Stromal Macrophages Research Articles

Studies with 1,2-dithiole-3-thione as a chemoprotector of hydroquinone-induced toxicity to DBA/2-derived bone marrow stromal cells.

Stromal cells from DBA/2 mouse bone marrow have been shown to be susceptible to cytotoxicity induced by several redox-active metabolites of benzene, including hydroquinone (HQ). Treatment with HQ also alters the composition of stromal cell populations by preferentially killing stromal macrophages compared to stromal fibroblasts. This cytotoxicity can be prevented by 1,2-dithiole-3-thione (DTT) as a result of the induction of quinone reductase (QR), a quinone-processing enzyme, and glutathione. The inductive activities of DTT protected stromal cells against HQ-induced cytotoxicity and against HQ-induced impairment of stromal cell ability to support myelopoiesis. In vivo feeding of DTT to DBA/2 mice increased QR activity within the bone marrow compartment and protected bone marrow stromal cells isolated from the DTT-fed animals from ex vivo HQ challenge. Thus, the inducibility of cellular defense mechanisms and xenobiotic-processing enzymes by chemoprotective agents such as DTT may be a useful strategy for protecting against chemically induced bone marrow toxicities.

Studies with 1,2-Dithiole-3-Thione As a Chemoprotector of Hydroquinone-Induced Toxicity to DBA/2-Derived Bone Marrow Stromal Cells

Stromal cells from DBA/2 mouse bone marrow have been shown to be susceptible to cytotoxicity induced by several redox-active metabolites of benzene, including hydroquinone (HQ). Treatment with HQ also alters the composition of stromal cell populations by preferentially killing stromal macrophages compared to stromal fibroblasts. This cytotoxicity can be prevented by 1,2-dithiole-3-thione (DTT) as a result of the induction of quinone reductase (QR), a quinone-processing enzyme, and glutathione. The inductive activities of DTT protected stromal cells against HQ-induced cytotoxicity and against HQ-induced impairment of stromal cell ability to support myelopoiesis. In vivo feeding of DTT to DBA/2 mice increased QR activity within the bone marrow compartment and protected bone marrow stromal cells isolated from the DTT-fed animals from ex vivo HQ challenge. Thus, the inducibility of cellular defense mechanisms and xenobiotic-processing enzymes by chemoprotective agents such as DTT may be a useful strategy for protecting against chemically induced bone marrow toxicities.

Tumor necrosis factor and its receptors in human ovarian cancer. Potential role in disease progression.

The gene for tumor necrosis factor, TNF, was expressed in 45 out of 63 biopsies of human epithelial ovarian cancer. In serous tumors, there was a positive correlation between level of TNF expression and tumor grade. TNF mRNA was found in epithelial tumor cells and infiltrating macrophages, whereas TNF protein localized primarily to a subpopulation of macrophages within and in close proximity to tumor areas. mRNA and protein for the p55 TNF receptor gene localized to the tumor epithelium and tumor, but not to stromal macrophages. The p75 TNF receptor was confined to infiltrating cells. Cells expressing TNF mRNA were also found in ovarian cancer ascites and TNF protein was detected in some ascitic fluids. In 2 out of 12 biopsies of normal ovary, TNF mRNA was detected in a minority of cells in the thecal layer of the corpus luteum. Serum levels of TNF and its soluble receptor did not correlate with extent of TNF expression in matched biopsies. Northern and Southern analysis revealed no gross abnormality of the TNF gene. The coexpression of TNF and its receptor in ovarian cancer biopsies suggests the capacity for autocrine/paracrine action. TNF antagonists may have therapeutic potential in this malignancy.

Role of cytokines in the regulation of bone resorption.

The process of bone remodeling involves complex interactions between the osteoclast, the primary bone-resorbing cell, and other cells in its microenvironment. These interactions can regulate bone resorption through two processes: (1) effects on the number of osteoclasts present at a given site and (2) effects on the bone-resorbing capacity of individual osteoclasts. Cells present in the osteoclast microenvironment include marrow stromal cells, osteoblasts, macrophages, T-lymphocytes, and marrow cells. These cells, as well as the osteoclast itself, produce cytokines that can affect osteoclast formation and osteoclast activity. In vitro model systems using rodent organ cultures or long-term marrow culture systems, and in vivo models have demonstrated that cytokines such as interleukin-1, M-CSF, tumor necrosis factor, and interleukin-6 can stimulate the formation and bone-resorbing capacity of osteoclasts. In contrast, cytokines such as interleukin-4, gamma-interferon, and transforming factor-beta inhibit both osteoclast formation and osteoclast activity. The relative proportions of these cytokines in the marrow microenvironment may play a critical role in regulating osteoclast activity. Knowledge of cytokines that affect osteoclast formation and activity and their capacity to modulate the bone-resorbing process should provide critical insights into normal calcium homeostasis and disorders of bone turnover such as osteoporosis and Paget's disease of bone.

