Adrian I Erlebacher, M.D., Ph.D.

Strangers no more: Uterine NK cell recognition of the placenta in mice
Erlebacher, Adrian
2011 Mar 15;108(11):4267-4268, Proceedings of the National Academy of Sciences of the United States of America
— id: 127236, year: 2011, vol: 108, page: 4267, stat: Journal Article,

miR-30b/30d Regulation of GalNAc Transferases Enhances Invasion and Immunosuppression during Metastasis
Gaziel-Sovran, Avital; Segura, Miguel F; Di Micco, Raffaella; Collins, Mary K; Hanniford, Douglas; Vega-Saenz de Miera, Eleazar; Rakus, John F; Dankert, John F; Shang, Shulian; Kerbel, Robert S; Bhardwaj, Nina; Shao, Yongzhao; Darvishian, Farbod; Zavadil, Jiri; Erlebacher, Adrian; Mahal, Lara K; Osman, Iman; Hernando, Eva
2011 Jul 12;20(1):104-118, Cancer cell
To metastasize, a tumor cell must acquire abilities such as the capacity to colonize new tissue and evade immune surveillance. Recent evidence suggests that microRNAs can promote the evolution of malignant behaviors by regulating multiple targets. We performed a microRNA analysis of human melanoma, a highly invasive cancer, and found that miR-30b/30d upregulation correlates with stage, metastatic potential, shorter time to recurrence, and reduced overall survival. Ectopic expression of miR-30b/30d promoted the metastatic behavior of melanoma cells by directly targeting the GalNAc transferase GALNT7, resulted in increased synthesis of the immunosuppressive cytokine IL-10, and reduced immune cell activation and recruitment. These data support a key role of miR-30b/30d and GalNAc transferases in metastasis, by simultaneously promoting cellular invasion and immunosuppression
— id: 135264, year: 2011, vol: 20, page: 104, stat: Journal Article,

Acquisition and presentation of follicular dendritic cell-bound antigen by lymph node-resident dendritic cells
McCloskey, Megan L; Curotto de Lafaille, Maria A; Carroll, Michael C; Erlebacher, Adrian
2011 Jan 17;208(1):135-148, Journal of experimental medicine
Follicular dendritic cells (DCs [FDCs]) are prominent stromal cell constituents of B cell follicles with the remarkable ability to retain complement-fixed antigens on their cell surface for extended periods of time. These retained immune complexes have long been known to provide the antigenic stimulus that drives antibody affinity maturation, but their role in cellular immunity has remained unclear. In this study, we show that FDC-retained antigens are continually sampled by lymph node-resident DCs for presentation to CD8 T cells. This novel pathway of antigen acquisition was detectable when FDCs were loaded with purified antigens bound into classical antigen-antibody immune complexes, as well as after pregnancy, when they are loaded physiologically with antigens associated with the complement-fixed microparticles released from the placenta into maternal blood. In both cases, ensuing antigen presentation was profoundly tolerogenic, as it induced T cell deletion even under inflammatory conditions. These results significantly broaden the scope of FDC function and suggest new ways that the complement system and persistent antigen presentation might influence T cell activation and the maintenance of peripheral immune tolerance
— id: 120649, year: 2011, vol: 208, page: 135, stat: Journal Article,

Dendritic cell function at the maternal-fetal interface
Tagliani, Elisa; Erlebacher, Adrian
2011 Sep;7(5):593-602, Expert Review of Clinical Immunology
Understanding the evolutionary adaptation of the immune system to the developing fetus and placenta represents one of the most fascinating problems in reproductive biology. Recent work has focused on how the behavior of dendritic cells (DCs) is altered at the maternal-fetal interface to suit the unique requirements of pregnancy. This work has provided a significant new perspective into the long-standing immunological paradox of fetomaternal tolerance, and has opened up a new and intriguing area of research into the potential trophic role of uterine DCs in the peri-implantation period. Further research on the biology of uterine DCs promises to give insight into the pathogenesis of many clinically important disorders of pregnancy
— id: 137080, year: 2011, vol: 7, page: 593, stat: Journal Article,

Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1
Tagliani, Elisa; Shi, Chao; Nancy, Patrice; Tay, Chin-Siean; Pamer, Eric G; Erlebacher, Adrian
2011 Aug 29;208(9):1901-1916, Journal of experimental medicine
Tissue macrophages (Ms) and dendritic cells (DCs) play essential roles in tissue homeostasis and immunity. How these cells are maintained at their characteristic densities in different tissues has remained unclear. Aided by a novel flow cytometric technique for assessing relative rates of blood-borne precursor recruitment, we examined M and DC population dynamics in the pregnant mouse uterus, where rapid tissue growth facilitated a dissection of underlying regulatory mechanisms. We demonstrate how M dynamics, and thus M tissue densities, are locally controlled by CSF-1, a pleiotropic growth factor whose in situ level of activity varied widely between uterine tissue layers. CSF-1 acted in part by inducing M proliferation and in part by stimulating the extravasation of Ly6C(hi) monocytes (Mos) that served as M precursors. Mo recruitment was dependent on the production of CCR2 chemokine receptor ligands by uterine Ms in response to CSF-1. Unexpectedly, a parallel CSF-1-regulated, but CCR2-independent pathway influenced uterine DC tissue densities by controlling local pre-DC extravasation rates. Together, these data provide cellular and molecular insight into the regulation of M tissue densities under noninflammatory conditions and reveal a central role for CSF-1 in the coordination of M and DC homeostasis
— id: 137002, year: 2011, vol: 208, page: 1901, stat: Journal Article,

Immune surveillance of the maternal/fetal interface: controversies and implications
Erlebacher, Adrian
2010 Jul;21(7):428-434, Trends in endocrinology & metabolism
How the fetal 'allograft' avoids rejection during pregnancy remains a major unresolved immunological paradox. Recent work has suggested that fetomaternal tolerance is in fact maintained by a number of redundant mechanisms, but their relative importance has remained poorly defined. In this paper, I discuss an emerging controversy regarding the ability of maternal T cells to mediate fetal rejection at a time when they appear to be ignorant of fetal and placental antigens. This paradox within a paradox highlights two major research directions in the field of reproductive immunology that, when ultimately reconciled, promise to give significant insight into mechanisms of impaired fertility and compromised fetal and maternal health
— id: 110681, year: 2010, vol: 21, page: 428, stat: Journal Article,

Dendritic cell entrapment within the pregnant uterus inhibits immune surveillance of the maternal/fetal interface in mice
Collins, Mary K; Tay, Chin-Siean; Erlebacher, Adrian
2009 Jul;119(7):2062-73, Journal of clinical investigation
Embryo implantation induces formation of the decidua, a stromal cell-derived structure that encases the fetus and placenta. Using the mouse as a model organism, we have found that this tissue reaction prevents DCs stationed at the maternal/fetal interface from migrating to the lymphatic vessels of the uterus and thus reaching the draining lymph nodes. Strikingly, decidual DCs remained immobile even after being stimulated with LPS and exhibiting responsiveness to CCL21, the chemokine that drives DC entry into lymphatic vessels. An analysis of maternal T cell reactivity toward a surrogate fetal/placental antigen furthermore revealed that regional T cell responses toward the fetus and placenta were driven by passive antigen transport and thus the tolerogenic mode of antigen presentation that predominates when there is negligible input from tissue-resident DCs. Indeed, the lack of involvement of tissue-resident DCs in the T cell response to the fetal allograft starkly contrasts with their prominent role in organ transplant rejection. Our results suggest that DC entrapment within the decidua minimizes immunogenic T cell exposure to fetal/placental antigens and raise the possibility that impaired development or function of the human decidua, which unlike that of the mouse contains lymphatic vessels, might lead to pathological T cell activation during pregnancy
— id: 100612, year: 2009, vol: 119, page: 2062, stat: Journal Article,

