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  • 1. Copyright Ó Blackwell Munksgaard, 2004 AJRI 2004; 52: 233–236 American Journal of Reproductive Immunology Face-Offs in Reproductive Immunology: The Montreal Forum Meeting Report Croy BA, Baines MG. Face-offs in reproductive immunology: the B. Anne Croy1, Malcolm G. Baines2 Montreal forum meeting report. AJRI 2004; 52:233–236 Ó Blackwell 1 Department of Anatomy and Cell Biology, Queen's Munksgaard, 2004 University, Kingston, Ontario, Canada K7L 3N6; 2 Department of Microbiology and Immunology, McGill The combined 12th International Congress of Immunology (ICI) and University, Montreal, Quebec, Canada H3A 2T5 the 4th Annual Conference of the Federation of Clinical Immunological Societies (FOCIS) was held in Montreal, Canada July 18–23, 2004 and attracted over 6000 immunologists and almost 4000 abstracts. The host society, the Canadian Society for Immunology (CSI) spent many years in preparation for this large meeting and Key words: uterus, pregnancy, chemokine, cytokine, encouraged its members to propose topics for symposia and mini- immune, regulation, trophoblast symposia and to sponsor satellite meetings. With sponsorship of CSI; Address reprint requests to B. Anne Croy, Department of the Canadian Institutes of Health Research; the University of Guelph, Anatomy and Cell Biology, Queen's University, Kingston, Guelph, ON; Queen’s University, Kingston, ON; McGill University, Ontario, Canada K7L 3N6. Montreal, QU, Canada; and the American Society for Reproductive E-mail: croya@post.queensu.ca Immunology, a focused, highly successful, one day satellite meeting on human uterine immunology was held. The highlights of the Submitted August 26, 2004; presentations and discussions are reported. accepted September 8, 2004. INTRODUCTION whistle, introduced the ÔteamsÕ playing in the first period as the ÔMontreal ChemokinesÕ represented by The organization of the meeting was developed along Dr Ofer Mandelboim, (Lautenberg Center for General the theme of an ice hockey game. Dr Baines (McGill and Tumor Immunology, Hebrew University-Had- University, Montreal, QU, Canada), wearing a Mon- assah Medical School, Jerusalem) versus the ÔToronto treal Canadien’s Team shirt, opened the meeting with CytokinesÕ, represented by Dr Kotaro Kitaya (Depart- comments explaining the theme and its importance in ment of Obstetrics and Gynecology, Kyoto Prefectural Canada and in Montreal. The name of the meeting Ôthe University of Medicine, Kyoto, Japan). Dr Mand- forumÕ was chosen because of the importance of the elboim discussed the question of regulation of natural Montreal Forum as a scene of professional hockey killer (NK) cell recruitment to pregnant uterus.1 He Championships and home of Ôles CanadiensÕ. The proposed that CD56bright, CD16) NK cells expressing senate chambers of McGill University, where the the receptors CXCR3 and CXCR4 are preferentially meeting was held, were adjacent to the art’s buildings attracted by invasive trophoblasts that express SDF-1/ depicted in a photo of outdoor college hockey from CXCL12. He emphasized that the uterus is not the 1884 (Fig. 1) shown by Dr Baines to the 64 assembled only site of human CD56bright NK cell enrichment but participants. The meeting was a fine mixture of trainees reminded participants that similar cells are found in and experienced investigators and it provided an other sites such as tonsil and that more general ambiance that permitted extensive discussion between principals could be involved in trafficking of these all participants, in addition to the seven major cells. Mandelboim pointed out that ÔfineÕ tuning of cells symposium addresses. could be important and that the morphological approaches widely used in the field would not be sensitive enough to detect these events. He proposed THE GAME that the cell adhesion molecule CEACAM1 is binding to an unknown, novel decidual ligand that evokes First Period inhibition of cytotoxic function in human uterine Dr Croy (Queen’s University, Kingston, ON, Canada), natural killer (uNK) cells. He also discussed his studies decked out with a striped referee’s shirt and silver that are the first to suggest that uNK cells may act in AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY VOL. 52, 2004
  • 2. 234 / CROY AND BAINES Second Period The second period was devoted to discussions of the other key innate immune components involved in successful implantation, uterine dendritic cells and macrophages. Dr Yvette van Kooyk (Vrije Universiteit Medical Center, Amsterdam, The Netherlands) des- cribed her recent studies on cell movement and tolerance induction using human monocyte derived dendritic cells (DC), highlighting the importance of carbohydrates and c-type lectin receptors. It is known that DC homing involves the c-type lectin DC-SIGN. Dr van Kooyk shared her experiments indicating the importance of stage of maturity of DC on antigen uptake and signalling of activation or tolerance, echoing Mandelboim’s comments on Ôfine tuningÕ of Hockey at McGill 1884. (Library and Archives Canada) a cell determining its functional activity and emphasi- zing that DC are part of homeostatic mechanisms. Fig. 1. The centre building, which still stands and flies its flag, was the landmark delegates used to locate the McGill University Senate Decidual DC take up antigen but either have a low