Improved mouse models for the study of treatment modalities for immune-mediated platelet destruction

We found when using a mouse model of immune thrombocytopenia (ITP) that platelet (PLT) nadir could not be maintained in the face of daily PLT antibody, making interpretation of treatment modalities difficult. This finding was documented to be at least in part due to increased thrombopoiesis as a result of a compensated thrombocytolytic state. Thus, it was important to develop an improved mouse model of human ITP so as to maintain PLT nadir over time.

To maintain PLT nadir, we have developed two mouse models. One model uses single-dose sublethal total body gamma irradiation (TBI) in combination with daily low-dose PLT antibody administration while the second model uses escalation of the dose of PLT antibody over time. Both models maintain PLT nadir and allow for the study of treatment modalities without interference by marrow compensation.

Surprisingly, intravenous immune globulin (IVIG) shows no efficacy when using the TBI combination model but works well using the dose-escalation mouse model. In contrast, anti-TER-119 shows efficacy using either mouse model. Our results indicate that the mechanism of action of IVIG requires a functional marrow and/or involves a radiosensitive regulatory cell. However, IVIG works using the dose-escalation model without TBI and the increase in PLT counts correlates directly with reticulated PLTs suggesting that the IVIG mechanism involves effects on megakaryopoiesis/thrombopoiesis.

These mouse models should be useful for investigators wishing to maintain PLT nadir over prolonged periods of time for the study of mechanism and efficacy of various treatments for ITP.