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The Journal of Heart and Lung Transplantation Volume 25, Number 2S
91 FOXP3ⴙ T-CELLS REGULATE ANTI-DONOR RESPONSES IN THE GRAFT AFTER HEART TRANSPLANTATION C.C. Baan,1 I.E. Dijke,1 A.H. Balk,2 S.S. Korevaar,1 P.E. Zondervan,3 A.P. Maat,2 W. Weimar,1 1Internal Medicine, Erasmus MC, Rotterdam, Netherlands; 2Thorax Center, Erasmus MC, Rotterdam, Netherlands; 3Pathology, Erasmus MC, Rotterdam, Netherlands Regulatory CD4⫹ CD25bright⫹ FOXP3⫹ T-cells play a critical role in the control of immune responses. In immunosuppressed patients it is unknown whether FOXP3⫹ regulatory T-cells operate at the site of the transplant to maintain unresponsiveness to alloantigens. In this study, we determined if intragraft FOXP3 mRNA expression levels are associated with immunological quiescence in cardiac allograft recipients. Gene expression levels of FOXP3 and other markers expressed by regulatory T-cells like GITR, CTLA-4, and CD25 were measured by quantitative-PCR in time zero specimens (N⫽13) and posttransplant biopsies (N⫽58) from patients who never experienced an acute rejection episode (non-rejectors) (N⫽8) and from rejectors (N⫽8). Intragraft FOXP3 levels and GITR, CTLA-4 and CD25 were abundantly expressed in post-transplant biopsies compared to the time zero-specimens, irrespective of the ISHLT rejection grade (p ⬍0.01). After transplantation, FOXP3 was the only marker that discriminated between patients who did and who did not acutely reject their allograft. In biopsies from non-rejectors the FOXP3 mRNA expression levels were significantly higher than in nonrejection biopsies from rejectors (p ⬍0.05). Further analysis demonstrated a significant rise in intragraft mRNA levels of FOXP3, GITR, CTLA-4 and CD25 during a rejection episode (p⫽0.03). We conclude that FOXP3 expression is specifically upregulated within the allograft during an acute rejection episode and in patients who remained free from acute rejection. Both findings support the hypothesis that suppression of rejection leading to immunological quiescence is an active process resulting from anti-donor immune responses. FOXP3⫹ T-cells operate within the allograft of cardiac allograft recipients and are essential for unresponsiveness towards the transplanted organ.
92 SITAXSENTAN IMPROVES TIME TO CLINICAL WORSENING (TCW) IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH) R.J. Oudiz,1 A.E. Frost,2 E.C. Lawrence,3 N. Galie,4 R.J. Barst,5 1Liu Center for Pulmonary Hypertension, UCLA Medical Center, Los Angeles, CA; 2Baylor College of Medicine, Houston, TX; 3McKelvey Lung Transplantation Center, Emory University School of Medicine, Atlanta, GA; 4University of Bologna, Bologna, Italy; 5 Columbia University College of Physicians & Surgeons, New York, NY Purpose: Sitaxsentan, an oral, once-daily, highly selective endothelin A receptor antagonist, has been studied in two previously reported pivotal, randomized, double-blind, placebo controlled PAH studies. Here, we report a combined analysis of TCW from both studies. Procedures: The STRIDE-1 (12 weeks,n⫽178) and STRIDE-2 (18 weeks,n⫽245) trials included PAH patients with WHO Class II-IV: idiopathic PAH (56%), and PAH associated with connective tissue disease (28%) or congenital heart defects (16%). The two pivotal studies evaluated sitaxsentan doses of 50mg, 100mg, and 300mg.