Constraints in antigen presentation severely restrict T cell recognition of the allogeneic fetus
Erlebacher, Adrian; Vencato, Daniela; Price, Kelly A; Zhang, Dorothy; Glimcher, Laurie H
2007 May;117(5):1399-1411, Journal of clinical investigation
How the fetus escapes rejection by the maternal immune system remains one of the major unsolved questions in transplantation immunology. Using a system to visualize both CD4+ and CD8+ T cell responses during pregnancy in mice, we find that maternal T cells become aware of the fetal allograft exclusively through "indirect" antigen presentation, meaning that T cell engagement requires the uptake and processing of fetal/placental antigen by maternal APCs. This reliance on a relatively minor allorecognition pathway removes a major threat to fetal survival, since it avoids engaging the large number of T cells that typically drive acute transplant rejection through their ability to directly interact with foreign MHC molecules. Furthermore, CD8+ T cells that indirectly recognize fetal/placental antigen undergo clonal deletion without priming for cytotoxic effector function and cannot induce antigen-specific fetal demise even when artificially activated. Antigen presentation commenced only at mid-gestation, in association with the endovascular invasion of placental trophoblasts and the hematogenous release of placental debris. Our results suggest that limited pathways of antigen presentation, in conjunction with tandem mechanisms of immune evasion, contribute to the unique immunological status of the fetus. The pronounced degree of T cell ignorance of the fetus also has implications for the pathophysiology of immune-mediated early pregnancy loss.
— id: 72867, year: 2007, vol: 117, page: 1399, stat: Journal Article,

Trophoblast shedding and its immunological consequences
Erlebacher, A; Price, K; Zhang, D; Glimcher, LH
2006 APR 1 ;176(4):S230-S230, Journal of immunology
— id: 68845, year: 2006, vol: 176, page: S230, stat: Journal Article,

Cytotrophoblast induction of arterial apoptosis and lymphangiogenesis in an in vivo model of human placentation
Red-Horse, Kristy; Rivera, Jose; Schanz, Andrea; Zhou, Yan; Winn, Virginia; Kapidzic, Mirhan; Maltepe, Emin; Okazaki, Kelly; Kochman, Ronit; Vo, Kim Chi; Giudice, Linda; Erlebacher, Adrian; McCune, Joseph M; Stoddart, Cheryl A; Fisher, Susan J
2006 Oct;116(10):2643-2652, Journal of clinical investigation
We studied the vascular effects of invasive human cytotrophoblasts in vivo by transplanting placental villi to the fifth mammary fat pads or beneath the kidney capsules of Scid mice. Over 3 weeks, robust cytotrophoblast invasion was observed in both locations. The architecture of the mammary fat pad allowed for detailed analysis of the cells' interactions with resident murine blood vessels, which revealed specific induction of apoptosis in the endothelial cells and smooth muscle walls of the arterioles. This finding, and confirmation of the results in an in vitro coculture model, suggests that a parallel process is important for enabling cytotrophoblast endovascular invasion during human pregnancy. Cytotrophoblast invasion of the kidney parenchyma was accompanied by a robust lymphangiogenic response, while in vitro, the cells stimulated lymphatic endothelial cell migration via the actions of VEGF family members, FGF, and TNF-alpha. Immunolocalization analyses revealed that human pregnancy is associated with lymphangiogenesis in the decidua since lymphatic vessels were not a prominent feature of the nonpregnant endometrium. Thus, the placenta triggers the development of a decidual lymphatic circulation, which we theorize plays an important role in maintaining fluid balance during pregnancy, with possible implications for maternal-fetal immune cell trafficking
— id: 81164, year: 2006, vol: 116, page: 2643, stat: Journal Article,

