234 Placenta (1993, Vol. 18

The Thomas G. Wegmann Memorial Symposium on Reproductive

Immunology. Banff, Alberta, Canada, 12 September 1996

G. Vince

Department of Immunology, University of Liverpool, Duncan Building, Liverpool L69 36X, UK

The final day of the Thomas Wegmann Memorial Symposium on Reproductive Immunology began with a Symposium en- titled ‘Utero-placental encounters of the immune kind’ and a presentation by Dan Geraghty (Seattle) on the non-classical class I molecules HLA-G and HLA-E. HLA-E appears to particularly present peptide derived from other HLA mol- ecules including HLA-G. Examination of HLA-G-peptide interactions has shown that both the membrane bound and soluble form of HLA-G bind essentially the same set of peptides; these are derived from a variety of intracellular proteins and define a peptide consensus motif for HLA-G. Binding is to a limited array of peptides (around fivefold less than for classical class I HLA molecules); invasive cyto- trophoblast cells may therefore be able to present viral pep- tides, and binding of peptides for CMV to HLA-G has been demonstrated. Tom Gill (Pittsburgh) then discussed MHC- linked genes and the genetics of recurrent spontaneous abor- tion (RSA), with reference to the growth and reproduction complex (grc) of the rat. In humans, a ‘shared-allele’ test has demonstrated a significant excess of HLA-DR sharing in couples with RSA and a significant excess of HLA-DQsharing in couples with unexplained infertility who failed IVF treat- ment, suggesting that genes located in different parts of the class II MHC region affect different aspects of reproduction. In rats, deletions in the grc region are associated with fetal mortality, developmental defects and decreased resistance to cancer.

As part of a long-standing study of reproduction in the Hutterite communities of South Dakota, Carole Ober (Chicago) described recent work showing that Hutterite women have a fetal loss rate of no more than 15 per cent, favourably comparable with that of the general population and no Hutterite woman has yet been identified who meets the definition of RSA ( 2 3 consecutive spontaneous abortions). Examination of MHC haplotype inheritance in offspring of parents with HLA sharing showed bias against inheritance of the shared paternal haplotype with the unshared maternal haplotype. In such a situation, the fetus is then identical to the mother, putting forward the novel concept that fetal recog- nition of the mother is required. A consequence would be to predict a higher level of HLA homozygosity in RSA women as offspring will not recognize the mother as foreign (although the mother would recognize the offspring as foreign). This hypothesis is supported by data from Dr Oberon the Hutterite population showing an increased incidence of HLA-B homozygosity in women with increased fetal loss.

James Mowbray (London) reported on the presence of maternal IgG antibody [bound to a polymorphic 80-kD protein (R80K)] which could be eluted from syncytiotrophoblast at very low pH. It is believed that the binding of the maternal antibody to this antigen protects the trophoblast from maternal NK attack, and it was found to be absent from the serum of most women with RSA. Peter Johnson (Liverpool) then outlined recent work on the functional analysis of CD3 - large granular lymphocyte (LGL) clones derived from human first trimester decidua. Some CD3 - LGL clones express the killer inhibitory receptor (KIR) molecules CD94 and ~58 (the latter recognized by the mAb Hp3E4). Although LGL clones do exhibit NK cell cytoxicity against HLA-null target cells, this cytoxicity is reduced if cells are transfected with HLA-G. CD3 - LGL clones are also mostly positive for cytoplasmic CD35, and CD38 and produce a ThO-like pattern of cytokines, leading to suggestions that a main role for LGL in normal pregnancy is production of cytokines.

The final workshop of the meeting followed on ‘Critical problems in reproductive immunology’ with discussions on several pertinent issues, ranging from the role of NK cells, T cells and macrophages in pregnancy through the relevance of ‘the fetus as an allograft’ today to cytokines. Much interest- ing debate centred on the relevance of animal models to the human situation (or even the use of the human as a model for the horse!). General consensus was that whilst there are both differences and similarities, models can only be useful if used intelligently.

The afternoon session ‘Rationales and legacies of reproduc- tive immunology’ was given by close colleagues and former students of Tom Wegmann beginning with Pran Talwar (New Delhi) on the mechanisms of termination of pregnancy using Azadirachta Indica Neem extracts which have been shown to cause abortion in both rats and baboons. In the rat, this is accompanied by an increase in TNF-a and IFN-y, both in the placenta and systemically. There is an increase in CD@ cells in draining lymph nodes 96 h after treatment and an increase in CD4+ and CD8+ cells in the spleen, all suggestive of an immunomodulatory effect of Neem oil. Raj Rajhupathy (Kuwait), as well as providing anecdotes about Tom Wegmann, discussed the effects of irradiated placental cells from either CBA versus DBA (C/D, abortion prone) or CBA versus BALB (C/B, control) mice on CBA responder cells. C/B cells increased proliferation compared with C/D cells and this was accompanied by an increase in IL-3 and IL-5. In contrast, C/D cells increased TNF-a and IFN-y. Antibodies

Conference Reports

to CDS showed the predominant proliferating cell to be CDS+. Larry Guilbert (Edmonton and standing in for an indisposed Lakshmi Krishnan) continued the Wegmann theme by high- lighting the relationship between pregnancy and the immune response to infectious diseases. Pregnancy impairs the resol- ution of Leishmania ma~br infection with a corresponding decrease in IFN-y and an increase in Th2 cytokines. L. major infection was also deleterious to a concurrent pregnancy with an increase in resorptions accompanied by a decrease in production of Th2 cytokines IL-4 and 11-10 and an increase in TNF-o and IFN-y, suggesting a beneficial anti-parasitic Thl response can adversely affect pregnancy outcome.

Gerard Chaouat (Clamart), in his own inimitable style, examined Thl versus Th2 cytokine production in murine and human pregnancy. In the mouse, levels of IL-10 are decreased- in the placenta and decidua of the abortion-prone CBA versus DBA mating combination; fetal wastage is prevented by

235

addition of recombinant IL-10 and increased by in vivo injection of anti-IL-lo, confirming the importance of Th2 cytokines in successful murine pregnancy. Preliminary evi- dence points towards a reduction of IL-4 and an increase in TNF in women with RSA.

In the final presentation, Jane Yui (Vancouver) gave an account of the apoptotic effects of TNF-a (mediated by the p55 TNF receptor) on primary villous cytotrophoblast in culture. Apoptotic machinery in trophoblast appears to be constitutive but is normally suppressed by inhibitory factors, notably EGF. TNF may have a role in normal development via tissue homeostasis and trophoblast turnover but aberrant expression of TNF may lead to a premature depletion of cytotrophoblast and, consequently, syncytiotrophoblast dam- -age that cannot be repaired; this could lead both to adherence of activated leucocytes and to viral transmission across the hamaged cell surface.