SPONTANEOUS-ABORTION IN IMMUNODEFICIENT SCID MICE

PROBLEM: Immunodeficient SCID mice on the CB-17 have been used to test the role of ''rejection'' in a xenogeneic blastocyst transfer model o f recurrent miscarriage, but interpretation of the data requires knowi ng syngeneic within-species matings have a high success rate and do no t 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 i n syngeneically mated immunodeficient SCID mice on the CB-17 backgroun d 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 e ffective in ameliorating abortion in DBA/2J-mated CBA/J mice. Immunoco mpetent CB-17 +/+ mice showed an even higher rate of loss. The latter was also not affected by treatment with anti-asialo GMI antibody or by GM-CSF and was not prevented by tetracycline (which is effective in t he DBA/2-CBA/J system) or progesterone treatment. Mating experiments s howed a scid/+ x scid//+ cross gave the highest rate of loss, and it a ppeared that the presence of +/+-type embryos in the uterus could be a ugmenting abortion with selective discrimination against scid/scid emb ryos. High abortion rates were associated both with appearance of a co agulase-negative Staphylococcus sp. in feces and with loss of one comp onent of the SPF flora. Decidual tissue from mated CB-17 +/+ mice show ed premature release of TNF-alpha in absence of TGF-beta2-related supp ressor activity, and vascular lesions (fibrinoid necrosis), varying in extent, were associated with both scid/scid x scid/scid and +/+ x +/ pregnancies. TNF-alpha also appeared prematurely in pregnant scid/sci d mice, but the levels were lower (and areas of necrosis smaller than in +/+ x +/+ pregnancies). Outcrossing onto a C57B 1/6 background dram atically reduced the abortion rate, indicating an important genetic ef fect on susceptibility with heterogeneity protecting against abortion. CONCLUSIONS: SCID mice on the CB-17 background do not have a high rat e of successful syngeneic pregnancies, and a TNF-alpha induced vasculo pathy 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 rat e included the presence of embryos of the +/+ genotype in the uterus a nd treatment with anti-asialo GMI antibody. Abortion rates were not re duced 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 te mporary effect) and by outcrossing mice with a different (C57B 1/6) ba ckground. Together, the data suggest an infectious trigger (identity u ncertain) of the vasculopathy and an important genetic influence on su sceptibility with heterozygosity and a SCID mouse mutation providing a gainst abortion a degree of protection.