Immune Regulatory 1 Cells: A Novel and Potent Subset of Human T Regulatory Cells.

A subset of T regulatory cells (Tregs), identified by TIRC7 (T cell immune response cDNA 7) expression is designated as Immune Regulatory 1 Cells (IR1 cells). TIRC7 is an immune checkpoint inhibitor, co-localized with the T- cell receptor, HLA-DR and CTLA-4 during T-cell activation, which delivers regulatory signals via binding to its ligand, HLA-DR α2 domain. IR1 cells express FOXP3, and multiple other markers associated with immune suppression. They constitute as much as 10% of Tregs. IR1 cells strongly inhibit proliferation in mixed lymphocyte reactions, where they express high levels of IL-10. Ex vivo expansion of Tregs over 2 weeks in the presence of an agonist TIRC7 antibody disproportionately expands the IR1 Treg subset, while maintaining high expression of suppressive markers including CD39, IL-10, LAP and GARP. Ex vivo expanded IR1 cells are a potent, homogeneous, stable set of suppressor Tregs with the potential to modulate immune dysregulation. The characteristics of IR1 cells suggest a therapeutic advantage over polyclonal Tregs for therapeutic interventions. Early restoration of immune homeostasis using IR1 cells has the potential to fundamentally alter the natural history of conditions characterized by abnormalities in the T regulatory cell compartment.

Renal insufficiency and end-stage renal disease in the heart transplant population.

BACKGROUND: Renal insufficiency and end-stage renal disease (ESRD) are important problems in the cardiac transplant population, and are associated with significant morbidity, mortality and financial cost. We undertook this study to define pre-operative or early post-operative predictors of subsequent renal insufficiency and ESRD. METHODS: We studied 370 patients at Brigham and Women's Hospital who received heart transplants between 1984 and 1999, with up to 10-year follow-up. We evaluated 2 time-dependent primary outcomes: early reduction in GFR, and development of ESRD at any timepoint. Cox proportional hazards modeling was used in both univariate and multivariate analyses. RESULTS: The mean estimated glomerular filtration rate (GFR) fell 24% within the first post-transplant year, and remained stable thereafter. By actuarial analysis, 23% of patients developed a 50% reduction in GFR by the third year, and 20% developed ESRD by the tenth year of follow-up. In Cox multivariate analysis, significant predictors of post-transplant ESRD included: GFR <50 ml/min (hazards ratio [HR] 3.69, p = 0.024); high mean cyclosporine trough in the first 6 months (HR 5.10, p = 0.0059); and presence of diabetes (HR 3.53, p = 0.021). Conclusions about renal insufficiency outcome were limited by difficulties with accurate estimation of GFR and with definition of renal insufficiency. CONCLUSIONS: The results of this study underscore the magnitude of the problem of renal insufficiency and ESRD in the heart transplant population. In addition, these data suggest that patients at high risk for these outcomes can be identified early, even pre-operatively, to guide post-operative management.

The relationship between serum calcium and phosphate levels and cardiac valvular procedures in the hemodialysis population.

BACKGROUND: Cardiac valvular disease is a common complication in hemodialysis patients, with a prevalence of up to 9%. In these patients, calcium-phosphate imbalance is associated with systemic and cardiac calcification. We investigated the relationship between abnormal calcium and phosphate levels and valvular disease sufficiently severe to require an invasive procedure. METHODS: We analyzed data from 12,509 hemodialysis patients from the US Renal Data System database, 204 of whom underwent a valvular procedure. All were prevalent in-center dialysis patients as of 1993, when cross-sectional data were collected. RESULTS: In a Cox multivariate model, a serum phosphate level of 5.0 mg/dL or greater (>/=1.62 mmol/L) was associated with increased risk for a valvular procedure compared with a phosphate level less than 5 mg/dL (<1.62 mmol/L; hazard ratio, 1.47; P = 0.033). A calcium level less than 8.8 mg/dL (<2.2 mmol/L) was associated with fewer valvular procedures compared with a normal calcium level (hazard ratio, 0.61; P = 0.018). However, a high calcium level (>10.5 mg/dL [>2.63 mmol/L]) had no significant relationship with the outcome (hazard ratio, 0.89; P = 0.65) compared with a normal level. Calcium-phosphate product was not significant as an interaction term and therefore was not included in the final analysis. The relationship of parathyroid hormone (PTH) level to outcome was not significant. CONCLUSION: A serum phosphate level of 5.0 mg/dL or greater (>/=1.62 mmol/L) is associated with increased risk for a valvular procedure, and a low calcium level is associated with fewer valvular procedures. There is no compelling evidence that elevated calcium or PTH levels have a significant relationship to valvular disease that results in an invasive procedure.

Cutaneous neoplasms in renal transplant recipients.

Cutaneous neoplasms are much more common in renal transplant recipients than in the general population, and are the most common malignancies in these patients. This is the case with basal cell carcinoma, and even more so with squamous cell carcinoma. Many risk factors for development of such malignancies are similar to those in the general population. However, in the transplant population, such cancers appear at an earlier age, behave more aggressively, and frequently appear at multiple sites. Therefore, diligence on the part of the patient and on the part of his or her health care providers is of utmost importance. Treatment options include reduction in immunosuppression, but preventive maintenance remains the primary focus of efforts to limit these malignancies.