HIT is a severe autoimmune disorder that predisposes to arterial and venous thrombosis. HIT is notable for several reasons, including the remarkable prevalence of otherwise immunologically healthy individuals exposed to heparin who develop self-reactive antibodies to a normal host protein, PF4, when it is released following platelet activation. Current clinical challenges in HIT include over-diagnosis and over-treatment and well as the risks of anticoagulating patients with thrombocytopenia and other hemostatic challenges such as recent surgery. In this proposed study, we will try to obtain in-depth understanding of the pathogenic ternary complex using crystallographic studies. We will try to expand our understanding of the PF4 tetramerization process and the creation of a novel type of antigenic epitope. We will try to develop a panel of PF4 mutants in different states of oligomerization that may provide a more reliable diagnostic method. We will also humanize RTO, maintain its PF4-monomer binding ability, but minimize the human immune response in preparation for potential future clinical studies.
The proposed studies will combine biophysical, serological, cellular and in vivo models to study the mechanism of PF4 tetramer assembly and antigen formation critical to the pathogenesis of HIT, develop novel diagnostics based on the PF4 monomer, and develop a humanized RTO to prevent HIT in a preclinical model.
|Khandelwal, Sanjay; Ravi, Joann; Rauova, Lubica et al. (2018) Polyreactive IgM initiates complement activation by PF4/heparin complexes through the classical pathway. Blood 132:2431-2440|
|Cai, Zheng; Zhu, Zhiqiang; Greene, Mark I et al. (2016) Atomic features of an autoantigen in heparin-induced thrombocytopenia (HIT). Autoimmun Rev 15:752-5|