Spontaneous Abortion in Immunodeficient SCID Mice
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PROBLEM: Immunodeficient SCID mice on the CB‐17 have been used to test the role of “rejection” in a xenogeneic blastocyst transfer model of recurrent miscarriage, but interpretation of the data requires knowing syngeneic within‐species matings have a high success rate and do not require immunotrophic factors expected only in immunocompetent non‐T‐cell deficient mice.METHOD: Resorption rates were studied in a SCID CB‐17 barrier facility that provided the mice used to test the role of immunology in the resorption model.RESULTS: Spontaneous resorption in syngeneically mated immunodeficient SCID mice on the CB‐17 background occurred at an unexpectedly high rate and could not be prevented by treatment with anti‐asialo GM1 antibody or GM‐CSF, both of which are effective in ameliorating abortion in DBA/2J‐mated CBA/J mice. Immunocompetent CB‐17 +/+ mice showed an even higher rate of loss. The latter was also not affected by treatment with anti‐asialo GM1 antibody or by GM‐CSF and was not prevented by tetracycline (which is effective in the DBA/2‐CBA/J system) or progesterone treatment. Mating experiments showed a scid/+ × scid//+ cross gave the highest rate of loss, and it appeared that the presence of +/+‐type embryos in the uterus could be augmenting abortion with selective discrimination against scid/scid embryos. High abortion rates were associated both with appearance of a coagulase‐negative Staphylococcus sp. in feces and with loss of one component of the SPF flora. Decidual tissue from mated CB‐17 +/+ mice showed premature release of TNF‐cc in absence of TGF‐β2‐related suppressor activity, and vascular lesions (fibrinoid necrosis), varying in extent, were associated with both scid/scid × scid/scid and +/+ × +/+ pregnancies. TNF‐α also appeared prematurely in pregnant scid/scid mice, but the levels were lower (and areas of necrosis smaller than in +/+ × +/+ pregnancies). Outcrossing onto a C57B1/6 background dramatically reduced the abortion rate, indicating an important genetic effect on susceptibility with heterogeneity protecting against abortion.CONCLUSIONS: SCID mice on the CB‐17 background do not have a high rate of successful syngeneic pregnancies, and a TNF‐α induced vasculopathy may be responsible. Abortion was not caused by immunodeficiency leading to loss of immunotrophism because immunocompetent non‐SCID CB‐17 mice had a higher rate of loss. Factors augmenting the abortion rate included the presence of embryos of the +/+ genotype in the uterus and treatment with anti‐asialo GM1 antibody. Abortion rates were not reduced by treatments effective in the DBA/2‐mated CBA/J mouse model but were reduced by re‐establishing a new colony with defined flora (a temporary effect) and by outcrossing mice with a different (C57B1/6) background. Together, the data suggest an infectious trigger (identity uncertain) of the vasculopathy and an important genetic influence on susceptibility with heterozygosity and a SCID mouse mutation providing against abortion a degree of protection.
