy individuals, a situation that appears more complex than previously described in aged individuals

Suppression of Allograft Rejection by Tim-1-Fc through Cross-Linking with a Novel Tim-1 Binding Partner on T Cells

Engagement of T-cell immunoglobulin mucin (Tim)-1 on T cells with its ligand, Tim-4, on antigen presenting cells delivers positive costimulatory signals to T cells. However, the molecular mechanisms for Tim-1-mediated regulation of T-cell activation and differentiation are relatively poorly understood. Here we investigated the role of Tim-1 in T-cell responses and allograft rejection using recombinant human Tim-1 extracellular domain and IgG1-Fc fusion proteins (Tim-1-Fc). In vitro assays confirmed that Tim-1-Fc selectively binds to CD4+ effector T cells, but not dendritic cells or natural regulatory T cells (nTregs). Tim-1-Fc was able to inhibit the responses of purified CD4+ T cells that do not express Tim-4 to stimulation by anti-CD3/CD28 mAbs, and this inhibition was associated with reduced AKT and ERK1/2 phosphorylation, but it had no influence on nTregs. Moreover, Tim-1-Fc inhibited the proliferation of CD4+ T cells stimulated by allogeneic dendritic cells. Treatment of recipient mice with Tim-1-Fc significantly prolonged cardiac allograft survival in a fully MHC-mismatched strain combination, which was associated with impaired Th1 response and preserved Th2 and nTregs function. Importantly, the frequency of Foxp3+ cells in splenic CD4+ T cells was increased, thus shifting the balance toward regulators, even though Tim-1-Fc did not induce Foxp3 expression in CD4+CD25− T cells directly. These results indicate that Tim-1-Fc can inhibit T-cell responses through an unknown Tim-1 binding partner on T cells, and it is a promising immunosuppressive agent for preventing allograft rejection

Cross-Reactivity of Herpesvirus-Specific CD8 T Cell Lines Toward Allogeneic Class I MHC Molecules

Although association between persistent viral infection and allograft rejection is well characterized, few examples of T-cell cross-reactivity between self-MHC/viral and allogeneic HLA molecules have been documented so far. We appraised in this study the alloreactivity of CD8 T cell lines specific for immunodominant epitopes from human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV). CD8 T cell lines were generated after sorting with immunomagnetic beads coated with either pp65495–503/A*0201, BMLF1259–267/A*0201, or BZLF154–64/B*3501 multimeric complexes. Alloreactivity of the CD8 T cell lines against allogeneic class I MHC alleles was assessed by screening of (i) TNF-α production against COS-7 cells transfected with as many as 39 individual HLA class I-encoding cDNA, and (ii) cytotoxicity activity toward a large panel of HLA-typed EBV-transformed B lymphoblastoid cell lines. We identified several cross-reactive pp65/A*0201-specific T cell lines toward allogeneic HLA-A*3001, A*3101, or A*3201. Moreover, we described here cross-recognition of HLA-Cw*0602 by BZLF1/B*3501-specific T cells. It is noteworthy that these alloreactive CD8 T cell lines showed efficient recognition of endothelial cells expressing the relevant HLA class I allele, with high level TNF-α production and cytotoxicity activity. Taken together, our data support the notion that herpes virus-specific T cells recognizing allo-HLA alleles may promote solid organ rejection

Perturbation of the T cell receptor repertoire occurs with increasing age in dogs

PURPOSE: The use of the Schirmer strips (SS) as a tool in the characterisation of dry eye disease, depends upon the quantitative assessment of tear production and constituents. The aim of this study was to ascertain the extent to which the properties of commercially available SS can vary and the way in which this baseline information may relate to their comparability in clinical use. METHODS: Five SS were analysed: Clement Clarke®, TearFlo®, Bio Schirmer®, Omni Schirmer® and JingMing®. Various aspects of their physical appearance and physicochemical behaviour were measured, including size, weight, and thickness together with surface morphology (assessed by SEM) and aqueous uptake and release behaviour (including the influence of each strip on protein retention and eluent osmolarity). RESULTS: All physical parameters varied between the strips studied for example the Clement Clark was the largest, thickest, and heaviest strip assessed in this study. SEM images showed that each of the SS had unique surface morphologies. Statistically significant differences among the strips were found for uptake (p=0.001) and release volume (p=0.014). Clement Clarke absorbed the highest volume over a fixed time period (23.8±1.6μl) and Omni the lowest (19.3±0.5μl). Clement Clarke showing the highest eluent osmolarity value (5.0±0.0mOsm/L) and TearFlo the lowest (2.8±0.4mOsm/L). CONCLUSION: The five strips investigated in this study indicate that there is no standardisation of commercial strips, despite the fact that the need for standardisation was recognised over fifty years ago. This study provides useful baseline information relating to SS comparability in clinical use

