Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells.

During a search for genes that maintain T cell quiescence, we determined that Tob, a member of an anti-proliferative gene family, was highly expressed in anergic T cell clones. Tob was also expressed in unstimulated peripheral blood T lymphocytes and down-regulated during activation. Forced expression of Tob inhibited T cell proliferation and transcription of cytokines and cyclins. In contrast, suppression of Tob with an antisense oligonucleotide augmented CD3-mediated responses and abrogated the requirement of costimulation for maximal proliferation and cytokine secretion. Tob associated with Smad2 and Smad4 and enhanced Smad DNA-binding. The inhibitory effect of Tob on interleukin 2 (IL-2) transcription was not mediated by blockade of NFAT, AP-1 or NF-kappaB transactivation but by enhancement of Smad binding on the -105 negative regulatory element of the IL-2 promoter. Thus, T cell quiescence is an actively maintained phenotype that must be suppressed for T cell activation to occur.

CD8+ T cell subsets TC1 and TC2 cause different histopathologic forms of murine cardiac allograft rejection.

BACKGROUND: CD4+ T cell effector function is sufficient to mediate allograft rejection, and it is suggested that CD8+ T cell-mediated effects are dependent on CD4+ T cell help. CD8+ T cells can be classified into at least two functional subsets: Tc1, producing high amounts of interferon (IFN)-gamma and Tc2, producing interleukin (IL)-4, -5, -10, and -13 and low levels of IFN-gamma. Because these subsets express different chemokine receptors, they may have different capabilities of migrating into grafts. Once in the graft, each subset may perform different effector functions dependent on the cytokines it produces. We asked whether allospecific CD8+ T cells, in the absence of CD4+ T cells, are capable of mediating rejection of a primarily vascularized allograft, and if Tcl and Tc2 cells differ in their ability to mediate rejection. METHODS: Hearts from H-2d mice were transplanted into H-2b RAG 1-/- recipients. Without manipulation, these fully mismatched allografts would survive indefinitely due to the absence of mature T and B cells. We adoptively transferred allo-(H-2d)-reactive Tcl or Tc2 cells from H-2b mice into each recipient. Grafts were harvested and analyzed on predefined timepoints, rejection was graded on a modified ISHLT scale. RESULTS: On day 7, grafts from Tc1- or Tc2-injected animals showed grade 1-2 parenchymal rejection with stable phenotype and comparable distribution of graft infiltrating CD8+ T cells. Adoptive transfer of IFN-gammahigh Tc1, but not of IFN-gammalow Tc2 cells was followed by the development of graft vasculitis, as well as graft arteriopathy. Adoptive transfer of IL-4high IL-5high Tc2, but not of IL-4low IL-5low Tc1 cells lead to extensive infiltration of eosinophils and formation of giant cells. CONCLUSIONS: Both Tc1 and Tc2 cells can mediate murine cardiac allograft rejection in the absence of CD4+ T cell help, although each subset elicits a different type of inflammatory response. In this model, cytokine secretion of either functional CD8+ T effector cell subset is an important effector mechanism in the process of allograft rejection: IFN-gammahigh Tc1 cells are important in early graft vasculitis, although IL-4high IL-5high Tc2 cells promote recruitment of secondary effectors like eosinophils.

Do urinary tract infections trigger chronic kidney transplant rejection in man?

PURPOSE: Urinary tract infections are frequent after kidney transplantation but little is known about the impact on long-term survival. As chronic rejection is the major cause of graft loss in the long term, we retrospectively analyzed the role of urinary tract infections in this process. MATERIALS AND METHODS: We included in the study all adult patients who received kidney transplants at our unit between 1972 and 1991, which ensured followup of at least 5 years, and we focused on the relationship between urinary tract infections and the incidence of chronic rejection episodes. To analyze the influence of urinary tract infections on chronic rejection patients were separated into those in whom biopsy proved chronic rejection developed within the first 5 years after transplantation (chronic rejection group 225) and those without apparent signs of chronic rejection during that period (control group 351). The correlation between urinary tract infections per year and the incidence of chronic rejection was analyzed. RESULTS: Patients with chronic rejection had more urinary tract infections per year than controls. In the first year after transplantation both groups had the highest incidence of urinary tract infections but thereafter the rate of urinary tract infections per year declined. However, the incidence consistently remained higher in the chronic rejection group. This difference reached significance by year 3 after transplantation. Furthermore, a high rate of urinary tract infections correlated with an early onset of chronic rejection. CONCLUSIONS: Urinary tract infections are an important risk factor for the onset of chronic rejection, and early and intense treatment is critical.

[Integrated concept for implementing clinical training in emergency medicine]. / Integratives Konzept in der Durchführung des "Praktikums der Notfallmedizin".

Since 1993 special lectures in emergency medicine are part of curriculum in the study of medicine at German universities. To intensify practical teaching in this field an integrative concept was followed in performing emergency training, the experiences of which are described in this paper. Seminars dealing with the most important subjects of preclinical care were combined with practical training blocks such as attendance at operations of the preclinical emergency physician service, resuscitation training using computerised resuscitation models (Mega Code), and an anatomical training course for endotracheal intubation, coniotomy, thoracic drainage, or central venous catheterisation on a corpse. If supported by physicians, senior students may supervise groups of 4 to 5 students during the Mega Code training in a tutorial system, thus allowing to intensify practical education. Since the integrative concept is based on cooperation of different medical specialties, the students expect one or two physicians to be chiefly responsible for the entire course. Additional dates during the semester interfere with the students' leisure activities and require individual practical activity. This means giving up a passively receptive attitude. However, as reflected by the results of the exams and questionnaires, response to this step of improvement in Emergency Medical Education has been very positive. Future efforts are directed at including more physicians as practical supervisors, scattering of training dates, an increase in compulsory practical participation such as one-day attendance at an intensive care unit, and intensified exams on practical issues. However, the improvement of the quality of teaching is imperative in the job planning of the medical profession.