Differential transcription of Eomes and T-bet during maturation of mouse uterine natural killer cells
Tayade, Chandrakant; Fang, Yuan; Black, Gordon P; V A, Paffaro Jr; Erlebacher, Adrian; Croy, B Anne
2005 Dec;78(6):1347-1355, Journal of leukocyte biology
During human and rodent uterine decidualization, transient but abundant numbers of uterine natural killer (uNK) cells appear, proliferate, and differentiate. uNK cells share features with peripheral NK cells but are specialized to promote interferon-gamma (IFN-gamma)-mediated, pregnancy-associated, structural changes in maternal placental arteries. In CD8+ T cells and NK cells, the transcription factors T-bet and eomesodermin (Eomes) regulate maturation and effector functions, including IFN-gamma production. No studies are reported for uNK cells. Implantation sites in T-bet null mice, which have a defect in NK cell maturation, had uNK cells normal in morphology and number and normally modified spiral arteries. As Eomes null mice are not viable, real-time polymerase chain reaction comparisons between C57Bl/6J (B6) and alymphoid (Rag2(0/0)gammac(0/0)) mice were used to assess uNK cell expression of T-bet, Eomes, and the target genes IFN-gamma, granzyme A, and perforin. Gestation dated (gd) uterine tissues (mixed cell composition) and 200 morphologically homogeneous, laser-capture, microdissected uNK cells of different maturation stages were used. In uterus, Eomes transcripts greatly outnumbered those of T-bet, whether donors were nonpregnant or pregnant, and increased to gd10. In uNK cells, transcripts for T-bet, Eomes, and IFN-gamma were most abundant in mature stage cells, and transcripts for granzyme A and perforin were lower at this stage than in immature or senescent cells. Thus, Eomes dominance to T-bet discriminates regulation of the uNK cell subset from that observed for peripheral NK cells
— id: 59378, year: 2005, vol: 78, page: 1347, stat: Journal Article,

Maintenance of mouse trophoblast stem cell proliferation by TGF-beta/activin
Erlebacher, Adrian; Price, Kelly A; Glimcher, Laurie H
2004 Nov 1;275(1):158-169, Developmental biology (Orlando)
Mouse trophoblast stem (TS) cells can be grown indefinitely in vitro with FGF4 and embryonic fibroblast conditioned media (EFCM). Here, we report that the active protein components of EFCM include TGF-beta and the related factor activin, and that long-term continuous TS cell proliferation is possible in media supplemented with only serum, FGF4, and TGF-beta. As trophoblasts are an epithelial cell type, the promotion of TS cell proliferation represents an unusual function for TGF-beta and activin since TGF-beta in particular is well known as an inhibitor of nontransformed epithelial cell proliferation. Our data suggest that constitutive FGF signaling in TS cells selectively inhibits the ability of TGF-beta to repress c-myc expression, a central component of the TGF-beta cytostatic transcriptional response previously observed to be lost in other epithelial cell types upon oncogenic Ras transformation
— id: 59380, year: 2004, vol: 275, page: 158, stat: Journal Article,

Ovarian insufficiency and early pregnancy loss induced by activation of the innate immune system
Erlebacher, Adrian; Zhang, Dorothy; Parlow, Albert F; Glimcher, Laurie H
2004 Jul;114(1):39-48, Journal of clinical investigation
We describe a murine model of early pregnancy failure induced by systemic activation of the CD40 immune costimulatory pathway. Although fetal loss involved an NK cell intermediate, it was not due to lymphocyte-mediated destruction of the fetus and placenta. Rather, pregnancy failure resulted from impaired progesterone synthesis by the corpus luteum of the ovary, an endocrine defect in turn associated with ovarian resistance to the gonadotropic effects of prolactin. Pregnancy failure also required the proinflammatory cytokine TNF-alpha and correlated with the luteal induction of the prolactin receptor signaling inhibitors suppressor of cytokine signaling 1 (Socs1) and Socs3. Such links between immune activation and reproductive endocrine dysfunction may be relevant to pregnancy loss and other clinical disorders of reproduction
— id: 59381, year: 2004, vol: 114, page: 39, stat: Journal Article,

National Institute on Drug Abuse Conference report on placental proteins, drug transport, and fetal development
Thadani, Pushpa V; Strauss, Jerome F 3rd; Dey, Sudhansu K; Anderson, Virginia M; Audus, Kenneth L; Coats, Karen S; Cross, James C; Erlebacher, Adrian; Ganapathy, Vadivel; Linzer, Daniel I; Miller, Richard K; Novak, Donald A; Rapaka, Rao S; Sadovsky, Yoel; Salafia, Carolyn M; Soares, Michael; Unadkat, Jashvant
2004 Dec;191(6):1858-1862, American journal of obstetrics & gynecology
The use of illicit and licit drugs during pregnancy is a major public health concern because of potential adverse effects on the fetus and the risk to maternal health. Because the placenta is the primary link between the mother and the conceptus and is essential for the growth and survival of the fetus, abnormalities in placental formation and function resulting from drug use could have a major influence on pregnancy outcome. At present, little information is available on the impact of abused drugs on placental biology alone or in combination with other 'host' factors (eg, stress, infections). This prompted the National Institute on Drug Abuse (NIDA) to convene a meeting of experts in placental biology to review cutting-edge research with the mission to translate existing information to new clinical and research initiatives in the drug abuse field. This report summarizes the presentations and research recommendations resulting from the workshop discussions
— id: 59379, year: 2004, vol: 191, page: 1858, stat: Journal Article,

