Date of Award:

5-1985

Document Type:

Dissertation

Degree Name:

Doctor of Philosophy (PhD)

Department:

Animal, Dairy, and Veterinary Sciences

Department name when degree awarded

Interdepartmental Program in Toxicology

Committee Chair(s)

Reed P. Warren

Committee

Reed P. Warren

Committee

Raghubir Sharma

Committee

William Brindley

Committee

Roger Coulombe

Committee

LeGrande Ellis

Abstract

A number of immune abnormalities have been found in epileptic patients treated with antiepileptic drugs (AED). The alterations seen range from mild suppression of immunoglobulins to severly impaired humoral and cellular immunities. There is evidence for both drug effects and genetic or acquired factors as contributors to these abnormalities. In order to examine the basis for immune abnormalities in patients with epilepsy, a number of experimental designs were employed: clinical studies, in vitro studies, and use of an animal model.

Peripheral blood mononuclear cells (PBMC) isolated from epileptic patients currently receiving AED were found to have a reduced OKT4+/0KT8+ ratio. A reduced natural killer (NK) cell activity was found which may be due to a low proportion of Leu 11+ cells. A reduced NK cell activity was also found in healthy siblings of the patients, indicating a possible genetic basis for the level of this activity. Antibody-dependent cell-mediated cytotoxicity (ADCC), mitogenic responses, and total rosette-forming cells of PBMC isolated from patients were found to be normal.

The AED phenytoin has been associated with a variety of immune function alterations and lymphoma. In this study, phenytoin was found to depress basal and augmented NK cell activity of human cells in a dose-dependent manner in vitro. This depression was reversible following short-term exposure and at levels considered therapeutic. Phenytoin also depressed ADCC, thus one mechanism by which phenytoin alters immune function is by its depression of cell-mediated cytotoxicity. In contrast to results obtained with phenytoin, the AED carbamazepine did not significantly alter NK cell activity, but the diluent propylene glycol depressed activity.

NFS mice given phenytoin produced lower specific antibody titers following antigen challenge. Body weights, specific organ weights for thymus, spleen, and liver, and blood cell counts were normal in these mice. The protocol was well tolerated by the animals at phenytoin dosages ranging from therapeutic to neurotoxic. Susceptibility to murine hepatitis virus was found to be increased in mice given a high dose of phenytoin. This animal model should allow investigations into toxic dose levels and mechanisms by which phenytoin and other AED alter immune function.

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