Senior Investigator
Transfusion Medicine, Vascular Biology & Cell Therapy
Jacquelyn Fredrick Endowed Chair for Foundational Research
Professor
Departments of Pharmacology and Toxicology and Cell Biology, Neurobiology and Anatomy
Medical College of Wisconsin
Doctoral Training
St. Louis University, PhD, 1983
Our laboratory divides its attention between (1) identifying the effects of anti-platelet antibodies on platelet and endothelial cell function, and (2) the development of novel protein and cellular therapy reagents that target and eliminate B cell popula-tions responsible for the production of pathological auto- and allo- anti-platelet antibodies. Techniques employed range from sophisticated use of custom animal models of platelet alloimmunity to platelet and endothelial cell functional assays to structural biology models of antibody/antigen interactions.
The Immunobiology of Fetal/Neonatal Allo-and Auto-Immune Thrombocyto-penia: Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT), is a non-malignant hematologic bleeding disorder that arises when maternal antibodies specific for fetal platelet alloantigens cross the placenta and remove a baby’s platelets from circula--tion in the fetal and/or neonatal period. Cases of mild thrombocytopenia often resolve without incident, but 10-20% of severely thrombocytopenic cases are unpredictably associated with major organ bleeds such as intracranial hemorrhage (ICH), which can cause irreversible brain damage and death. More than 35 polymorphic Human Platelet Alloantigens (HPAs) on seven membrane glycoproteins have thus far been identified. Among these, HPA-1a (formerly known as PlA1) is the most clinically significant cause of FNAIT in the US, being responsible for the vast majority of FNAIT cases, and is most frequently associated with ICH and other adverse pregnancy complications.
Current studies seek to:
The detailed mechanisms revealed by correlating in vitro functional effects with detailed structural information and FNAIT severity in vivo may provide novel pathophysiological insights that will inform and enable predictions of FNAIT severity in humans.
Antigen-guided, targeted elimination of specific B cell populations as a novel strategic therapy for allo- and auto-immunity: In 1993, Eshhar and colleagues constructed a chimeric molecule comprised of the variable region of antibody specific for a tumor-associated antigen fused to the signaling domain of the T cell antigen receptor (TCR). When expressed in T cells, this chimeric molecule conferred both antibody-like specificity and signal transduction capabilities that together mediated lysis of target cells. Since that time, these so-called CAR-T cells have found widespread use in treating a variety of hematologic malignancies. In 2016, Ellebrecht et al. reimagined the use of CAR T cells for targeted therapy of autoimmune disease, using T cells engineered to express a chimeric protein comprised of all or parts of an autoantigen (rather than an antibody) fused to the TCR transmembrane and cytoplasmic signaling domains to seek out, bind, and eliminate autoreactive surface immunoglobulin-expressing memory B cells and, indirectly, their autoantibody-producing plasma cell progeny. They termed this novel form of cellular therapy Chimeric AutoAntibody Receptor (CAAR) T cell therapy, with the distinct advantage that only those B cells expressing the offending autoantibody would be eliminated, leaving the rest of the otherwise protective immune system intact, thereby avoiding the need for chronic immunosuppressive therapy that leaves patients at risk of opportunistic infections. Two projects are underway: One involved in developing a cellular therapy for the autoimmune thrombocytopenia (ITP) and the other developing protein and cellular reagents for treating FNAIT.
For ITP, we are employing lentiviral technology to develop CAAR T cells expressing the extracellular domain of the platelet membrane glycoprotein (GP)IIb-IIIa complex. Preclinical studies in mice will be performed in order to examine whether targeting B cells expressing GPIIb-IIIa-specific antibodies can reduce the titer of circulating anti-platelet antibodies. If successful, these studies will provide the strategic and con-ceptual framework necessary to advance such treatments to patients with ITP.
The second project involves the generation and use of novel protein and cellular reagents designed to target B cell populations responsible for producing anti-HPA-1a alloantibodies. These reagents include:
Huiying Zhi, MD
Research Scientist II
Cathy Paddock
Senior Research Technologist
Jaganmoy Choudhury, MSc, PhD
Postdoctoral Fellow
Nanyan Zhang, MD, PhD
Research Scientist II
Alyssa Moroi, PhD
Research Scientist I
Douglas Franklin
Animal Technician
A complete list of my published work can be found in MyNCBI Bibiography using the following link: http://www.ncbi.nlm.nih.gov/sites/myncbi/peter.newman.1/bibliography/41153642/public/?sort=date&direction=ascending.