Chambers, for the Montreal Forum: Face-Offs in Reproductive capacity to stimulate T cells or may regulate the T cell Immunology. The meeting carried on the time honoured hockey activation process. van Kooyk showed that some tradition of Canada. decidual and endometrial DCs express CD14 and CD68 but not DC-SIGN. However, DCs expressing all an antigen presentation capacity for T cells and three markers were clearly associated with decidual described the NKp46-GFP-transgenic mouse model CD56+, ICAM3+ NK cells.3 She also suggested that he has developed to use in testing his hypotheses. studies on functions of DC-SIGN+ DC should shed Dr Kitaya reported his studies of the cycling light on functions of DC-SIGN expressing human human uterus.2 He detailed the cycle dependent trophoblast in both adhesion and antigen presentation. positions for the expression of NK cell growth and Ramsey McIntire, a senior research trainee with activation molecules that may account for the three to Dr Joan Hunt (University of Kansas Medical Center, fourfold increase in CD56bright, CD16) uNK cells Kansas City, KS, USA) then discussed her current during the secretory phase of the menstrual cycle. work on the effects of soluble, trophoblast-derived UNK cell growth and activation are promoted in human leukocyte antigen (HLA)-G in regulation of culture by interleukin (IL)-15 but not estradiol or macrophage function.4 Macrophages differ from the progesterone. However, progestrone increases expres- cell types discussed by the earlier speakers because they sion of IL-15 and possibly other NK cell-activating are a stable uterine population, not numerically altered cytokines. Dr Kitaya also provided data on cycle- during the menstrual cycle. The Hunt laboratory has modulated endometrial expression of cell homing developed human recombinant soluble HLA-G5 and molecules, such as L-selectin ligands, that supported -G6 suitable for in vitro studies. Exposure of mono- the hypothesis that CD56bright, CD16) NK cells home cytes or macrophage cell lines to each protein induced to secretory phase endometrial tissue domains expres- cytokine production and gene expression that was sing these ligands. Further, he showed secretory phase shared as well as non-overlapping and consistent with associated endometrial expression of the CXCR3 an immunosuppressed phenotype. Treatment induced ligand Mig and post-implantation expression of the no loss of viability and increased transforming growth CXCR4 ligand SDR-1a/b, in addition to other che- factor (TGF)-b1 but not IL-10. These data supported mokine ligands. It was clear that cell recruitment to the hypothesis that trophoblast cells expressing HLA- the uterus changes over the cycle and microdomains G regulate maternal macrophages and lymphocytes to are created within the endometrium where specific cell induce an environment compatible with gestational adhesion molecules and chemokines are enriched. success. Kitaya correlated gains in specific signals with eleva- As a result of the informal morning discussions, ted progesterone levels but asked the participants to Dr Charu Kaushic (McMaster University, Hamilton, maintain an awareness for contributions of non- ON, Canada) was asked to present her clinical findings immune mechanisms, such as blood shear forces, in from an immunohistochemical study of DC and lymphocyte distribution within both the cycling and macrophages in over 30 human cervical samples. pregnant uterus. She emphasized the contradictory physiological Ó BLACKWELL MUNKSGAARD, 2004
  • 3. MONTREAL FORUM MEETING / 235 requirements of the immune system with activation for patients, Karumanchi proposed that VEGF’s role is pathogen monitoring at the external surface of the to promote fenestration in the glomerulus of the reproductive tract and suppression to promote fetal kidney, visible at the ultrastructural level and that a survival. Following the general discussion of the roles reduction in this process may underlie pre-eclamptic of macrophages and dendritic cells in successful symptoms. He drew attention to the experiences of pregnancy and embryo loss, the referee signalled the renal cancer patients treated with antibodies to VEGF end of the second period and the sides retired for who, after several months of treatment, present with lunch. headaches, hypertension and proteinuria, symptoms that resemble pre-eclamptic like complaints. Third Period The final major address was by Dr Linda Giudice, the The third period face-off featured three talks from Chief of the Division of Reproductive Endocrinology authors who have published microarray studies invol- and Infertility at Stanford University, Stanford, CA, ving women. Dr Jack Strominger (Harvard University, USA. Dr Giudice described the gene profiling work Cambridge, MA, USA) and his associate Dr Hernan from her research team that has focused on endomet- Kopchow based their presentations on information riosis.8 She reminded participants that in patients, not from gene expression arrays comparing CD56+ cells only the ectopic, but also the eutopic endometrium is from blood and first trimester decidua.5 Consistent abnormal. Many of the molecules identified as differ- with the earlier presentations, their work strongly entially expressed in her studies have immunological suggests that uterine NK cells are a distinct subset. functions such as matrix