Human neonatal thrombocytopenia is attributed to the transplacental transfer of maternal antiplatelet antibodies. However, evidence that the antibodies cross the placenta, interact with fetal platelets, and cause the destruction or delayed production of platelets has been difficult to obtain. Determination of mechanisms underlying the disease has recently been facilitated by the development of a heritable animal analog. Heritable severe combined anemia and thrombocytopenia (scat) in the mouse is associated with an IgG-precipitable antibody against a 110kD platelet protein. The antibody is detected in both the pregnant scat/+ mother and over 80% of the affected pups. Evidence suggests some pups die in utero. The scat/scat pups are bruised at birth, have few platelets, and hemorrhage into the brain, intestine and other tissues postnatally. The mutant mouse is an excellent model to study the genesis of the bleeding disorder. We have recently shown, by transferring scat/scat ovaries to a surrogate immunodeficient mother devoid of functional T and B cells, that the disease can occur in the absence of maternal antibody. It is, however, possible that the pups produce an immune response to their own or their mother's platelets. We have further determined that the birth mother must carry a wild type (=) allele at the scat locus in order to generate affected scat/scat pups. Our working hypothesis is that a maternal factor (as yet undefined) perturbs fetal platelets; the mother responds to the aberrant platelets by generating the 110kD platelet antibody; and the antibody exacerbates the disease in the fetus. The long term goals are to identify the maternal-fetal interactions leading to the disease phenotype.
Specific Aims are: (1) To determine whether platelet specific antibody is necessary at any stage for disease development; (2) To determine whether the antibody plays a significant role in decreased fetal survival; (3) To establish when the wild type gene exerts its effect on the mutant cells in utero; (4) To determine whether the wild type gene activates the disease process in scat/scat mice with no disease phenotype; and (5) To map the chromosomal location of the scat locus.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL049761-04
Application #
2225821
Study Section
Special Emphasis Panel (ZHL1-CSR-C (01))
Project Start
1992-09-30
Project End
1999-02-28
Budget Start
1995-09-01
Budget End
1999-02-28
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Jackson Laboratory
Department
Type
DUNS #
042140483
City
Bar Harbor
State
ME
Country
United States
Zip Code
04609