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We studied 41 renal cell carcinomas, classified according to histologic grades G1 through G3, by indirect immunofluorescence microscopy using a panel of monoclonal antibodies (MAb) against various integrin subunits, and the basement membrane (BM) components laminin and collagen type IV. Selected cases also were immunostained using the avidin-biotin-complex method. The alpha 3 and beta 1 integrin subunits were detected in tumor cells of all the carcinomas. All G1 carcinomas, like normal tubular epithelial cells, expressed the alpha 6 subunit, whereas it was lacking in 20% and 40% of G2 and G3 carcinomas, respectively. Furthermore, when alpha 6 was expressed, a lack of basally polarized organization of the subunit, coupled with disorganization of the BM components, correlated with histologic grade. Another feature that appeared to characterize the more anaplastic tumors was their high level (80%) of the alpha v subunit expression as compared with its absence in the G1 carcinomas. Stromal myofibroblasts, identified by double-labeling with anti-myosin, were often characterized by the expression of the alpha 1, alpha 3, alpha 5 and beta 1 subunits. These results indicate that changes in integrin expression in renal cell carcinomas may be correlated with their degree of histologic malignancy.
Human CD31 is a recently characterized molecule present on leukocytes, platelets, and endothelium. Its function is not known. Because it is a member of the immunoglobulin superfamily and structurally homologous to carcinoembryonic antigen, a putative intercellular adhesion molecule, it is believed that CD31 may function also as an adhesion molecule. In this report, we characterize the cellular reactivity of a monoclonal antibody to a murine protein that is homologous to CD31. To delineate the cellular reactivity of the murine CD31 homologue recognized by our monoclonal antibody, we used immunoperoxidase and immunoelectron microscopic techniques. The most striking finding was that the putative murine homolog of CD31 is expressed in particularly high amounts on endothelium-adherent lymphocytes transmigrating across sinusoidal or venular vascular boundaries. Such a distribution was apparent in draining murine lymph nodes during the peak of an immune response after immunization with a protein antigen in adjuvant, a situation in which there are many transmigrating lymphocytes. Immunoelectron microscopic analysis also shows that CD31 is predominantly distributed on portions of transmigrating lymphocytes that are in contact with or adjacent to areas of contact with endothelial cells. These findings suggest a previously undescribed role for CD31 in lymphocyte recruitment and transmigration.
Tissues from fetuses and neonates of control and streptozotocin (STZ)-treated Sprague-Dawley rats were used to study the content and distribution of the hydrophobic surfactant protein B (SP-B) and the mRNAs for SP-B and SP-C using immunohistochemistry, RNA blotting, and tissue in situ hybridization. A dose of 50 mg/kg STZ was used to treat female rats before mating. The fetuses were sacrificed at fetal days 18 through 21 and neonates were obtained on neonatal days 1 and 2 (day of birth = end of day 22). At fetal day 18, SP-B was barely detectable by immunohistochemistry in control animals but the levels were progressively increased through gestation and easily detected by fetal day 21. At all fetal ages, SP-B was decreased in the STZ group compared with control animals. Both SP-B and SP-C mRNA were detectable at fetal day 18 in the control group and increased with advancing gestational age. In fetal lungs from the STZ group, SP-B and SP-C mRNA also showed an increase with advancing gestational age, but the levels were decreased compared with controls at fetal days 18, 20, and 21 (P less than 0.05). At fetal day 19, this difference did not achieve statistical significance. Differences between the two groups were no longer detected by neonatal days 1 and 2. The difference between the STZ and control groups, in both protein (SP-B) and mRNA (SP-B and SP-C), diminished with advancing fetal age but remained significant up to fetal day 21.(ABSTRACT TRUNCATED AT 250 WORDS)
Tissue specific non-MHC alloantigens play a crucial role in allograft immunity. However, their structural properties have remained elusive, largely due to their inability to induce a strong antibody response. We report the characterization of a monkey heteroantiserum, MHK-I, raised against human kidney cells, that serologically reacts specifically with kidney cells after extensive absorptions of anti-HLA class I and II reactivities. The non-MHC MHK-I-binding molecule(s) is expressed only in the renal cortex on the glomerulus, peritubular capillaries, venous endothelium, and tubular epithelium. Immunochemically, MHK-I recognizes a kidney-specific non-MHC alloantigen of Mr 90,000 to 100,000 (90 kD). These properties of MHK-I are similar to those of the previously characterized alloantibodies eluted from rejected kidneys. These alloantibodies bind to the kidney from which the antibody was eluted and to a few others but are unlike MHK-I, which binds to extracts prepared from all human kidneys. Biochemical analysis by two-dimensional electrophoresis (pI ranging between 4.5 and 5.5) and peptide fingerprinting provide further evidence that the alloantigen is polymorphic. These findings imply that the non-MHC kidney-specific molecule(s) may function as target(s) for immune destruction of renal allografts.