Report of an incident during the use of the Servo-ventilator 900 in paediatric anesthesia.

peer reviewedThe authors report the occurrence of an incident during the use of the Servo-ventilator 900 for paediatric anesthesia; it consisted in self-oscillation of the gas column contained in the patient respiratory circuit. After having analysed the incident and outlined the various ways of avoiding it, attention is drawn to the importance of the total circuit volume of the respirator. The respiratory circuit chosen for ventilating children, has a compliance of 1.3 ml/cm H2O

Progress on modeling EM interaction with complex systems: applications to aircraft and automobiles

Summary form only given. The EM topology method was developed at the end of the 1980s. Experimental validations performed during the last 2-3 years, have permitted to achieve a significant progress pertaining to the assessment of effects of electromagnetic aggressions on complex systems. Such complex cabling systems are present in automobiles (600 m of cables in one car), aircrafts or ships. The practical importance of the evaluation of these effects needs no demonstration, as the cars and airplanes are equipped, as seen above with hundreds of meters of cables through which are transmitted vital informations for the operation of the vehicle and which are submitted to external (radars, radio and TV emitters) or internal (cellular phones) aggression

Early Stage Results after Oesophageal Resection for Malignancy - Colon Interposition Vs. Gastric Pull-Up

OBJECTIVE: The aims of our study were to determine if using the colon as a digestive transplant after oesophagectomy for cancer was associated with increased postoperative complications, and to assess the impact of preoperative radiochemotherapy on postoperative hospital outcome. METHODS: From January 1990 to December 1998, 130 patients underwent oesophageal resection for malignancy. There were 103 males and 27 females (age: 61.3+/-11.5 years). Indications were squamous cell carcinoma in 69 patients and adenocarcinoma in 61. Preoperatively 30 patients (eight in stage IIB, 18 in stage III, and four in stage IV) received radiochemotherapy. There were 84 subtotal oesophagectomies, with anastomosis in the neck in 44 patients and at the thoracic inlet in 40, and 46 distal oesophageal resections. Digestive continuity was restored with the stomach in 92 patients (age: 63.4+/-10.2 years) and the colon in 38 (age: 52.3+/-12.8 years). With the exception of age (P<0.0001), there was no significant preoperative difference between gastric and colonic groups. RESULTS: Hospital mortality was 8.5% (11 patients), decreasing from 18.5% (before 1993) to 3.8% (since 1993). One patient (2.5%) died in the colonic graft group and ten (11%) in the gastric pull-up group (P=0.17). Postoperative complications occurred in 40 patients (31%), respectively, in ten (26%) and 30 (33%) patients after colonic and gastric transplants (P=0.48), and were pulmonary insufficiency or infection in 29 patients, anastomotic fistula in six, myocardial infarction in five, recurrent nerve palsy in four, renal insufficiency in three, and cerebrovascular accident in one. All fistulas occurred in the gastric pull-up group. The incidence of postoperative pulmonary complications was 70% (21/30 patients) in the subgroup who received preoperative radiochemotherapy, as compared to 11% (5/44 patients) in the subgroup of comparable staging, but without preoperative treatment (P<0.001). CONCLUSIONS: Colonic grafts are not associated with increased postoperative mortality or complications. Our results suggest that preoperative neoadjuvant treatment significantly increases postoperative pulmonary complications

Electromagnetic topology and soil effects applied to EMC problems

Considerable efforts have been made in the past to characterize the coupling of an electromagnetic wave to a structure, the simplest configuration being a cable parallel to the ground surface. If the height of the wire above ground is smaller than the free-space wavelength of the disturbing signal, the transmission-line theory is often used but since the ground impedance is frequency dependent, recent works have been done to model correctly the ground in the time-domain. Furthermore the incident field propagating along the ground surface may be distorted by obstacles such as hills and valleys and the effect of terrain topography may play a leading role in certain configurations. The interaction with the system itself has often be treated by considering separately the external and internal interaction. The objective of the topological approach is to get both a quantitative tool to relate the external signal to a response somewhere within the system and a qualitative one allowing a clear decomposition of the system in terms of successive shields and penetration paths. The latest developments and suggested further studies are outline

Influence of Thermal Treatment on Magnetomechanical Damping of 49Fe-49Co-2V Alloy

The 2V Permendur alloy (49Fe-49Co-2V) is very useful for electrical applications requiring high magnetic flux densities. The improvement of its magnetic (maximum permeability, coercive force) and magnetomechanical (damping) properties is achieved by various thermal treatments. The results are discussed according to the influence of order, grain size, internal stresses and d.c. applied field