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Immunologic surveillance for rejection detection in human heart transplantation offers many potential advantages. To date, investigative efforts have focused primarily on the acquired immune system, particularly the lymphocyte. Little attention has been given to aspects of innate immune function. We have previously reported that perioperative neutrophil adhesion molecule expression is associated with early rejection episodes after human cardiac transplantation. Herein we have investigated the utility of neutrophil immunosurveillance in human heart transplant recipients at later time points. We recruited patients more than 3 months after transplantation. Neutrophil assessment was performed simultaneously with an endomyocardial biopsy that showed rejection. No significant relationship was seen between neutrophil maturity (P = .622; n = 34), adhesion marker expression (P = .567; n = 34), respiratory burst (P = .604; n = 34), or apoptosis rates (P = .662; n = 34) and contemporary rejection status at >3 months after transplantation. However, interesting relationships were noted between neutrophil adhesion markers at this late stage and historical rejection status. Higher levels of the adhesion protein CD11b observed at this late stage were significantly associated with a history of higher rejection grades in the first postoperative biopsy (Spearman rank coefficient 0.359; R = 0.304; P = .005; n = 62). Other aspects of neutrophil function and persistence were not significantly associated with rejection history. This finding, combined with the previously reported findings, supports a role for an individual phenotype in neutrophil function in early rejection episodes after transplantation.

The focus of research in allograft rejection has targeted the lymphocyte, with little attention given to the neutrophil. Recent data indicate that a perioperative neutrophil influx into the cardiac allograft influences early rejection. Factors that influence neutrophil transendothelial migration might offer predictive markers of rejection. We explored the relationship between the number of circulating neutrophils in heart transplant recipients and the development of rejection. Differential white cell counts were obtained prior to transplantation and concurrently with subsequent endomyocardial rejection surveillance biopsies for 53 heart transplant recipients undergoing 410 biopsies. Preoperative differential white cell counts had no relationship with rejection. In the first 3 months after transplantation, no relationship was found between contemporary differential white cell counts and rejection. However, more than 3 months following surgery, rejection grade positively correlated on univariate analysis with neutrophil counts and the usage of cyclosporine, prednisolone, and mycophenolate. There was no relationship with eosinophils or lymphocytes. Multivariate analysis demonstrated a persistent relationship among rejection severity, neutrophil count, and prednisolone usage. A significant positive association of higher steroid usage with higher rejection grades must reflect efforts to treat patients with rejection. The significant association of higher neutrophil counts with higher rejection severity might suggest a pathological contribution to rejection. However, given the neutrophilia response to acute steroid administration, we must conclude that the neutrophil association was related to steroid administration. The absence of a relationship between white cell counts and rejection suggests that functional rather than antiproliferative strategies may offer the greatest therapeutic potential.

Background: A common clinical problem following organ transplantation is the development of renal failure due to calcineurin inhibitors. Sirolimus offers the potential of providing appropriate immunosuppression without nephrotoxicity. This study evaluates the impact of sirolimus monotherapy on renal function in patients late following heart transplantation and correlates trough sirolimus levels with area-under-the-concentration time curve measurements., Methods: Six male patients with renal impairment late following heart transplantation (mean 8 years) were offered sirolimus therapy. Calcineurin inhibition was discontinued in all patients on commencing sirolimus. Patients started on sirolimus 2 to 5 mg/d orally. Venous blood samples for pharmacokinetic studies and repeat creatinine clearance were performed before and 6 weeks after commencement of sirolimus in all subjects., Results: Sirolimus trough levels accurately reflected sirolimus area-under-the-concentration time curve measurements. There was no change in renal function. Mean creatinine clearance prior to commencing sirolimus was 26.7 (12.2) mL/min and the post-sirolimus creatinine clearance performed 6 weeks later was 23.4 (11.7) mL/min (P = .64)., Conclusions: Trough levels of sirolimus correlate with drug exposure and may be used to monitor sirolimus therapy. No improvement in renal function following calcineurin inhibitor withdrawal occurred in this cohort., (Copyright 2004 Elsevier Inc.)