BACKGROUND - Little is known about the factors regulating growth and maintenance of human leptomeningeal cells. The influence of cerebrospinal fluid on these functions is also unknown. Possible mediators include the transforming growth factor-beta (TGF beta) family, three closely related peptides that regulate proliferation and numerous other physiologic processes in most mesenchymal cells.
EXPERIMENTAL DESIGN - Expression of both mRNA and protein for TGF beta isoforms TGF beta 1, TGF beta 2, and TGF beta 3 as well as TGF beta-competing activity were evaluated in primary human leptomeningeal cultures by Northern blot analysis, immunohistochemistry, and a radioreceptor assay, respectively. TGF beta 1, TGF beta 2, and TGF beta 3 immunoreactivity was also evaluated in brain sections containing leptomeninges from which these cell cultures were established. An additional study analyzed human cerebrospinal fluid for TGF beta-like activity.
RESULTS - Transcripts for TGF beta 1, TGF beta 2 and TGF beta 3 were detected in RNA from each of the eight leptomeningeal cultures. Significant TGF beta 1 immunoreactivity was detected in leptomeningeal tissue from five of eight cases. TGF beta 2 and TGF beta 3 immunostaining was seen in eight and seven of the cases, respectively. Similarly, cells cultured from these meninges exhibited variable TGF beta 1 and extensive TGF beta 2 and TGF beta 3 immunoreactivity. Radioreceptor assays of conditioned media from four cultures demonstrated significant latent TGF beta-like activity. TGF beta radioreceptor competing activity was also detected by radioreceptor assay in normal blood-free cerebrospinal fluid from 32 patients without neurological disease. In addition, pooled cerebrospinal fluid (from six additional patients) exhibited dose dependent TGF beta-like activity in the radioreceptor assay, stimulation of AKR-2B cell growth in soft agar and inhibition of growth in CCL-64 cell assays suggesting that cerebrospinal fluid contains TG beta-like activity.
CONCLUSIONS - These findings suggest that the human leptomeninges synthesize TGF beta 1, TGF beta 2 and TGF beta 3 and secrete latent TGF beta s at least in vitro. Human cerebrospinal fluid may also contain TGF beta isoforms. Collectively, these observations raise the possibility that members of the TGF beta family contribute to biologic processes of the leptomeninges.
The transforming growth factor-beta (TGF beta) family in mammals includes three closely related peptides that influence proliferation and numerous physiologic processes in most mesenchymal cells. In this study, Northern blots, immunohistochemistry, TGF beta radioreceptor assays, TGF beta receptor affinity labeling and [3H] thymidine incorporation were used to evaluate whether primary cell cultures of human meningiomas synthesize the three TGF beta isoforms, bear TGF beta receptors, and respond to TGF beta. Transcripts for TGF beta 1 and 2 were detected in the three cases analyzed. Transforming growth factor-beta 1 immunoreactivity was detected in three of six cases, and TGF beta 2 and 3 immunoreactivity were detected in each case analyzed. Media conditioned by cells cultured from six meningiomas also contained latent TGF beta-like activity. Transforming growth factor-beta receptor cross-linking studies identified TGF beta binding sites corresponding to the type 1, type 2, and type 3 receptors on meningioma cells. Treatment with active TGF beta 1 produced a statistically significant reduction in [3H] thymidine incorporation after stimulation with 10% fetal calf serum and epidermal growth factor in all six cases studied.
Eight lines of transgenic mice expressing a mouse mammary tumor virus (MMTV) human transforming growth factor-alpha (TGF alpha) fusion gene were established. Three lines with distinctive phenotypes are presented. All have proliferative changes of the mammary gland. One line has sebaceous gland hyperplasia of the skin. Five histologic patterns of mammary gland hyperplasia based on two of these lines were identified: cystic hyperplasia, solid hyperplasia, dysplasia, adenoma, and adenocarcinoma. Human TGF alpha mRNA and protein were produced in all patterns but appeared reduced in solid hyperplasia, dysplasia, and adenocarcinoma. TGF alpha immunoreactivity in the mammary tissue, cystic fluid, and serum did not show significant differences; hyperplasia developed in 65% of multiparous mice and 45% of virgin mice by 12 months of age. Adenocarcinoma developed in 40% of multiparous mice and 30% of virgin mice by 16 months of age. These transgenic lines may provide useful models of mammary and sebaceous gland hyperplasia analogous to human disease.