Intrinsic susceptibility of mouse trophoblasts to natural killer cell-mediated attack in vivo
Erlebacher, Adrian; Lukens, Amanda K; Glimcher, Laurie H
2002 Dec 24;99(26):16940-16945, Proceedings of the National Academy of Sciences of the United States of America
Protecting the fetus and placenta from the maternal immune system has long been considered a function of placental trophoblasts. Here, we present two related lines of evidence that contradict this assumption. First, we show that transformed mouse trophoblast cell lines akin to human choriocarcinomas form tumors in syngeneic and immunodeficient mice, yet are rejected in immunocompetent allogeneic mice. Second, we show that wild-type trophoblasts are rapidly killed after i.v. injection into allogeneic mice. In both cases, the pattern of trophoblast killing in different strains of immunodeficient mice indicated that rejection involved host natural killer cells, and this was corroborated by in vitro killing assays. The apparent intrinsic susceptibility of mouse trophoblasts to immune attack strongly suggests that it is instead some property of the pregnant uterus that is of primary importance in preventing rejection of the fetus
— id: 59382, year: 2002, vol: 99, page: 16940, stat: Journal Article,

Why isn't the fetus rejected?
Erlebacher A
2001 Oct;13(5):590-593, Current opinion in immunology
The long-standing question of how the fetal allograft avoids immune rejection during pregnancy has lately been generating renewed interest. Recent insights have emerged from studies in mice on uterine NK cells, NKT cells, complement inhibition and the reproductive effects of 1-methyl-tryptophan
— id: 61589, year: 2001, vol: 13, page: 590, stat: Journal Article,

Inhibition of TGF-beta receptor signaling in osteoblasts leads to decreased bone remodeling and increased trabecular bone mass
Filvaroff E; Erlebacher A; Ye J; Gitelman SE; Lotz J; Heillman M; Derynck R
1999 Oct;126(19):4267-4279, Development
Transforming growth factor-beta (TGF-beta) is abundant in bone matrix and has been shown to regulate the activity of osteoblasts and osteoclasts in vitro. To explore the role of endogenous TGF-(beta) in osteoblast function in vivo, we have inhibited osteoblastic responsiveness to TGF-beta in transgenic mice by expressing a cytoplasmically truncated type II TGF-beta receptor from the osteocalcin promoter. These transgenic mice develop an age-dependent increase in trabecular bone mass, which progresses up to the age of 6 months, due to an imbalance between bone formation and resorption during bone remodeling. Since the rate of osteoblastic bone formation was not altered, their increased trabecular bone mass is likely due to decreased bone resorption by osteoclasts. Accordingly, direct evidence of reduced osteoclast activity was found in transgenic mouse skulls, which had less cavitation and fewer mature osteoclasts relative to skulls of wild-type mice. These bone remodeling defects resulted in altered biomechanical properties. The femurs of transgenic mice were tougher, and their vertebral bodies were stiffer and stronger than those of wild-type mice. Lastly, osteocyte density was decreased in transgenic mice, suggesting that TGF-beta signaling in osteoblasts is required for normal osteoblast differentiation in vivo. Our results demonstrate that endogenous TGF-beta acts directly on osteoblasts to regulate bone remodeling, structure and biomechanical properties
— id: 61590, year: 1999, vol: 126, page: 4267, stat: Journal Article,

