Dominant negative suppression of major histocompatibility complex genes occurs in trophoblasts.

BACKGROUND: Polymorphic class I and II major histo-: compatibility complex (MHC) genes are not transcribed in trophoblasts although many immune system cells express these genes constitutively. To study the molecular biology of MHC suppression for the purposes of potential transgenic animal development, we examined the effect on MHC expression in B cells by fusing them with trophoblasts. METHODS: Trophoblasts and B cells with separate selection markers were fused with polyethylene glycol. After growth in double selection media, the hybrids were analyzed for HLA-A, -B, -C, -DR, -DP, and -DQ expression by fluorescence-activated cell scanning and class I and II mRNA by Northern blotting. Class II promoter activity in trophoblasts was then analyzed by transfection of a lethal reporter construct and subsequently, the class II transactivator. RESULTS: Class I and II surface antigens and their corresponding mRNA were completely suppressed in the hybrids. The lethal reporter construct demonstrated that class II suppression resulted from lack of activation of the class II promoter. This in turn was caused by lack of functional class II transactivator. CONCLUSIONS: These data indicate that dominant negative trophoblast factors, either directly or indirectly, suppress expression of the MHC genes. If these factors can be cloned, the potential exists for developing transgenic animals that cannot express MHC or peptide antigen to T cell receptors through the MHC system.

What is the appropriate size criterion for resection of thoracic aortic aneurysms?

Although many articles have described techniques for resection of thoracic aortic aneurysms, limited information on the natural history of this disorder is available to aid in defining criteria for surgical intervention. Data on 230 patients with thoracic aortic aneurysms treated at Yale University School of Medicine from 1985 to 1996 were analyzed. This computerized database included 714 imaging studies (magnetic resonance imaging, computed tomography, echocardiography). Mean size of the thoracic aorta in these patients at initial presentation was 5.2 cm (range 3.5 to 10 cm). The mean growth rate was 0.12 cm/yr. Overall survivals at 1 and 5 years were 85% and 64%, respectively. Patients having aortic dissection had lower survival (83% 1 year; 46% 5 year) than the cohort without dissection (89% 1 year; 71% 5 year). One hundred thirty-six patients underwent surgery for their thoracic aortic aneurysms. For elective operations, the mortality was 9.0%; for emergency operations, 21.7%. Median size at time of rupture or dissection was 6.0 cm for ascending aneurysms and 7.2 cm for descending aneurysms. The incidence of dissection or rupture increased with aneurysm size. Multivariable regression analysis to isolate risk factors for acute dissection or rupture revealed that size larger than 6.0 cm increased the probability by 32.1 percentage points for ascending aneurysms (p = 0.005). For descending aneurysms, this probability increased by 43.0 percentage points at a size greater than 7.0 cm (p = 0.006). If the median size at the time of dissection or rupture were used as the intervention criterion, half of the patients would suffer a devastating complication before the operation. Accordingly, a criterion lower than the median is appropriate. We recommend 5.5 cm as an acceptable size for elective resection of ascending aortic aneurysms, because resection can be performed with relatively low mortality. For aneurysms of the descending aorta, in which perioperative complications are greater and the median size at the time of complications is larger, we recommend intervention at 6.5 cm.