ResearchSelf versus non-self discrimination is one of the basic tenets of immunology. Our laboratory focuses on understanding how this self "tolerance" (or unresponsiveness) is learned by both B cells and T cells and applying it using a novel gene therapy approach. Thus, we have expressed model epitopes (as IgG fusion proteins) in retroviral vectors for infection of B cells or stem cells for lymphoid precursors, leading to the induction of tolerance. This is also being applied to modulation of diabetogenic peptides, myelin basic protein in MS, anti-fVIII inhibitors in hemophilia, and potentially to eliminate potentially harmful humoral responses in HIV infection. Our approach has obvious ramifications a variety of autoimmune disorders including uveitis and for gene therapy in general. Moreover, if coupled with co-stimulatory products, this approach may be utilized on augmenting immune responsiveness in cancer patients. Understanding the mechanisms of tolerance induced by B-cell gene therapy, as well as clinical application in collaboration with biotech companies, comprise the current focus of our group.
PublicationsLei, T-C. and Scott, D.W. Induction of tolerance to fVIII inhibitors by gene therapy with immunodominant A2 and C2 domains presented by B-cells as Ig fusion proteins. BLOOD 105: 4865-70.
Xu, B. and Scott, D.W. A novel retroviral gene therapy approach to inhibit specific antibody production and suppress experimental autoimmune encephalomyelitis induced by MOG and MBP. 2004. Clin. Immunol. 111: 47-52.
Saenko, E.L., Ananyeva, N.M., Kouiavskaia, D.V., Khrenov, A.V., Anderson, J.A.M., Shima, M., Qian, J. and Scott, D.W. 2002. Hemophilia A: Effects of inhibitory antibodies on Factor VIII functional Interactions and approaches to prevent their action. Hemophilia 8: 1-11.
Melo, M.,Qian, J., El-Amine, M., Agarwal, R., Soukhareva, N.,Kang, Y. and Scott, D.W. 2002. Gene transfer of immunoglobulin-fusion proteins into B cells prevents and treats autoimmune diseases. J. Immunol. 168: 4788-95.
Qian, J., Saenko, E. and Scott, D.W., 2003. Co-stimulation blockade, hemophilic inhibitors and tolerance. Thrombosis & Hemostasis. 86: 1343-44.
El-Amine, M., Melo, M.E., and Scott, D.W. 2001. Gene Therapy for Tolerance and Autoimmunity: Soon to be Fulfilled Promises? J. Clin. Immunol. 99: 1-6.
El-Amine, M., Melo, M., Kang, Y., Nguyen, H.,Qian, J. and Scott, D.W. 2000. Mechanisms of Tolerance Induction by a Gene Transferred Peptide-IgG-Fusion Protein Expressed in B-lineage cells. J. Immunol. 165: 5631-36.
Agarwal, R. K., Kang, Y., Zambidis, E., Scott, D.W., Chan, C. and Caspi, R.R. 2000. Retroviral gene transfer of an immunoglobulin-antigen fusion protein protects from autoimmune disease. J. Clin. Invest. 106: 245.
Kang, Y., Melo, M., Deng, E., Tisch, R., El-Amine, M. and Scott, D.W. 1999. Induction of hyporesponsiveness to intact multi-determinant foreign protein via retroviral-mediated gene expression: the IgG scaffold is important for induction and maintenance of immunological hyporesponsiveness. Proc. Nat. Acad. Sci., 96: 8609. Personal HistoryDavid W. Scott, Ph.D. is Professor of Surgery and a Professor of Microbiology & Immunology at the University of Maryland School of Medicine. In addition, he has recently held faculty appointments at the medical schools of George Washington University (where he was first chair of Immunology) and Georgetown University. Dr. Scott began his professional career in 1969 following the receipt of his Ph.D. in Immunology from Yale University. Following this, he served as a post-doctoral fellow in Oxford, England with Sir James Gowans. In 1971, he then joined the faculty at Duke University as an Assistant Professor of Immunology in the Department of Microbiology and Immunology. He was promoted to the position of Associate Professor of Immunology in 1974 and to full Professor in 1979. In 1983, Dr. Scott was named Dean's Professor of Immunology at the University of Rochester Medical School, and he became the Head of the Immunology Division of the U. of Rochester medical school's Cancer Center. In 1994, he became the Head of the newly-formed Immunology Department at the Holland Laboratory, the R&D center of the American Red Cross. Over the course of his career, Dr. Scott has served on the editorial boards of major immunological journals and as a member of study sections of the National Institutes of Health, the National Multiple Sclerosis Society and the American Cancer Society. In 2004, he received the Distinguished Service Award from the American Association of Immunologists, and in 2006 served as Boerhaave honorary Professor at Leiden University Medical School in the Netherlands. He has contributed to over 180 research papers on a variety of subjects, including immunologic tolerance, B cell and T cell signaling, gene therapy, and cell cycle control and apoptosis. He is the author of two textbooks, including a recent monograph entitled The Nature of Immunologic Tolerance.
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