Light and electron-microscopic changes in the colon of the guinea pig after treatment with anthranoid and non-anthranoid laxatives.

Male guinea pigs were treated with senna pods, sennosides, danthron or bisacodyl by gastric intubation for 14 consecutive days. The animals were then killed and the intestine was evaluated by light and electron-microscopic techniques. Macroscopically, the mucosa of the cecum and upper colon was brown in color in the animals receiving anthranoid laxatives. No visible changes were detectable in the bisacodyl group. Evaluation by light and electron microscopy revealed cytoplasmic degeneration and increased apoptosis in the colonic surface epithelium after all laxatives. Most of the resulting apoptotic bodies were found in the lamina propria or had been phagocytosed by stromal macrophages, where they had been transformed into dark brown (anthranoids) or grey to light brown (bisacodyl) pigments. The intestinal changes were most pronounced in the cecum and decreased towards the distal part of the colon. It can be concluded that the morphological changes in the large intestine were similar in anthranoid and non-anthranoid treatment, with the exception that the pigments found in macrophages differed in color and were therefore not always detectable macroscopically.

Decreased haematopoietic colony growth in long-term bone marrow cultures of HIV-positive patients

Deficiencies in bone marrow stromal cells, i.e. fibroblasts, macrophages, endothelial cells and adipocytes, are considered to play a pathophysiological role in HIV-associated haematopoietic failure. Long-term bone marrow cultures (LTBMC) enable the longitudinal investigation of haematopoietic progenitor cell and bone marrow stromal growth. Therefore, in this study, the haematopoietic colony growth of bone marrow from patients with severe HIV infection was compared to that from healthy controls in LTBMC. The total cumulated number of colony-forming units/granulocyte-macrophage (CFU-GM) was 6.7-fold higher (293.6% vs. 44.0%, p < 0.01), that of colony-forming units/granulocyte-erythrocyte-macrophage-megakaryocyte (CFU-GEMM) was 3.5-fold higher (28.7% vs 8.3%), and that of burst-forming units/erythrocyte (BFU-E) was 31.1-fold higher (68.4% vs 2.2%) than that from HIV-positive patients, respectively (colony number before LTBMC = 100%). In contrast, the cumulated cell number at the end of LTBMC from HIV-positive patients was not reduced (cell numbers in percent of initially seeded cells: HIV-positive 418.4%, HIV-negative 397.1%). The significantly reduced colony-forming capacity over a significantly shorter time span, without reduction in the absolute cell number, in LTBMC from patients with severe HIV-infection as compared to healthy controls, suggests that uncoupling between cell proliferation and differentiation is a pathophysiological mechanism in HIV-dependent haematopoietic failure.

A selective culture system for generating terminal deoxynucleotidyl transferase-positive lymphoid cells in vitro. V. Detection of stage-specific pro-B-cell stimulating activity in medium conditioned by mouse bone marrow stromal cells.

The selective in vitro generation of rat, mouse, and human terminal deoxynucleotidyl transferase-positive (TdT+ lymphoid cells in our long-term xenogeneic bone marrow (BM) culture system is characterized by physical interaction between the developing lymphocytes and mouse BM-adherent stromal cells and macrophages. In the present study, experiments in which micropor)us membrane culture inserts were inoculated with rat BM cells demonstrated that although the generation of primitive B-lineage lymphoid cells requires the presence of a mouse BM feeder layer, cognitive recognition events are not necessary. Similarly, cell-free (and serum-free) medium conditioned with mouse BM (but not thymus or spleen) adherent cells and stromal-cell lines therefrom supported the proliferation of early rat lymphoid cells in a dose-dependent manner. Double immunofluorescence for incorporated bromo-deoxyuridine (BrdU) and early B-lineage markers of rat BM lymphoid cells maintained in culture inserts or conditioned medium (CM), and studies of their in vitro and in vivo developmental potentials, indicated that the lymphoproliferative response resulted from the selective stimulation of lymphoid stem and/or progenitor cells. The most primitive of these target cells had a HIS24+ HIS50- TdT- cμ- sIg-, pre-pro-B-cell phenotype. Whereas this subset normally constitutes less than 2% of B-lineage BM cells in vivo, it comprises more than 25% of total lymphoid cells in vitro. In addition, the number of TdT+ cells, predominantly of the early pro-B-cell phenotype (HIS24+ HIS50- TdT- cμ- sIg-), was increased approximately tenfold above input levels. Based on these and previous findings, a schematic model is proposed for the developmental pathway of early B-lineage cells in rat BM from the level of the committed (possibly common) lymphoid stem cell to that of the pre-B-cell.

