Constrictive bronchiolitis obliterans (CBO) is the major impediment to lung transplant success. Donor major histocompatibility complex (MHC) antigens are thought to be the stimuli for transplant CBO, but CBO develops despite immunosuppressive regimens. Our previous CBO models, induced through sustained pulmonary toxicant exposure, suggested that alloimmune antigens are not invariably required for CBO. We hypothesize that both alloimmune and autoimmune processes destroy bronchial cartilage.
We selected DA (Dark Agouti) and BBDR (Bio Breeding diabetic resistant) inbred rats; models of collagen arthritis through genetic control of gelatinase pathways. We also used SD (Sprague-Dawley) outbred rats, used for models of inflammatory collagen breakdown. Tracheas of DA rats were implanted subcutaneously on the backs of BBDR and SD recipients and allowed to heal 6 weeks without immunosuppressants. At necropsy, bronchoalveolar lavage (BAL) was performed. Lung, transplant sites, and tracheas were examined from basic and trichrome-stained paraffin sections. All sera were tested for anti-nuclear antibodies (ANA). Transforming growth factor (TGF) beta was measured on lung homogenate supernatants.
At 2 weeks, rejection scabs were only seen on the BBDR rats. BAL cell counts were normal (>94% macrophages), but macrophages from BAL of BBDR rats were loaded with foreign material not seen in normals. Histology showed widespread emphysema/septal destruction. Peribronchial lymphocytic inflammation and intraluminal granulation were seen, resembling papaverine-induced CBO. No positive ANA was seen, although TGF beta was elevated.CONCLUSIONS: Models of rejection were produced in DA/BBDR rats, with activated BAL cells and peribronchial inflammation. ANA showed no autoimmune globulins. We reject the “autoimmune” hypothesis at 6 weeks; scabs at the implant site appeared only in inbred animals with MHC mismatch.
Animal models of CBO are necessary to determine pathways that produce this irreversible process. Our pilot tests and lymphocyte studies underway have the potential to improve understanding of CBO.
J.A. Svetlecic, None.