Identification of the basic immunologic defect in canine X-linked severe combined immunodeficiency disease
Abstract
The focus of this thesis is on the immunologic abnormalities associated with the only known animal model of X-linked SCID in man, canine XSCID. Examination of the cell surface antigen expression of peripheral blood lymphocytes (PBL) revealed a decreased percentage of mature T cells in XSCID dogs. However, nearly one-half of the dogs had nearly normal percentages of mature T cells in their PBL. The proliferative response of these mature T cells to mitogenic or PMA/A23187 stimulation was severely depressed. The inability of XSCID T cells to proliferate even when supplied with activated PKC and increased levels of calcium, by PMA and A23187, suggests that the gene defect resides in events distal to the generation of these second messengers. The addition of interleukin-2 (IL-2) was unable to normalize the proliferative response of the XSCID dog's PBL to mitogenic or PMA/A23187 stimulation. Examination of IL-2 receptor (IL-2R) expression and IL-2 production by PBL following mitogenic stimulation demonstrated that XSCID PBL were incapable of significantly up-regulating their IL-2R, yet they were able to produce normal amounts of IL-2. The gene defect in XSCID dogs, therefore, impairs the expression of IL-2R, yet does not affect the production of IL-2. A dramatic decrease in thymic weight and cellularity was observed for XSCID thymuses. This large decrease in the total number of thymocytes suggests that the XSCID gene may be necessary for the proliferative burst in early T cell development. Flow cytometric evaluation of the thymocytes from XSCID dogs revealed a significant decrease in the percentages of CD3(L)+, and CD4+CD8+ thymocytes. Thus, the XSCID gene defect also profoundly alters the acquisition of CD3, CD4, and CD8, in XSCID thymuses. In conclusion, the XSCID gene defect in the dog both hinders the production of mature T cells at an early stage in T cell development, and prevents the proliferation of mature T cells.
Degree
Ph.D.
Advisors
Felsburg, Purdue University.
Subject Area
Immunology
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