metalloproteinases, cathespin One of the well-known major differences between D, VEGF, progesterone receptor, glycodelin and IL-15. uterine and blood CD56bright cells is the stronger Haptoglobulin, which is significantly up regulated in cytolytic activity of the blood subset. This research patients, stimulates IL-6 production while suppressing team applied confocal microscopy to address move- phagocytosis of macrophages. Neuromodulators and ment of the microtubule organizing centre and their receptors were altered, an area receiving little perforin-containing granules to the synapse in both current study. Enzymes modifying sugars were also cell types conjugated with target cells. They observed shifted significantly and would be important for modi- that uNK cells conjugated but failed to polarize their fication of homing molecules that had been discussed microtubule organizing centre and lytic machinery earlier in the day. efficiently. Dr Ananth Karumanchi (Beth Israel Deaconess Medical Center, Boston, MA, USA) described his OVERTIME AND CONCLUSIONS studies related to pre-eclampsia and his hypothesis that a placental factor destroys endothelium leading to The presentations of the third period were discussed and placental ischaemia, and maternal endothelial dysfunc- the whistle, indicating a brief refreshment break. Then, tion. From microarray analyses of 19 pre-eclamptic all the speakers assembled in front of the audience for an patients and 15 normotensive pregnant women, the animated free-for all Ôshoot outÕ discussion. After endogenous inhibitor of vascular endothelial cell 90 min, the silver whistle was blown for the final time growth factor (VEGF) signalling, soluble fms-like and over 50 people convened nearby for dinner and tyrosine kinase (sFlt-1), was identified as highly up- further discussion of how to proceed forward in studies regulated. To extend understanding of the possible role of women’s reproductive health. The key messages from of sFlt-1 in pre-eclampsia, Adenovirus vectors expres- the meeting were to focus on the biochemistry and sing sFlt-1 or control Fc constructs were administered functions of lectin receptors, carbohydrate ligands and to pregnant rats. This caused increased blood pressure, the meaning of their modifications; to understand the glomerular swelling, endothelial damage, vascular precise nature and the regulation of fine tuning (i.e. one occlusion and proteinuria, all signs of pre-eclampsia.6 cell at different levels of function) which must involve Administration of soluble sFlt-1 induced even greater soluble mediators and to integrate hypotheses with areas hypertension and proteinuria strongly suggesting a outside of immunology, such as the physical hydrody- critical role for this factor in the aetiology of pre- namics of blood flow and endocrine influences on cell eclampsia. Because sFlt-1 binds to and neutralizes the function. It was a well-played ÔgameÕ. functions of both VEGF and placenta growth factor (PlGF), measurements of sFlt-1, VEGF1 or PlGF are potential diagnostic indicators for this disease. Indeed, REFERENCES free VEGF and free PlGF has been recently reported to be lower in the plasma of women with pre- 1. Hanna J, Wald O, Goldman-Wohl D, Prus D, Markel G, eclampsia.7 Drawing from his work with renal Gazit R, Katz G, Haimov-Kochman R, Fujii N, Yagel S, AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY VOL. 52, 2004
  • 4. 236 / CROY AND BAINES Peled A, Mandelboim O: CXCL12 expression by invasive killer cells are a unique NK cell subset with immuno- trophoblasts induces the specific migration of CD16- modulatory potential. J Exp Med 2003; 198:1201–1212. human natural killer cells. Blood 2003; 102:1569–1577. 6. Maynard SE, Min J-Y, Merchan J, Lim K-H, Li J, 2. Kitaya K, Nakayama T, Daikoku N, Fushiki S, Honjo H: Mondal S, Libermann TA, Morgan JP, Sellke FW, Still- Spatial and temporal expression of ligands for CXCR3 man IE, Epstein FH, Sukhatme VP, Karumanchi SA: and CXCR4 in human endometrium. J Clin Endocrinol Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) Metab 2004; 89:2470–2476. may contribute to endothelial dysfunction, hypertension, 3. Kammerer U, Eggert AO, Kapp M, McLellan AD, and proteinuria in preeclampsia. J Clin Invest 2003; Geijtenbeek TBH, Dietl H, van Kooyk Y, Kampgen E: 111:649–658. Unique appearance of proliferating antigen-presenting 7. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, cells expressing DC-SIGN (CD209) in the decidua of early Yu KF, Schisterman EF, Thadhani R, Sachs BP, Epstein human pregnancy. Am J Pathol 2003; 162:887–896. FH, Sibai BM, Sukhatme VP, Karumanchi SA: Circula- 4. Morales PJ, Pace JL, Platt JS, Phillips TA, Morgan K, ting angiogenic factors and the risk of preeclampsia. N Fazleabas AT, Hunt JS: Placental cell expression of Engl J Med 2004; 350:672–683. HLA-G2 isoforms is limited to the invasive trophoblast 8. Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor phenotype. J Immunol 2003; 171:6215–6224. RN, Osteen K, Lessey BD, Giudice LC: Expression pro- 5. Koopman LA, Kopcow HD, Rybalov B, Boyson JE, filing of endometrium from women with endometriosis Orange JS, Schatz F, Masch R, Lockwood CJ, Schachter reveals candidate genes for disease-based implantation AD, Park PJ, Strominger JL: Human decidual natural failure and infertility. Endocrinology 2003; 144:2870–2881. Ó BLACKWELL MUNKSGAARD, 2004