Interleukin 4 regulates induction of sialoadhesin, the macrophage sialic acid-specific receptor.

Sialoadhesin is a nonphagocytic lectin-like receptor found on a restricted population of tissue macrophages in lymphoid and hemopoietic tissues. In bone marrow, it is localized to areas of contact between the resident stromal macrophages and developing granulocytes, which together form myeloblastic clusters. Sialoadhesin is highly specific for sialylated glycoconjugates and may play a role in adhesion and trophic hemopoietic cell interactions, although its function is unknown. Resident peritoneal macrophages do not express high levels of sialoadhesin in vitro unless an inducing element found in normal mouse serum is present. The restricted in vivo location of this marker and its induction by mouse serum prompted us to examine the possible influence of various cytokines on its expression, measured by a sheep erythrocyte rosetting assay. None of the cytokines tested was able to induce sialoadhesin; however, interleukin 4 (IL-4) prevented the induction in the presence of serum. Expression of other macrophage markers was not influenced in parallel, and Western blotting showed that sialoadhesin antigen in cell lysates was selectively reduced by IL-4. Inhibition by IL-4 was dose dependent, could be blocked by antibodies to both IL-4 and the IL-4 receptor, and was overcome by increased serum concentrations. IL-4 is therefore a potent cytokine regulator of the sialic acid-specific receptor implicated in macrophage-hemopoietic cell interactions.

Communication between stem cells and the hematopoietic microenvironment. Experimental data and models of interaction

The aim of this review is to analyze the different ways by which stem cells and microenvironmental cells may interact. Stem cells are defined as immature cells that ensure the continuous renewal of blood cells. This small set of marrow cells comprises different kinds of cells, differing by their degree of maturity, their commitment, self-renewal ability and repopulating capacity. Microenvironmental cells are fixed marrow cells involved in stem cell survival, proliferation and differentiation. In vivo studies on the distribution within spleen or marrow, of stem cells injected to lethally irradiated mice, have suggested that cells of the microenvironment play a significant role in stem cell proliferation and differentiation. This role has been demonstrated using an in vitro model, i.e. the long-term marrow cultures as described in 1976 by M. Dexter. Analysis of stem cell maintenance in this culture system has made it possible to define the different means by which stromal cells and macrophages (the microenvironmental cells) may control stem cell behavior. Different molecules play a critical role: cytokines (growth factors and inhibitors), adhesion molecules (cell adhesion molecules and molecules belonging to the extracellular matrix) and eventually small peptides. It appears nowadays possible to materially represent the hemopoietic niche, whose existence was postulated by R. Schofield 10 years ago for theoretical reasons related to the the physiology of stem cells.

Stromal macrophages of the choroid plexus situated at an interface between the brain and peripheral immune system constitutively express major histocompatibility class II antigens

Using immunocytochemistry we have shown that there is a population of macrophages within the stroma of the choroid plexus of rats and mice which expresses high levels of major histocompatibility complex Class II antigens. In whole mount preparations of the choroid plexus, the morphology and regular distribution of these cells is similar to the Langerhans cells of the skin. These cells reside at an important interface between the central nervous system and the peripheral immune system and their possible role in immune-mediated diseases of the central nervous system is discussed.

Papillary Renal Cell Carcinoma

Papillary renal cell carcinoma is an uncommon variant of renal cell carcinoma which has unique features including hypovascularity or avascularity, extensive stromal macrophage infiltration and better prognosis than that for nonpapillary renal cell carcinoma. Two cases of papillary renal cell carcinoma presenting hypovascular or avascular angiology are presented. Histologically, the two tumors had a purely papillary structure. Papillae were lined by a layer of epithelial cells which lacked prominent cellular atypia, and there were numerous macrophages in the stroma. In addition, in one patient, extensive calcification of the tumor capsule was present. Furthermore, our experience in the present study with imprint cytology indicates that it offers corroborative information for the intraoperative diagnosis made on the basis of frozen section examination.

