No abstract

The ras p21 GTPase-activating protein (GAP) was purified from human placental tissue. Internal amino acid sequence was obtained from this 120,000-dalton protein and, by means of this sequence, two types of complementary DNA clones were isolated and characterized. One type encoded GAP with a predicted molecular mass of 116,000 daltons and 96% identity with bovine GAP. The messenger RNA of this GAP was detected in human lung, brain, liver, leukocytes, and placenta. The second type appeared to be generated by a differential splicing mechanism and encoded a novel form of GAP with a predicted molecular mass of 100,400 daltons. This protein lacks the hydrophobic amino terminus characteristic of the larger species, but retains GAP activity. The messenger RNA of this type was abundantly expressed in placenta and in several human cell lines, but not in adult tissues.

Colony stimulating factor-1 (CSF-1) is a glycoprotein growth factor required for the proliferation and differentiation of mononuclear phagocytic cells (reviewed in ref. 1). A 10,000-fold elevation of mouse uterine CSF-1 during pregnancy, suggested by studies of the bone marrow colony stimulating activity of uterine extracts, was recently demonstrated by radioimmunoassay (RIA). This increase and the observations that placenta and choriocarcinoma cell lines express c-fms messenger RNA and the c-fms proto oncogene product (CSF-1 receptor) respectively, suggest an additional role for CSF-1 in pregnancy. We now show that uterine CSF-1 concentration is regulated by the synergistic action of female sex steroids, oestradiol-17 beta (E2) and progesterone (P) and that the elevation in CSF-1 concentration can be attributed to the preferential expression of an alternatively spliced CSF-1 mRNA by uterine glandular epithelial cells. These findings indicate that CSF-1, under hormonal influence, plays a role in placental development and function and that steroid hormones may regulate developmental processes via their effects on the expression of tissue-specific growth factors.

Killer cell immunoglobulin-like receptors (KIR) interact with HLA class I ligands to regulate NK cell development and function. These interactions affect the outcome of unrelated donor (URD) hematopoietic cell transplantation (HCT). We have shown previously that donors with KIR B vs. KIR A haplotypes improve the clinical outcome for patients with acute myelogenous leukemia (AML) by reducing the incidence of leukemic relapse and improving leukemia free survival (LFS). Both centromeric and telomeric KIR B genes contribute to the effect, but the centromeric genes are dominant. They include the genes encoding inhibitory KIR that are specific for the C1 and C2 epitopes of HLA-C. We used an expanded cohort of 1532 T-cell replete transplants to examine the interaction between donor KIR B genes and recipient Class I HLA KIR ligands. The relapse protection associated with donor KIR B is enhanced in recipients who have one or two C1-bearing HLA-C allotypes, compared to C2 homozygous recipients, with no effect based on donor HLA. The protective interaction between donors with ≥2 vs. 0–1 KIR B-motifs and recipient C1 was specific to transplants with class I mismatch at HLA-C (RR of LFS 0.57 [0.40–0.79]; P=0.001) irrespective of the KIR ligand mismatch status of the transplant. The survival advantage and relapse protection in C1/x recipients compared to C2/C2 recipients was similar irrespective of the particular donor KIR B genes. Understanding the interactions between donor KIR and recipient HLA class I can be used to inform donor selection to improve outcome of URD HCT for AML.

Complementary DNA (cDNA) clones encoding human macrophage-specific specific colony-stimulating factor (CSF-1) were isolated. One cDNA clone codes for a mature polypeptide of 224 amino acids and a putative leader of 32 amino acids. This cDNA, which was cloned in the Okayama-Berg expression vector, specifies the synthesis of biologically active CSF-1 in COS cells, as determined by a specific radioreceptor assay, macrophage bone marrow colony formation, and antibody neutralization. Most of the cDNA isolates contain part of an intron sequence that changes the reading frame, resulting in an abrupt termination of translation; these cDNA's were inactive in COS cells. The CSF-1 appears to be encoded by a single-copy gene, but its expression results in the synthesis of several messenger RNA species, ranging in size from about 1.5 to 4.5 kilobases.