Abstracts
S75
Based on the overall risk-benefit analyses of these trials, 100mg once daily is considered to be the optimal dose and only those patients were evaluated in this analysis. Because TCW was defined slightly differently in STRIDE 1 and STRIDE 2, the STRIDE-2 definition was retrospectively applied to the STRIDE-1 data, and was defined as: hospitalization for worsening PAH, death, transplantation, initiation of new chronic PAH therapy, or deterioration in WHO functional class and ⱖ 15% decrease from baseline in six-minute walk. TCW was defined from the date of the first dose of study drug until the first clinical event. Subjects were censored at discontinuation and at study completion. Results: 115 patients were treated with sitaxsentan 100mg and 119 with placebo. Sitaxsentan improved TCW compared with placebo (p⫽0.0464), with events occurring in 4% of the sitaxsentan patients and 11% of the placebo patients (figure). Conclusion: Sitaxsentan improves time to clinical worsening in patients with PAH.
Disclosure: The author is a clinical investigator and advisor for Encysive Pharmaceuticals.
93 COMBINATION OF BOSENTAN WITH PROSTANOIDS OR SILDENAFIL IN PULMONARY ARTERIAL HYPERTENSION WAS WELL TOLERATED: RESULTS FROM THE TRAX DATABASE J. Carlsen,1 D.G. Kiely,2 M.M. Hoeper,3 E. Segal,4 M. Humbert,5 1 Medical Dept., Rigshospitalet, Copenhagen, Denmark; 2Dept.of Respiratory Medicine, Royal Hallamshire Hospital, Sheffield, United Kingdom; 3Dept.of Respiratory Medicine, Medical School, Hannover, Germany; 4Global Drug Safety Dept., Actelion Pharmaceuticals, Allschwil, Switzerland; 5Service de Pneumology, Hospital Antoine Beclere, Clamart, France Purpose: Pulmonary arterial hypertension (PAH) is a devastating disease, for which several treatment modalities have proved successful. Little is known about the safety of combination therapy based on the oral dual ETA/ETB antagonist bosentan. We report the results of the postmarketing surveillance program TRAX that was established to monitor the safety profile of bosentan under daily clinical practice conditions. The present analysis focuses on the bosentan/prostanoid (B⫹P) and bosentan/sildenafil (B⫹S) subgroups. Methods: Web-based non-interventional prospective database, which provided treatment and drug monitoring algorithms and collected potential signals, categorized as either safety or non-safety. Potential safety signals included adverse events with focus on elevations of ALT/AST.
91 FOXP3ⴙ T-CELLS REGULATE ANTI-DONOR RESPONSES IN THE GRAFT AFTER HEART TRANSPLANTATION C.C. Baan,1 I.E. Dijke,1 A.H. Balk,2 S.S. Korevaar,1 P.E. Zondervan,3 A.P. Maat,2 W. Weimar,1 1Internal Medicine, Erasmus MC, Rotterdam, Netherlands; 2Thorax Center, Erasmus MC, Rotterdam, Netherlands; 3Pathology, Erasmus MC, Rotterdam, Netherlands Regulatory CD4⫹ CD25bright⫹ FOXP3⫹ T-cells play a critical role in the control of immune responses. In immunosuppressed patients it is unknown whether FOXP3⫹ regulatory T-cells operate at the site of the transplant to maintain unresponsiveness to alloantigens. In this study, we determined if intragraft FOXP3 mRNA expression levels are associated with immunological quiescence in cardiac allograft recipients. Gene expression levels of FOXP3 and other markers expressed by regulatory T-cells like GITR, CTLA-4, and CD25 were measured by quantitative-PCR in time zero specimens (N⫽13) and posttransplant biopsies (N⫽58) from patients who never experienced an acute rejection episode (non-rejectors) (N⫽8) and from rejectors (N⫽8). Intragraft FOXP3 levels and GITR, CTLA-4 and CD25 were abundantly expressed in post-transplant biopsies compared to the time zero-specimens, irrespective of the ISHLT rejection grade (p ⬍0.01). After transplantation, FOXP3 was the only marker that discriminated between patients who did and who did not acutely reject their allograft. In biopsies from non-rejectors the FOXP3 mRNA expression levels were significantly higher than in nonrejection biopsies from rejectors (p ⬍0.05). Further analysis demonstrated a significant rise in intragraft mRNA levels of FOXP3, GITR, CTLA-4 and CD25 during a rejection episode (p⫽0.03). We conclude that FOXP3 expression is specifically upregulated within the allograft during an acute rejection episode and in patients who remained free from acute rejection. Both findings support the hypothesis that suppression of rejection leading to immunological quiescence is an active process resulting from anti-donor immune responses. FOXP3⫹ T-cells operate within the allograft of cardiac allograft recipients and are essential for unresponsiveness towards the transplanted organ.
