Publications

During 1988 through 1990, California experienced its worst measles epidemic in more than a decade, with 16,400 reported cases, 3,390 hospital admissions, and 75 deaths. More than half of the patients were younger than 5 years; the highest incidence was among infants younger than 12 months. The epidemic centered in low-income Hispanic communities in southern and central California. The major cause of the epidemic was low immunization levels among preschool-aged children and young adults. Rates of complications, admission to hospital, and death were surprisingly high. Outbreak control efforts met with indeterminate success. Problems with these efforts included insufficient funding early in the epidemic and disappointing public response to community-based immunization campaigns. The cost of medical care and outbreak control for the epidemic is conservatively estimated at $30.9 million. Unless the level of immunization in preschool-aged children is increased, this type of epidemic will probably recur.

NF-kappa B and AP-1 represent distinct mammalian transcription factors that target unique DNA enhancer elements. The heterodimeric NF-kappa B complex is typically composed of two DNA binding subunits, NF-kappa B p50 and NF-kappa B p65, which share structural homology with the c-rel proto-oncogene product. Similarly, the AP-1 transcription factor complex is comprised of dimers of the c-fos and c-jun proto-oncogene products or of closely related proteins. We now demonstrate that the bZIP regions of c-Fos and c-Jun are capable of physically interacting with NF-kappa B p65 through the Rel homology domain. This complex of NF-kappa B p65 and Jun or Fos exhibits enhanced DNA binding and biological function via both the kappa B and AP-1 response elements including synergistic activation of the 5' long terminal repeat of the human immunodeficiency virus type 1. These findings support a combinatorial mechanism of gene regulation involving the unexpected cross-coupling of two different classes of transcription factors to form novel protein complexes exhibiting potentiated biological activity.

Renal plasma filtration is a critical physiologic function that depends upon the precise composition and arrangement of the constituent extracellular matrix proteins within the glomerular basement membrane (GBM). The GBM develops during renal embryogenesis by the fusion of discrete basement membranes produced independently by endothelial and visceral epithelial cells, and, possibly from matrix secreted by the mesangial cells. In the mature animal, however, the epithelial cell has generally been accepted as the sole source of all GBM constituent proteins. Although the final structures and distributions of the component proteins have been defined by histochemical techniques, the individual contributions of the three resident glomerular cell types to the maintenance and turnover of the mature GBM remain uncertain. We report the application of a new technique, in situ reverse transcription (ISRT), for the localization of RNA transcripts of nine major GBM protein components within the closely apposed cells of the glomerulus. Using this technique, we demonstrate that in normal adult rat glomeruli the RNA transcripts for heparan sulfate proteoglycan and the laminin-S chain are primarily expressed by visceral epithelial cells, while Type IV alpha-1 and alpha-2 collagen transcripts were restricted to the endothelial cells in a heterogeneous pattern. RNA transcripts for entactin and the laminin-A and -B2 chains were expressed by all three glomerular cell types, while laminin-B1 and fibronectin transcripts were limited to the mesangium. These findings demonstrate that GBM synthesis in the mature animal is not restricted to the epithelial cell and that all intrinsic glomerular cells contribute to the production of GBM protein components. The ISRT technique also provided the additional, and unexpected, finding that appreciable synthetic heterogeneity exists within individual glomerular cell types.

Integrins are cell adhesion receptors that mediate cell-extracellular matrix and cell-cell interactions. Each integrin consists of two glycoprotein subunits (alpha and beta). We have previously described a novel integrin beta-subunit, beta 6, which is expressed in cultured epithelial cells. beta 6 can associate with alpha v to form the fibronectin-binding heterodimer alpha v beta 6. Here we report the tissue distribution of beta 6 integrin mRNA determined by in situ hybridization of a beta 6 cRNA probe with representative frozen tissue sections from a rhesus monkey tissue bank. We detected beta 6 mRNA exclusively in epithelial cells. However, beta 6 mRNA expression varied greatly among different epithelia. High levels of beta 6 mRNA were found only in two very specialized epithelial cell types: a portion of the kidney tubule epithelium, termed macula densa, and the endometrial epithelium of secretory phase uterus. In the endometrium, beta 6 expression was highest in the differentiated epithelium of functional layer glands, suggesting that beta 6 expression can be regulated in a differentiation-dependent manner. beta 6 expression may also depend on the stage in the estrous cycle, since we found much lower beta 6 mRNA levels in a specimen of proliferative phase endometrium. Epithelium in several other tissues, including salivary gland ducts, gall bladder, and epididymis, contained detectable levels of beta 6 mRNA, albeit much lower than in macula densa and endometrium. In other epithelia, including skin and lung, beta 6 mRNA was undetectable. Taken together, these results suggest that in normal adult primates beta 6 expression is regulated in a cell type-specific manner, restricted to a few epithelial tissues.

The polymerase chain reaction was used to evaluate cytokine gene expression in bronchoalveolar lavage (BAL) cells and peripheral blood leukocytes in 31 human lung transplant recipients. All patients were maintained on a triple immunosuppression regimen consisting of CsA, AZA, and prednisone. Posttransplant survival ranged from 0.5 to 100.5 months (mean = 16.3 months). Cytokines IL-1 alpha, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, TNF-beta, and IFN-gamma were studied. In BAL, transcripts for IL-1 alpha, IL-7, IL-8, and TNF-beta were found in over 60% of samples and those for IL-5, IL-6, and IFN-gamma in 40-50%, while IL-2 and IL-4 mRNA were rarely found (< 20%). Considerable variation in the frequency of cytokine gene expression between BAL and peripheral blood was observed. When analyzed for the presence of acute pulmonary allograft rejection (without infection), transcripts for IL-4 and IL-6 in BAL demonstrated the greatest increase in frequency compared with nil rejection (P = 0.07 and P = 0.17, respectively). Pulmonary infection (without rejection) was associated with a modest increase in the expression of genes for IL-1 alpha and IFN-gamma (> 10%). Transcripts for IL-4 were not found in association with pulmonary infection, suggesting that this cytokine may be useful as a discriminatory rejection marker.