PROBLEM: At least two dendritic cell‐associated molecules have been shown to contribute to the successful outcome of organ and tissue allografts in mice, namely CD200 and MD‐1. CD200 is up‐regulated in rodent transplantation models where successful inhibition of rejection is accomplished, and is believed to signal immunosuppression following engagement of a receptor, CD200R, on macrophages and/or γδ T‐cell receptor (γδ TCR+ cells MD‐1 is implicated in controlling expression of costimulatory molecules including CD80/CD86 which induce an immunorejection response, and thus inhibition of MD‐1 expression also facilitates increased graft survival MD‐1 also stabilizes expression of CD14, part of the receptor complex for LPS. As well as the inhibition of rejection which follows blockade of MD‐1 expression and/or augmentation of CD200 expression, an altered polarization in cytokine production is seen, with increased expression of interleukin‐4 (IL‐4), IL‐10 and transforming growth factor‐β (TGF‐β), and decreased IL‐2, interferon‐γ (IFN‐γ) and tumor nerosis factor‐α (TNF‐α). Successful pregnancy in allopregnant mice also depends upon control of graft rejection mechanisms. Proinflammatory T‐helper 1 (Th1) cytokines (TNF‐α + IFN‐γ + IL‐1) have been shown to cause spontaneous abortion in mice by activating a novel prothrombinase, fibrinogen‐like peptide (fibroleukin) fgl2, which may promote fibrin deposition in the graft rejection process; expression of IL‐10, TGF‐β, and progesterone‐induced blocking factor (PIBF) in contrast leads to lowering of abortion rates. Interestingly, the spontaneous abortion rates in abortion‐prone CBA × DBA/2 matings and in the low abortion rate CBA × BALB/c matings were lower than the frequency of implantation sites showing fibrinhi + fgl2 (mRNA)hi, implying regulation of the pro‐abortion consequences of fgl2 expression.
METHODS: We have investigated, by
in situhybridization, CD200, MD‐1 and fgl2 expression in implantation sites in different strains of mice, and studied the effects of anti‐MD‐1, anti‐CD200 and CD200Fc immunoadhesin on fetal and allograft survival. The role of indoleamine dioxygenase (IDO) was evaluated.
RESULTS: CD200 mRNA expression occurred in the same sites as fgl2 mRNA. Anti‐CD200 antibody raised the abortion rate to predicted levels, and infusion of a CD200 immunoadhesin reduced the abortion rate, as did an anti‐MD‐1 antibody. The latter also improved organ and tissue graft survival. Suppression by antigen‐presenting macrophages triggered by CD200 is dependent upon intact IDO activity.
CONCLUSION: Regulation of CD200 and MD‐1 expression may control both pregnancy and allograft survival.