Immunology Graduate Group

Peter J. Felsburg, V.M.D., Ph.D.
Trustee Professor of Immunology
Department of Clinical Studies,
Veterinary School of Medicine

Address: Room 4035 RYAN/6010
Office Phone: (215) 898-3527
Lab Phone: (215) 898-8180
Fax: (215) 898-3662
Email: felsburg@mail.vet.upenn.edu

Education:
V.M.D., University of Pennsylvania
Ph.D., University of Pennsylvania
B.S., Pennsylvania State University

Research Interest

Role of the common gamma chain in lymphoid development and function, and immune reconstitution following hematopoietic stem cell transplantation and gene therapy. 

Research Summary

OOur laboratory has identified and characterized an X-linked severe combined immunodeficiency (XSCID) in dogs which is due to mutations in the common gamma (gc) subunit of the IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptors. Canine XSCID, unlike genetically engineered gc-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 gc and its associated cytokines in mice compared to their role in humans and dogs suggesting gc-deficient dogs may be a more relevant model for studying the role of the gc in man.

A central role for the gc, 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, since limited T cell development does occur in human and canine XSCID, we are investigating how T cell development occurs independent of a functional gc. We have also shown, using gnotobiotic XSCID dogs, that environmental stimuli influence gc-independent pathways of T cell development. Since <FONT FACE="Symbol">g</FONT>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 gc in regulating Toll-like receptor and Nod2 expression in intestinal epithelial cells.

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 capacity of mesenchymal stem 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 over-expression of the gc on downstream signaling pathways.

 

The gc gene mutation in our XSCID colony, derived from a single female carrier, is a 4 bp deletion causing a frame-shift that results in a premature stop codon in exon 1 and a predicted polypeptide of 21 aa. The mutation in these dogs, which precludes the production of a functional protein, represents a naturally occurring gc "knock-out".

 

Recent Publications:
  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 (gc) in human lymphocyte development and function. Immunol. Res. 17: 63-73, 1998.

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 immunodeficient 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

 

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