Developmental regulation of sialoadhesin (sheep erythrocyte receptor), a macrophage-cell interaction molecule expressed in lymphohemopoietic tissues.

Stromal macrophages in lymphohemopoietic tissues express novel macrophagerestricted plasma membrane receptors involved in nonphagocytic interactions with other hemopoietic cells. One such receptor with lectinlike specificity for sialylated glycoconjugates on sheep erythrocytes and murine hemopoietic cells has been characterized immunochemically and termed sialoadhesin. We have examined sialoadhesin expression during mouse development to learn more about its regulation and function. Immunocytochemical, rosetting, and Western blot studies show that sialoadhesin is first detected on fetal liver macrophages on day 18 of development, 7 days after numerous F4/80+ macrophages are found within erythroblastic islands. In spleen and bone marrow, sialoadhesin appears between day 18 and birth, in parallel with myeloid development. Strongly labeled macrophages in the marginal zone of spleen, characteristic of adult lymphoid tissues, appeared gradually between 1–4 Isolation of fetal liver macrophages at day 14 confirmed that sialoadhesin was not involved in the binding of erythroblasts, which is mediated by a distinct cationdependent receptor (Morris et al., 1988, p. 649). Sialoadhesin could be expressed by isolated fetal liver macrophages after cultivation in adult mouse serum, a known source of inducer activity, but was not dependent on the presence of this inducer, unlike adultderived madrophages. Fetal plasma contained inducing activity on day 13, but adult levels were not reached until 2 weeks postnatally. These studies show that sialoadhesin is differentially regulated compared with the erythroblast receptor and F4/80 antigen, that it is not required for fetal erythropoiesis, and that its induction on stromal macrophages is delayed until the onset of myeloid and lymphoid development. Sialoadhesin provides a marker to study maturation and functions of macrophages during ontogeny of the lymphohemopoietic system.

An immunohistochemical study of testicular biopsies in childhood acute lymphoblastic leukemia: reactivity of normal testicular components and leukemic infiltrates.

We performed an immunohistochemical analysis of frozen sections from testicular biopsies from 23 children with acute lymphoblastic leukemia. Eleven cases were infiltrated by leukemia. Tumor cells were immunostained by a panel of antibodies that identified CD10, CD43, CD19, CD3, CD7, and MHC class I and II. The immunoreactivity of normal testicular components was also studied. Normal testis showed no CD10 reactivity. Wide variation in the number of stromal macrophages identified by CD11c was found. Transferrin receptor (CD71) was expressed by some stromal macrophages, by seminiferous tubules, and by Leydig cells. B lymphocytes were absent from the testicular stroma but small numbers of T lymphocytes were consistently present. MHC class I and II were expressed by most stromal cells but not by seminiferous tubules.

Changes in decidual stromal cell function associated with labour.

To determine whether decidual cells produce altered levels of prostaglandins after labour. Decidual stromal cells and macrophages were isolated before and after labour, and the production of prostaglandins E2 and F2 alpha measured. Changes in the numbers of cyclooxygenase enzyme positive cells were assessed by immunocytochemistry. Decidual stromal cells obtained after labour produced 30 times more prostaglandins E2 and F2 alpha in culture than cells obtained before labour. The increased production persisted for up to 72 h of culture, and was associated with an increase in the numbers of cyclooxygenase-positive cells from less than 5% to greater than 95%. No changes in macrophage function were observed. Increased levels of prostaglandins E2 and F2 alpha were released from decidual stromal cells after labour, suggesting that these cells may be an important source of prostaglandins in labour.

