CM-1 Clinical Transplantation Lung Howard University Hospital Department of Transplantation Clive O. Callender, MD. Arturo Hernandez, MD

CM-2 Objective Current Status of Lung Transplantation

CM-3 No of Transplanted Organs vs Waiting List 2004 Recovered Transplanted Waiting List Total 25,237 26,539 86,378 Kidney 12,575 15,671 (9,025) 57,910 PTA 2, PAK K-P879 2,410 Liver 6,4055,780 (5,457)17,133 Intestine Heart 2,096 1,9613,237 Lung 1,973 1,168 3,852 Heart-lung Source: 2005 OPTN/SRTR Annual Report,

CM-4 Graft Survival Follow-up Period 1 Year 10 Years Tx Tx Kidney Deceased Donor Graft Survival 89.0% 40.5% Patient Survival 94.6% 60.7% Kidney: Living Donor Graft Survival 95.1% 56.4% Patient Survival 97.9% 76.4% Kidney-Pancreas Kidney Graft Survival 91.7% 52.5% Pancreas Graft Survival 85.8% 53.6% Liver Deceased Donor Graft Survival82.2% 52.5% Patient Survival 81.7% 67.0% Intestine Graft Survival 73.8% 22.0% Heart Graft Survival 86.8% 51.1% Lung Graft Survival 81.4% 22.1% Heart-Lung Graft Survival 55.8% 24.6% UNOS/SRTR, 2003

CM-5 Current Status of Lung Transplantation Long term survival—50% die by 5 years Bronchiolitis obliterans (chronic rejection)— primary cause of poor survival Future of lung transplantation is prevent bronchiolitis obliterans

CM-6 Lung Transplantation Pre-Cyclosporine Era, Pre-1983 Time (days) (4) (12) (19) (28) (38) At risk: % free from death

CM-7 Worldwide Lung Transplantation Numbers Source: International Society of Heart and Lung Transplantation (ISHLT); UNOS Lung transplants performed worldwide, by year Emphysema/COPD Idiopathic pulmonary fibrosis Cystic fibrosis Alpha-1 antitrypsin deficiency Primary pulmonary hypertension Sarcoidosis Retransplant/graft failure Other 1.8% 2.6% 4.2% 39.0% 10.4% 17.0% 16.0% 9.0% Primary diagnosis, 01/ /

CM-8 Comparative Transplantation Survival Rates Primary lung transplant by underlying diagnosis Primary kidney, liver, and heart transplant *Kidney, liver, and heart data extrapolated from OPTN Annual Report, Chiron Briefing Document Figure 2.2-1

CM-9

CM-10 Clinical Manifestations of Chronic Rejection Two methods for the diagnosis of chronic rejection –Histologically through transbronchial biopsy (OB) –Clinically through sustained decline in pulmonary function (Bronchiolitis Obliterans Syndrome, BOS) –OB and BOS are histologic and clinical manifestations of the same process Patients develop progressive shortness of breath, graft failure, airflow obstruction, recurrent pulmonary infections Once chronic rejection develops, airway damage is progressive and irreversible –Patients die of graft failure/pneumonia

CM-11 Causes of Death Following Lung Transplantation

CM-12 Despite Best Current Systemic Treatment and Patient Management, Chronic Rejection Eventually Affects Most Patients Years from transplant Calcineurin inhibitors Anti-metabolitesPrednisone CsA Tac AZA MMF % of patients Plus induction, plus pulsed intensifications prn Source: ISHLT, market research Despite best available therapy % chronic rejection-free survival

CM-13 New Concept: Avoid Increasing Systemic Immunosuppression Infection GERD Others Infection GERD Others Immune activation Immune activation Increase systemic immune suppression Increase systemic immune suppression BOS Non Nonalloimmunefactors:

CM-14 Epithelial injury Inflammation Fibroblastic repair Pathway to Chronic Rejection Non-alloimmune stimuli Airway ischemia Viruses Bacterial - PSEUDOMONAS Oxidant stress Reflux Alloimmune stimuli Recurrent acute vascular rejection Lymphocytic bronchitis

CM-15 Lymphocytic Bronchitis/Bronchiolitis

CM-16 Acute Rejection Acute rejection is a perivascular process diagnosed by transbronchial biopsy

CM-17 Separate Interventions for Separate Processes Systemic immunosuppression rejection and ongoing injury, inflammation and fibrosis ending in bronchiolitis obliterans Systemic administration to avert vascular rejection, halting lymphocytic recruitment and activation