Blocking the CD28/B7 and/or CD154/CD40 costimulatory pathways promotes long-term allograft survival in many transplant models where CD4+ T cells are necessary for rejection. When CD8+ T cells are sufficient to mediate rejection, these approaches fail, resulting in costimulation blockade-resistant rejection. To address this problem we examined the role of lymphotoxin-related molecules in CD8+ T cell-mediated rejection of murine intestinal allografts. Targeting membrane lymphotoxin by means of a fusion protein, mAb, or genetic mutation inhibited rejection of intestinal allografts by CD8+ T cells. This effect was associated with decreased monokine induced by IFN-γ (Mig) and secondary lymphoid chemokine (SLC) gene expression within allografts and spleens respectively. Blocking membrane lymphotoxin did not inhibit rejection mediated by CD4+ T cells. Combining disruption of membrane lymphotoxin and treatment with CTLA4-Ig inhibited rejection in wild-type mice. These data demonstrate that membrane lymphotoxin is an important regulatory molecule for CD8+ T cells mediating rejection and suggest a strategy to avoid costimulation blockade-resistant rejection.

Prescribing is a fundamental activity of general practice and prescriptions are a major cost to the health service. Yet the art and practical details of prescribing are rarely learnt in medical school; junior doctors lack confidence in writing prescriptions ( Illing, 2008 ). Prescribing is not straightforward and involves a complicated decision-making process, by both patient and doctor, whose intricacies and governing factors are not yet well understood but where inadequate skills translate to suboptimal prescribing (Jackson et al., 2002). The prescribing process is not simply about choosing a medicine and writing a prescription.

Fractures occur in 11 to 26% of renal allograft recipients after transplantation despite improvements in bone and mineral disorders. This high fracture rate is likely a consequence of accelerated osteopenia. The cause of posttransplant bone loss is multifactorial, and patients with insulin-dependent diabetes mellitus and renal failure may have additional fracture risks such as low turnover bone disease. This retrospective cohort study was undertaken to determine the long-term incidence and the potential risk factors of posttransplant fractures in patients with insulin-dependent diabetes mellitus undergoing combined kidney-pancreas allograft transplantation. Thirty-five patients with insulin-dependent diabetes mellitus who received a combined kidney-pancreas allograft between 1987 and 1992 were evaluated. Thirty-five kidney allograft recipients matched for age, gender, and the date of transplant were also reviewed. The fracture incidence in the kidney-pancreas group was 49% after transplantation. The rate of first fracture after kidney-pancreas transplantation was 12.1% per patient year, resulting in a 5-yr fracture-free rate of 48%. The initial fracture occurred at a mean of 31.06 +/- 19.9 mo. Steroid exposure was found to increase the risk of fracture, and analysis by means of a Cox regression model estimated that an increase in cumulative steroid exposure of 10 mg/kg at any given month increased the hazard of sustaining a fracture by 9% (95% confidence interval for hazard ratio, 1.01 to 1.18; P = 0.031). This analysis suggests that kidney-pancreas recipients are at significant risk of sustaining a fracture within a few years after transplantation.

Pretreatment of organ allografts to reduce graft immunogenicity is an attractive and potentially clinically applicable concept. We have studied the effect of perfusing rat pancreases with anti-class II monoclonal antibody (MoAb), to remove class II- positive accessory cells from the intact organ, on prolongation of allograft survival after transplantation. The capacity of pancreatic islets obtained from these perfused organs to stimulate proliferation of allogeneic T-lymphocytes was studied in a mixed islet-lymphocyte culture (MILC). There was a significant prolongation in pancreas-allograft survival when intact pancreases were transplanted after a 3-h normothermic perfusion with MoAb reactive with class II antigens (16.2 +/- 3.6 days, n = 19) compared with control animals (11.0 +/- 1.4 days, n = 24). In vitro treatment of islets with MoAb and complement (CI) inhibited their stimulatory capacity in the MILC, as measured by [3H]thymidine uptake. Similarly, the stimulatory capacity of islets removed from perfused pancreases was also abrogated when MoAb was included in the perfusate. Although reduction in graft immunogenicity, by increasing allograft survival, was achieved by a 3-h pretreatment regimen, it was not sufficient to inhibit rejection altogether in our transplant model.

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