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Member Information
Peter J. Felsburg, VMD, PhD
Trustee Professor of Immunology
Office Phone: 215-898-3527
Office Fax: 215-898-3663
Email: felsburg@mail.vet.upenn.edu
Website(s): http://www.med.upenn.edu/immun/Faculty/felsburg.html
Education: VMD 1969, University of Pennsylvania; PhD, 1973 University of Pennsylvania
Keywords: X-linked severe combined immunodeficiency, Common gamma chain, Hematopoietic stem cell transplantation, Gene therapy, Lymphocyte development, Cytokine signaling, Oncoretroviral vectors, Lentiviral vectors
Research and/or Clinical Interests:
Role of the common gamma chain in lymphoid development and function, and immune reconstitution following hematopoietic stem cell transplantation and gene therapy.
Summary:
Our laboratory has identified and characterized an X-linked severe combined immunodeficiency (XSCID) in dogs which is due to mutations in the common gamma (?c) subunit of the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptors. Canine XSCID, unlike genetically engineered ?c-deficient mice, has a clinical and immunologic phenotype virtually identical to human XSCID. It appears that species-specific differences exist in the role of the ?c and its associated cytokines in mice compared to their role in humans and dogs suggesting ?c-deficient dogs may be a more relevant model for studying the role of the ?c in man.
A central role for the ?c, and the cytokines with which it interacts, in T cell development is demonstrated by the profound T cell defect in human and canine XSCID. However, the fact that limited T cell development does occur in human and canine XSCID suggests that aspects of T cell development can occur independently of a functional ?c. It is becoming clear that the cytokines associated with receptors containing the ?c are capable of signaling in non-lymphoid cells through pathways different from those attributed to lymphoid cells. We are actively evaluating whether the limited T cell development observed in XSCID may be due to one or more cytokines signaling through nonconventional signaling pathways that are independent of a functional ?c. We have also shown that environmental stimuli influence ?c-independent pathways of T cell development. Since ?c-dependent cytokines have differing roles in human and canine B cell development than in the mouse, the XSCID dog is also being used to study the role of these cytokines in B cell development and function. We are also utilizing the model to study the role of the ?c in the "cross-talk" between intestinal epithelial cells and intestinal intraepithelial lymphocytes and its importance in maintaining normal intestinal intestinal homeostasis.
Hematopoietic stem cell transplantation (HSCT) is presently the only treatment available to cure patients with XSCID, however, the major immunologic problem in human XSCID patients following HSCT is the lack of donor B cell engraftment with resultant poor reconstitution of humoral immune function. We have shown that following HSCT of XSCID dogs, engraftment of donor B cells and reconstitution of normal humoral immune function is attained. We are using this unique model to determine which variable(s) contribute to the successful engraftment of donor B cells. We are also testing the ability of allogeneic bone marrow stromal cells transduced with IL-7 to accelerate thymopoiesis following HSCT.
XSCID dogs represent an ideal large animal pre-clinical model for developing and evaluating strategies for human gene therapy. Current studies include evaluating the efficacy (quality and durability of immune reconstitution) and safety of retroviral and lentiviral gene therapy. The safety studies include integration site analysis and evaluation of potential overexpression of the ?c on downstream signaling pathways.
Representative Publications:
Henthorn, P.S., Somberg, R.L., Fimiani, V.M., Puck, J.M., Patterson, D.F., and Felsburg, P.J.: IL-2R? gene microdeletion demonstrates that canine X-linked severe combined immunodeficiency is a homologue of the human disease. Genomics 23: 69-74, 1994.
Somberg, R.L., Robinson, J.P., and Felsburg, P.J.: T lymphocyte development and function in dogs with X-linked severe combined immunodeficiency. J. Immunol.153: 4006-4015, 1994.
Somberg, R.L., Tipold, A., Hartnett, B.J., Moore , P.F., Henthorn, P.S., and Felsburg, P.J.: Postnatal development of T cells in dogs with X-linked severe combined immunodeficiency. J. Immunol. 156: 1431-1435, 1996.
Felsburg, P.J., Somberg, R.L., Hartnett, B.J., Suter, S.F., Henthorn, P.S., Moore, P.F., Weinberg, K.I., and Ochs, H.D.: Full immunological reconstitution following non-conditioned bone marrow transplantation for canine X-linked severe combined immunodeficiency. Blood 90: 3214-3221, 1997.
Felsburg PJ, Somberg, RL, Hartnett BJ, Henthorn PS, and Carding SR: Canine X-linked severe combined immunodeficiency: a model for investigating the requirement for the common gamma chain (?c) in human lymphocyte development and function. Immunol. Res. 17: 63-73, 1998.
Hartnett, B.J., Henthorn, P.S., Moore, P.F., Weinberg, K.I., Ochs, H.D., and Felsburg, P.J.: Bone marrow transplantation for canine X-linked severe combined immunodeficiency. Vet. Immunol. Immunopathol. 69: 137-144, 1999.
Hartnett, B.J., Somberg, R.L., Krakowka, S., Ochs, H.D., and Felsburg, P.J.: B cell function in canine X-linked severe combined immunodeficiency. Vet. Immunol. Immunopathol. 75: 121-134, 2000.
Hartnett, B.J., Yao , D., Suter, S.E., Henthorn, P.S., Moore, P.F., McSweeney, P.A., Nash, R.A., Weinberg, K.I., and Felsburg, P.J.: Transplantation of X-linked severe combined imunodeficient dogs with CD34 + bone marrow cells. Biol. Blood Marrow Transpl 8: 188-197, 2002.
Felsburg, P.J., Hartnett, B.J., Gouthro, T.A., and Henthorn, P.S.: Thympoiesis and T cell development in common gamma chain deficient dogs. Immunol, Res.: 27: 235-245, 2003.
Ting, S.S., Hartnett, B.J., Malech, H ., and Felsburg, P.J.: Gene therapy in canine X-linked Severe combined immunodeficiency by RD114 pseudotyped oncoretroviral vector. Blood 100: 427, 2002.
Ting, S.S., Christopher, S., Choi, U., DeLeon, J., Linton, G., Theobald-Whiting, N., Malech, H., and Felsburg, P.J.: In vivo oncoretroviral gene transfer by intravenous injection of RD114-pseudotyped oncoretroviral vector achieves early and significant lymphoid marking in XSCID dogs. Blood: in press.
Lan, J., Singh, J., Cruickshank, S., Egan, C., Graham, A., Felsburg, P.J., and Carding, S.R.: The cytoplasmic pattern recognition receptor Nod2 is upregulated by intestinal epithelial cells in vivo in response to microbial challenge and inflammation. GUT: in press.