Role for interleukin-1 (IL-1) in benzene-induced hematotoxicity: inhibition of conversion of pre-IL-1 alpha to mature cytokine in murine macrophages by hydroquinone and prevention of benzene-induced hematotoxicity in mice by IL-1 alpha

Chronic exposure of humans to benzene (BZ), a myelotoxin, causes aplastic anemia and acute leukemia. The stromal macrophage that produces interleukin-1 (IL-1), a cytokine essential for hematopoiesis, is a target of BZ's toxicity. Monocyte dysfunction and decreased IL-1 production have been shown to be involved in aplastic anemia in humans. Hydroquinone (HQ), a toxic bone marrow (BM) metabolite of BZ, causes time- and concentration-dependent inhibition of processing of the 34-Kd pre-interleukin-1 alpha (IL-1 alpha) to the 17-Kd mature cytokine in murine P388D1 macrophages and BM stromal macrophages, as measured by Western immunoblots of cell lysate proteins using a polyclonal rabbit antimurine IL-1 alpha antibody. HQ over a 10-fold concentration range had no effect on the lipopolysaccharide (LPS)-induced production of pre- IL-1 alpha precursor or on cell viability or DNA and protein synthesis. Stromal macrophages obtained from the femoral BM of C57Bl/6 mice exposed to BZ (600 or 800 mg/kg body weight) for 2 days were incapable of processing the 34-Kd pre-IL-1 alpha to the mature 17-Kd cytokine when stimulated in culture with LPS. Stromal macrophages from mice coadministered BZ and indomethacin, a prostaglandin H synthase (PHS) inhibitor that has been shown to prevent BZ-induced myelotoxic and genotoxic effects in mice when coadministered with benzene were able to convert the pre-IL-1 alpha to mature cytokine. Administration of recombinant murine IL-1 alpha (rMuIL-1 alpha) to mice before a dose of BZ that causes severe depression of BM cellularity completely prevents BM depression, most probably by bypassing the inability of the stromal macrophage in BZ-treated animals to process pre-IL-1 alpha to the mature cytokine.

Role for Interleukin-1 (IL-1) in Benzene-Induced Hematotoxicity: Inhibition of Conversion of Pre-IL-lα to Mature Cytokine in Murine Macrophages by Hydroquinone and Prevention of Benzene-Induced Hematotoxicity in Mice by IL-lα

Chronic exposure of humans to benzene (BZ), a myelotoxin, causes aplastic anemia and acute leukemia. The stromal macrophage that produces interleukin-1 (IL-1), a cytokine essential for hematopoiesis, is a target of BZ's toxicity. Monocyte dysfunction and decreased IL-1 production have been shown to be involved in aplastic anemia in humans. Hydroquinone (HQ), a toxic bone marrow (BM) metabolite of BZ, causes time- and concentration-dependent inhibition of processing of the 34-Kd pre-interleukin-1 alpha (IL-1 alpha) to the 17-Kd mature cytokine in murine P388D1 macrophages and BM stromal macrophages, as measured by Western immunoblots of cell lysate proteins using a polyclonal rabbit antimurine IL-1 alpha antibody. HQ over a 10-fold concentration range had no effect on the lipopolysaccharide (LPS)-induced production of pre-IL-1 alpha precursor or on cell viability or DNA and protein synthesis. Stromal macrophages obtained from the femoral BM of C57Bl/6 mice exposed to BZ (600 or 800 mg/kg body weight) for 2 days were incapable of processing the 34-Kd pre-IL-1 alpha to the mature 17-Kd cytokine when stimulated in culture with LPS. Stromal macrophages from mice coadministered BZ and indomethacin, a prostaglandin H synthase (PHS) inhibitor that has been shown to prevent BZ-induced myelotoxic and genotoxic effects in mice when coadministered with benzene were able to convert the pre-IL-1 alpha to mature cytokine. Administration of recombinant murine IL-1 alpha (rMuIL-1 alpha) to mice before a dose of BZ that causes severe depression of BM cellularity completely prevents BM depression, most probably by bypassing the inability of the stromal macrophage in BZ-treated animals to process pre-IL-1 alpha to the mature cytokine.

Purification and properties of sialoadhesin, a sialic acid-binding receptor of murine tissue macrophages.

Macrophage subpopulations in the mouse express a lectin-like receptor, sialoadhesin (originally named sheep erythrocyte receptor, SER), which selectively recognizes sialoglycoconjugates and is likely to be involved in cellular interactions of stromal macrophages in haematopoietic and lymphoid tissues. In this report we describe the purification and ligand specificity of sialoadhesin isolated from mouse spleen. Purified sialoadhesin, a glycoprotein of 185 kd apparent Mr, agglutinated sheep or human erythrocytes at nanomolar concentrations in a sialic acid-dependent manner. Low angle shadowing and electron microscopy showed that sialoadhesin consisted of a globular head region of approximately 9 nm and an extended tail of approximately 35 nm. To investigate the specificity for sialic acid, we studied the interaction of sialoadhesin with derivatized human erythrocytes, glycoproteins, and glycolipids. In conclusion, sialoadhesin specifically recognizes the oligosaccharide sequence Neu5Ac alpha 2----3Gal beta 1----3GalNAc in either sialoglycoproteins or gangliosides. These findings imply that specific sialoglycoconjugates carrying this structure may be involved in cellular interactions between stromal macrophages and subpopulations of haematopoietic cells and lymphocytes.