92 SITAXSENTAN IMPROVES TIME TO CLINICAL WORSENING (TCW) IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH) R.J. Oudiz,1 A.E. Frost,2 E.C. Lawrence,3 N. Galie,4 R.J. Barst,5 1Liu Center for Pulmonary Hypertension, UCLA Medical Center, Los Angeles, CA; 2Baylor College of Medicine, Houston, TX; 3McKelvey Lung Transplantation Center, Emory University School of Medicine, Atlanta, GA; 4University of Bologna, Bologna, Italy; 5 Columbia University College of Physicians & Surgeons, New York, NY Purpose: Sitaxsentan, an oral, once-daily, highly selective endothelin A receptor antagonist, has been studied in two previously reported pivotal, randomized, double-blind, placebo controlled PAH studies. Here, we report a combined analysis of TCW from both studies. Procedures: The STRIDE-1 (12 weeks,n⫽178) and STRIDE-2 (18 weeks,n⫽245) trials included PAH patients with WHO Class II-IV: idiopathic PAH (56%), and PAH associated with connective tissue disease (28%) or congenital heart defects (16%). The two pivotal studies evaluated sitaxsentan doses of 50mg, 100mg, and 300mg.
Abstracts
S75
Based on the overall risk-benefit analyses of these trials, 100mg once daily is considered to be the optimal dose and only those patients were evaluated in this analysis. Because TCW was defined slightly differently in STRIDE 1 and STRIDE 2, the STRIDE-2 definition was retrospectively applied to the STRIDE-1 data, and was defined as: hospitalization for worsening PAH, death, transplantation, initiation of new chronic PAH therapy, or deterioration in WHO functional class and ⱖ 15% decrease from baseline in six-minute walk. TCW was defined from the date of the first dose of study drug until the first clinical event. Subjects were censored at discontinuation and at study completion. Results: 115 patients were treated with sitaxsentan 100mg and 119 with placebo. Sitaxsentan improved TCW compared with placebo (p⫽0.0464), with events occurring in 4% of the sitaxsentan patients and 11% of the placebo patients (figure). Conclusion: Sitaxsentan improves time to clinical worsening in patients with PAH.
Disclosure: The author is a clinical investigator and advisor for Encysive Pharmaceuticals.
93 COMBINATION OF BOSENTAN WITH PROSTANOIDS OR SILDENAFIL IN PULMONARY ARTERIAL HYPERTENSION WAS WELL TOLERATED: RESULTS FROM THE TRAX DATABASE J. Carlsen,1 D.G. Kiely,2 M.M. Hoeper,3 E. Segal,4 M. Humbert,5 1 Medical Dept., Rigshospitalet, Copenhagen, Denmark; 2Dept.of Respiratory Medicine, Royal Hallamshire Hospital, Sheffield, United Kingdom; 3Dept.of Respiratory Medicine, Medical School, Hannover, Germany; 4Global Drug Safety Dept., Actelion Pharmaceuticals, Allschwil, Switzerland; 5Service de Pneumology, Hospital Antoine Beclere, Clamart, France Purpose: Pulmonary arterial hypertension (PAH) is a devastating disease, for which several treatment modalities have proved successful. Little is known about the safety of combination therapy based on the oral dual ETA/ETB antagonist bosentan. We report the results of the postmarketing surveillance program TRAX that was established to monitor the safety profile of bosentan under daily clinical practice conditions. The present analysis focuses on the bosentan/prostanoid (B⫹P) and bosentan/sildenafil (B⫹S) subgroups. Methods: Web-based non-interventional prospective database, which provided treatment and drug monitoring algorithms and collected potential signals, categorized as either safety or non-safety. Potential safety signals included adverse events with focus on elevations of ALT/AST.