Immune thrombocytopenias cause considerable morbidity and mortality throughout life. Major treatment options include splenectomy and intravenous immunoglobulin (IVIG). The diversity in response to these treatments implies a diversity in pathologic mechanisms. Yet to be explored is a role for thrombopoietin (TPO) therapy. The goal of this research is to produce mouse models of immune thrombocytopenia which recapitulate the pathologic features in man and provide a valid system within which to study therapy.
Specific Aim 1 is to place our human FcgammaRIIA transgene on a spontaneously autoimmune background, W/BF1, which generates immune thrombocytopenia. W/BF1 mice lack the equivalent of the human FcgammaRIIA gene. Our FcgammaRIIA transgenic mice sustain more severe immune thrombocytopenia following injection of anti-platelet antibodies than wild type mice, therefore establishing the importance of FcgammaRIIA. We will breed the IIA transgene onto the NZW and BXSB backgrounds and produce W/BF1 male mice in whom thrombocytopenia will be assessed as a function of FcgammaRIIA transgene status.
Aim 2 is to examine the response to splenectomy and IVIG therapy in W/BF1 mice. The hypothesis is that the presence of FcgammaRIIA on platelets and macrophages will diminish the effectiveness of the response. The mice will undergo splenectomy or receive IVIG, and we will measure the rate, magnitude and duration of response.
Aim 3 is to determine the effects of TPO therapy on immune thrombocytopenia in W/BF1 mice. The hypothesis is that exogenous pharmacologic doses of TPO will ameliorate immune thrombocytopenia despite continued antibody-mediated destruction. We will use daily subcutaneous injections of a TPO peptide mimetic alone or in combination with IVIG or splenectomy. We will determine the dose response and schedule needed to achieve the maximal increase in platelet count. Our mouse model of thrombocytopenia recapitulates the features of human disease and will lead to improved outcome for patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061865-03
Application #
6184549
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
2000-09-01
Budget End
2001-08-31
Support Year
3
Fiscal Year
2000
Total Cost
$238,500
Indirect Cost
Name
Thomas Jefferson University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
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