Expression of a divalent cation-dependent erythroblast adhesion receptor by stromal macrophages from murine bone marrow

Stromal macrophages in haemopoietic organs express novel surface receptors that are implicated in trophic interactions with developing blood cells. Macrophages isolated from foetal liver bind erythroblasts (Eb) by a divalent cation-dependent receptor (EbR), whereas stromal macrophages in adult bone marrow and lymphoid organs express a lectin-like receptor, sialoadhesin, which interacts with sialylated structures on sheep erythrocytes and murine haemopoietic cells. In order to learn more about the regulation of these haemagglutinins, we examined binding of Eb by stromal macrophages that had been isolated from adult murine tissues or generated in Dexter-type cultures of bone marrow. Macrophages were purified from bone marrow by collagenase digestion, adherence to a substratum and detachment of clustered haemopoietic cells, and tested for their ability to bind Eb from foetal liver or anaemic adult spleen. Freshly isolated bone marrow macrophages bound Eb mainly by a divalent cation-dependent activity that was not inhibited by neuraminidase treatment of Eb or by specific anti-sialoadhesin monoclonal antibodies, although these macrophages express sialoadhesin and Eb bear a potential ligand for this receptor. Macrophages obtained by digestion from other adult lymphoid tissues also bound Eb by a divalent cation-dependent activity, whereas blood monocytes and lavaged peritoneal macrophages failed to do so. Peritoneal macrophages could be induced to express high levels of sialoadhesin by cultivation in homologous mouse serum, but such macrophages did not acquire sialoadhesin-independent EbR activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Stromal Cells, Macrophages and Lymphoid Cells in the Head-kidney of Sea Bass (Dicentrarchus labrax L.). An Ultrastructural Study.

The ultrastructure of the stromal cells, macrophages and lymphoid cells in the head-kidney of the sea bass (Dicentrarchus labrax L.) was studied. Like mammals, stroma cell types here include endothelial and adventitial cells comprising the sinusoidal wall, fibroblast-like reticular cells related to scarce reticular fibres, and macrophage-type reticulum cells, the last probably corresponding to the resident macrophage population of higher vertebrates. Their possible role in the haemopoietic microenvironment is considered. Monocyte-macrophages, macrophages and melano-macrophages, probably corresponding to ontogenic or functional stages of the same cell type were identified and their functional significances are discussed. Scarce, free lymphoid cells or small clusters of lymphocytes but no lymphopoietic islets were recognizable. Large lymphocytes, small lymphocytes and very scarce developing and mature plasma cells were identified. The lymphoid function and defensive role of the head-kidney were analyzed.

Distribution of ICAM-1 Within Decidua and Placenta and its Gestational Age-Associated Changes

Intercellular adhesion molecule 1 (ICAM-1), a ligand of leukocyte function associated antigen 1 (LFA-1), is present on many cells, including monocyte/macrophages. ICAM-1 is considered to play an important role in the induction and maintenance of inflammatory responses by permitting leukocyte adhesion. Its expression is inducible on endothelial and epithelial cells exposed to various inflammatory cytokines (preceding expression of HLA-DR) and is maturation dependent in certain cell lines. The distribution of ICAM-1 in decidua and placenta was evaluated using peroxidase-antiperoxidase immunohistochemistry. In decidua of first and third trimesters, scattered ICAM-1-staining cells were observed. In placentas of first and third trimesters, all types of trophoblasts stained negatively for ICAM-1. Prior to 10 weeks of gestation, the villous stroma was uniformly ICAM-1 and HLA-DR unreactive. Beginning in the chorionic plate at approximately 10 weeks, scattered ICAM-1-positive stromal cells were observed, whereas stromal cells of the terminal villi revealed no ICAM-1. By 14-16 weeks, approximately 40-50% of the terminal villous stromal cells were ICAM-1 staining. This parallels the 40-50% of the villous stromal cells that share other immunohistochemical markers, such as EB-11, with monocyte/macrophages. The lack of functional maturation of the villous stromal macrophage may explain the rarity of chronic villitis early in gestation.