Kathleen P. Pratt, Ph.D.

Kathleen P. Pratt, Ph.D.

kathleen pratt

Name: Kathleen P. Pratt, Ph.D.

Department of Primary Appointment: Dept. of Medicine
Position: USU Faculty
Title: Associate Professor

Affiliated Departments: Molecular & Cell Biology,

Email: kathleen.pratt@usuhs.edu (link sends e-mail)
Office Phone: (301) 295-3607
Fax Number: (301) 295-3557

Profile

  • Ph.D. Cornell University
  • Postdoctoral training: University of Washington

Research: Immune tolerance, design of less immunogenic proteins, novel immunotherapies

Originally trained in biophysical and protein chemistry, my research interests have broadened to include studies of deleterious immune responses to protein antigens, e.g. therapeutic proteins, and novel approaches to characterize, prevent and treat these clinical disorders. My laboratory has particularly focused on the problem of neutralizing anti-drug antibodies in hemophilia A, clinically termed “inhibitors” because they inhibit normal blood coagulation. Hemophilia A patients lack functional circulating factor VIII (FVIII), and approximately 1 in 4 develops an inhibitor response following initial infusions of therapeutic FVIII. These immune responses can be difficult and extraordinarily expensive to manage, and patients with a persistent inhibitor have a low quality of life due to inadequate alternative treatments to prevent and manage bleeding episodes.  Anti-drug antibodies are a growing concern as more protein drugs are developed and tested in clinical trials. The reasons why some patients develop neutralizing antibodies, while others develop functional immune tolerance to infused proteins such as FVIII, are poorly understood. Our laboratory conducts studies of human T-cell and humoral responses to FVIII, which include detailed phenotyping of CD4 T cells and antibodies at various stages of the alloimmune response, e.g. using multicolor flow cytometry, ELISPOT/Fluorospot assays, tetramer analysis, surface plasmon resonance and other techniques. We are now launching a major effort to characterize mechanisms of inhibitor development and tolerance (achieved by some patients following intensive FVIII therapy) by flow cytometry, TCR repertoire profiling and transcriptomics analysis of FVIII-stimulated PBMCs isolated from appropriate cohorts of hemophilia A subjects and normal controls. A second, related project is to design and characterize recombinant FVIII proteins with modified T-cell and B-cell epitopes, with translational potential to avoid stimulation of effector T cells and/or neutralization by anti-FVIII antibodies. We also carry out collaborative studies with Prof. David Scott, whose lab is pursuing novel approaches to induce tolerance using animal models, including TCR transgenic and humanized hemophilia A mice. Finally, our mechanistic studies of alloimmune responses to FVIII have applications to other clinical disorders in which functional immune tolerance is desired, including transfusion-related immune responses and autoimmunity.

Selected publications:

Pratt KP, Shen BW, Takeshima K, Davie EW, Fujikawa K, Stoddard BL. 1999. Structure of the C2 domain of human factor VIII at 1.5 angstrom resolution. Nature 402: 439-42. PMID: 10586887

Spiegel PC, Jr., Jacquemin M, Saint-Remy J-MR, Stoddard BL, Pratt KP. 2001. Structure of a factor VIII C2-domain - Immunoglobulin G4k Fab complex: identification of an inhibitory antibody epitope on the surface of factor VIII. Blood98: 13-19. Plenary paper. PMID: 11418455

James EA, Kwok WW, Thompson AR, Pratt KP. 2007.Analysis of CD4 T-cell responses to FVIII in a mild hemophilia A patient indicates early loss of tolerance to a C2 domain self peptide and sustained loss of tolerance to the wild-type peptide J Thromb Haemostas5:2399-47. PMID: 18034765

Ettinger RA, James EA, Kwok WW, Thompson AR, Pratt KP. 2009. Lineages of human T-cell clones, including TH17/TH1 cells, isolated at different stages of anti-factor VIII immune responses. Blood 114: 1423-8. PMID: 19549986

Ettinger RA, James EA, Kwok WW, Thompson AR, Pratt KP. 2010. HLA-restricted T-cell responses to FVIII epitopes in a mild haemophilia A family with missense mutation FVIII-A2201P. 2010; Haemophilia 16:44-55. Invited article. PMID: 20536985

James EA , van Haren SD, Ettinger RA, Fjnvandraat K, Liberman J, Kwok WW, Voorberg J, Pratt KP. 2010. T-cell responses in two unrelated hemophilia A inhibitor subjects include an epitope at the factor VIII R593C missense site. J Thromb Haemostas 9:689-99. PMID: 21251204

Pratt KP: Inhibitory antibodies in hemophilia A. 2012. Current Opinion in Hematology 19: 399-405. Invited review. PMID: 22814650

Lewis KB, Hughes RJ, Epstein MS, Josephson NC, Kempton CL, Kessler CM, Key NS, Howard TE, Kruse-Jarres R, Lusher JM, Walsh CE, Watts RG, Ettinger RA, Pratt KP. 2013. Phenotypes of allo- and autoimmune antibody responses to FVIII characterized by surface plasmon resonance. PLOS One 8(5): e61120. PMID: 23667433

Scott DW, Pratt KP, Miao CH. 2013. Progress Towards Inducing Immunologic Tolerance to FVIII. Blood 121: 4449-56. Invited review. PMID: 23502223

Nguyen P-CT, Lewis KB, Ettinger RA, Schuman JT, Lin JC, Healey JF, Meeks SL, Lollar P, Pratt KP. 2014. High resolution mapping of epitopes on the C2 domain of factor VIII, using surface plasmon resonance. Blood 123(17): 2732-9.PMID: 24591205

Lin JC, Ettinger RA, Schuman JT, Zhang, A-H, Wamiq-Adhami, M, Nguyen P-Ct, Nakaya-Fletcher, SM, Puranik K, Thompson AR, Pratt KP. 2015. Six amino acid residues in a 1200 Å2 interface mediate binding of factor VIII to an IgG4  inhibitory antibody. PLoS One Jan 23;10(1):e0116577. PMID: 25615825

Gunasekera D, Ettinger RA, Liu M-C, Hughes RJ, Epstein MS, Cole SC, Barrett JC, Thompson AA, Withycombe J, Pratt KP. 2015. Factor VIII gene variants and inhibitor risk in hemophilia A patients. Blood 126(7): 895-904. PMID: 25617427 

Pratt KP. 2016. Engineering less immunogenic and antigenic factor VIIII proteins. Cellular Immunol. 301:12-17. PMID: 26566286