Doctoral Dissertations

Date of Award

8-1998

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Microbiology

Major Professor

Barry T. Rouse

Abstract

Lymphotoxin-alpha (LT-α) is a non-antibody product of activated lymphocytes with functions very similar to those of tumor necrosis factor-alpha (TNF-α). Surprisingly, the genetic disruption of the murine LT-α gene attributed critical functions related to lymphoid tissue development to the protein product of this gene. Although characterized extensively with respect to receptor interaction and associated ligands, information regarding the role played by LT-α in immune responses are lacking. At the molecular level, LT-α is involved in key signaling events during embryogenesis which, when lacking, apparently cannot be compensated for post-partum. The cell types expressing LT-α in either its homotrimeric or heterotrimeric form during development remain undefined. Further, although the tissues which express the receptors for the LT-α complexes are presumed to be of stromal support tissue in origin during development, this also remains unsubstantiated. While the experiments described in this dissertation do not address these developmental commdrums nor do they explore the molecular events involved in lymphoid tissue development, they attempt to systematically define which components of the LT-α deficient mouse's immune system are impaired and which are normal. Following the introductory information in Part 1, Part 2 explores which of the remaining lymphoid tissue compartments LT-α deficient mice are sufficient to provide immune responsiveness when isolated and used to reconstitute severe combined immunodeficient mice. Next, in Part 3, the expression of specific vascular addressins and cell adhesion molecules are compared between wild-type and LT-α deficient mice. In Part 4, the unimpaired homing and functional ability of whole splenocytes from LT-α deficient mice is reconfirmed. Additionally, the inability of wild-type cells to correct the deficient phenotype following adoptive transfer is verified. Part 5 attempts to define the role played by the spleen in the generation of mucosal immune responses in LT-α deficient mice and confirms that these mice possess compensatory mechanisms for the maintenance, albeit at reduced levels, of immune function. Finally, Part 6 examines the ability of lymphocytes from LT-α deficient mice to recognize and respond, both humorally and in a cell mediated fashion, to a live replicating virus delivered enterally or parenterally. The data presented in this dissertation is novel and as yet unpublished, the latter issue will hopefully soon be remedied.

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