- Planque, S. Escobar, M. A., Smith, K. C., Taguchi, H., Nishiyama, Y., Donnachie, E., Pratt, K. P., and Paul, S. Covalent inactivation of factor FVIII antibodies from hemophilia A patients by an electrophilic FVIII analog. J. Biol. Chem. 283:11876-11886. 2008.
- Burrell, B. E., Csencsits, K., Lu, G., Grabauskiene, S., and Bishop. D. K. CD8+ Th17 mediate costimulation blockade resistant allograft rejection in T-bet deficient mice. J. Immunol. 181:3906-3914. 2008.
- Csencsits, K., Wood, S. C., Lu, G., and Bishop, D. K. TGFβ gene transfer is associated with the development of regulatory cells. Am. J. Transplant. 5: 2378-2384, 2005.
Keri Csencsits Smith, Ph.D.
Pathology & Laboratory Medicine
(713) 500 - 7235
Cellular immunology, Mucosal Immunology
Ph.D. in Veterinary Molecular Biology, 2001
Montana State University
Transplantation immunology, University of Michigan, 2001-2005
The development of antibodies against FVIII remains a serious problem in the treatment of hemophilia A. Hemophiliacs with these inhibitor antibodies cannot receive therapeutic FVIII injections to control bleeding, and current therapies to treat these antibodies are expensive and often unsuccessful. Production of inhibitor antibodies has been linked to several factors, including genetics, inflammation, and the type of therapeutic FVIII injected. Furthermore, this response is also caused by a detrimental effect of the patients’ own immune response against FVIII, and is dependent upon both the actions of antibody secreting B cells, as well as “help” provided by T cells.
The research in my laboratory is focused on the investigation of the immunologic mechanisms that underlie the stimulation of B cells secreting anti-FVIII antibodies in hemophilia patients receiving therapeutic FVIII. An important consideration is the linking of inflammatory vs. regulatory pathways of T cell help. Recently, T cells characterized by their secretion of the IL-17 cytokine (known as Th17 cells) have been linked with the development of inflammatory disease. We hypothesize that Th17 cells play an important role in the development of inhibitor antibodies, by stimulating inflammation and driving the immune response towards the production of pathogenic anti-FVIII antibodies. Conversely, the development of regulatory T cells down-regulates the inflammatory immune response. Hence, it may be possible to “shift” the inflammatory pathway towards regulation and prevent the development of inhibitors in hemophilia patients receiving FVIII replacement therapy. We are also investigating the use of novel tolerogenic agents to control inflammatory immune responses against FVIII and prevent the production of anti-FVIII inhibitor antibodies.