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Keywords:

  • Abortion;
  • CD200;
  • graft rejection;
  • MD-1;
  • pregnancy immunology;
  • transplantation immunology

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 situ hybridization, 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.