Osteoblastic responses to TGF-beta during bone remodeling
Erlebacher A; Filvaroff EH; Ye JQ; Derynck R
1998 Jul;9(7):1903-1918, Molecular biology of the cell
Bone remodeling depends on the spatial and temporal coupling of bone formation by osteoblasts and bone resorption by osteoclasts; however, the molecular basis of these inductive interactions is unknown. We have previously shown that osteoblastic overexpression of TGF-beta2 in transgenic mice deregulates bone remodeling and leads to an age-dependent loss of bone mass that resembles high-turnover osteoporosis in humans. This phenotype implicates TGF-beta2 as a physiological regulator of bone remodeling and raises the question of how this single secreted factor regulates the functions of osteoblasts and osteoclasts and coordinates their opposing activities in vivo. To gain insight into the physiological role of TGF-beta in bone remodeling, we have now characterized the responses of osteoblasts to TGF-beta in these transgenic mice. We took advantage of the ability of alendronate to specifically inhibit bone resorption, the lack of osteoclast activity in c-fos-/- mice, and a new transgenic mouse line that expresses a dominant-negative form of the type II TGF-beta receptor in osteoblasts. Our results show that TGF-beta directly increases the steady-state rate of osteoblastic differentiation from osteoprogenitor cell to terminally differentiated osteocyte and thereby increases the final density of osteocytes embedded within bone matrix. Mice overexpressing TGF-beta2 also have increased rates of bone matrix formation; however, this activity does not result from a direct effect of TGF-beta on osteoblasts, but is more likely a homeostatic response to the increase in bone resorption caused by TGF-beta. Lastly, we find that osteoclastic activity contributes to the TGF-beta-induced increase in osteoblast differentiation at sites of bone resorption. These results suggest that TGF-beta is a physiological regulator of osteoblast differentiation and acts as a central component of the coupling of bone formation to resorption during bone remodeling
— id: 61591, year: 1998, vol: 9, page: 1903, stat: Journal Article,

Increased expression of TGF-beta 2 in osteoblasts results in an osteoporosis-like phenotype
Erlebacher A; Derynck R
1996 Jan;132(1-2):195-210, Journal of cell biology
The development of the skeleton requires the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts. The activities of these two cell types are likely to be regulated by TGF-beta, which is abundant in bone matrix. We have used transgenic mice to evaluate the role of TGF-beta 2 in bone development and turnover. Osteoblast-specific overexpression of TGF-beta 2 from the osteocalcin promoter resulted in progressive bone loss associated with increases in osteoblastic matrix deposition and osteoclastic bone resorption. This phenotype closely resembles the bone abnormalities seen in human hyperparathyroidism and osteoporosis. Furthermore, a high level of TGF-beta 2 overexpression resulted in defective bone mineralization and severe hypoplasia of the clavicles, a hallmark of the developmental disease cleidocranial dysplasia. Our results suggest that TGF-beta 2 functions as a local positive regulator of bone remodeling and that alterations in TGF-beta 2 synthesis by bone cells, or in their responsiveness to TGF-beta 2, may contribute to the pathogenesis of metabolic bone disease
— id: 61592, year: 1996, vol: 132, page: 195, stat: Journal Article,

Toward a molecular understanding of skeletal development
Erlebacher A; Filvaroff EH; Gitelman SE; Derynck R
1995 Feb 10;80(3):371-378, Cell
— id: 61593, year: 1995, vol: 80, page: 371, stat: Journal Article,

Despite expression in embryonic visceral mesoderm, H2.0 is not essential for Drosophila visceral muscle morphogenesis
Barad M; Erlebacher A; McGinnis W
1991 ;12(3):206-211, Developmental genetics
H2.0, a homeobox gene identified by homology to the Sex combs reduced homeobox of Drosophila, is expressed in all the cellular precursors of the visceral musculature. By analogy to the essential function of most other known homeobox genes in determining the fate of cells where they are expressed, we hypothesized that mutation of H2.0 would disrupt gut muscle development. In this paper, we show that a small deletion, which eliminates H2.0, has no detectable effect on normal gut morphogenesis, visceral muscle actin organization, or larval peristalsis
— id: 61594, year: 1991, vol: 12, page: 206, stat: Journal Article,