Identification and Inhibition of Specific Pathways Leading to Transplant Obliterative Bronchiolitis -an Experimental Approach in the Rat

21 5.2. Platelet-derived growth factor 23 6. CMV infection in lung transplantion 24 6.1. Human CMV 24 6.2. Rat CMV 25 6.3. Role of CMV infection in alloimmune activation 25 6.4. Treatment of CMV infection 27 7. Heterotopic tracheal transplantation as a model for OB 29 AIMS OF THE STUDY 30 METHODS 31 1. Heterotopic tracheal transplantations 31 2. Rat CMV infection 31 3. Drug regimens 32 4. Histological and immunohistological evaluation 33 5. In situ hybridisation 35 6. Statistical methods 35 RESULTS 36 1. The rat tracheal allograft model (I-IV) 36 2. Role of the CD28/B7 costimulatory pathway in the development of experimental OB (I) 37 3. Role of endothelin-1 in the development of experimental OB (II) 38 4. Effect of CMV infection on experimental OB (III,IV) 38 5. Inhibition of RCMV infection-enhanced experimental OB (I, III) 39 DISCUSSION 41 1. Early alloimmune activation is central for the development of OB 41 2. The dualistic role of the epithelium 43 3. ET-1 has both proinflammatory and proproliferative properties in the pathogenesis of OB 44 4. RCMV infection enhances alloimmune activation and SMC growth factor production 45 5. Limitations of the tracheal allograft model 47 6. Conclusions of the study 48 7. Summary 50 YHTEENVETO (FINNISH SUMMARY) 52 SAMMANFATTNING (SWEDISH SUMMARY) 54 ACKNOWLEDGEMENTS 56 REFERENCES 58 6 ORIGINAL PUBLICATIONS This thesis is based on the following publications referred to in the text by their Roman numerals: I Tikkanen JM, Lemström KB, Koskinen PK. Blockade of CD28/B7-2 costimulation inhibits experimental obliterative bronchiolitis in rat tracheal allografts: suppression of helper T cell type1-dominated immune response. II Tikkanen JM, Koskinen PK, Lemström KB. Role of endogenous endothelin-1 in transplant obliterative airway disease in the rat. Submitted. Prevention of cytomegalovirus infection-enhanced experimental obliterative bronchiolitis by antiviral prophylaxis or immunosuppression in rat tracheal allografts. ABBREVIATIONS APC antigen-presenting cell AZA azathioprine BALF bronchoalveolar lavage fluid bFGF basic fibroblast growth factor BOS bronchiolitis obliterans syndrome BrdU bromodeoxyuridine CMV cytomegalovirus CTLA cytotoxic T lymphocyte-associated antigen CD cluster of differentiation CF cystic fibrosis COPD chronic obstructive pulmonary disease CsA cyclosporine A DHPG ganciclovir (9-(1,3-dihydroxy-2-propoxymethyl)guanine) DSG 15-deoxyspergualin EGF epidermal growth factor ET-1 endothelin-1 ET-R endothelin receptor FEV 1 forced expiratory volume in one second HIS hyperimmune serum HLA human leukocyte antigen IFN-J interferon-J IGF-1 insulin-like growth factor-1 IL interleukin IPF idiopathic pulmonary fibrosis ISHLT International Society for Heart and Lung Transplantation MHC major histocompatibility complex MMF mycophenolate mofetil NO nitric …