Experiments were performed to determine the role of the immune response in rat periodontal disease. Germ-free rats were fed defined antigen-free liquid diets or a diet containing ovalbumin(OVA) as a prototype antigen. The OVA-fed rats demonstrated increased gingival lymphocytes (mainly T at early times), OVA-sensitized spleen cells, and increased periodontal bone loss. In further studies, rats pre-sensitized with OVA, and receiving OVA in the diet, showed elevated IgG antibody, sensitized spleen cells, and elevated periodontal bone loss scores. The concept that bone loss was due to mixed hypersensitivity reaction is consistent with the periodontal pathology. The effects of pre-immunization with A. actinomycetemcomitans (Aa) on periodontal bone loss in Actinobacillus (Aa) - infected rats was examined. Delayed hypersensitivity (DTH) was present in immunized rats throughout the experimental period. Sham-immunized rats showed DTH after 30 days of infection. In addition, immunized rats showed elevated bone loss scores. These experiments support the contention that a combination of hypersensitivity reactions (i.e., mixed hypersensitivity to Aa) could give rise to the periodontal pathology observed. Congenitally athymic rats (nude) were shown to have more periodontal bone loss than did normal littermates. However, bone loss in thymus-cell reconstituted nude rats was not different from that in control rats. Normal rats receiving Aa-sensitized T lymphocytes prior to infection with Aa demonstrated increased DTH and periodontal bone loss. These studies support the concept that T-cell functions and thymic regulation of immune responses can exert protective and/or destructive effects in periodontal disease. In order to modify disease, it will be necessary to enhance the protective aspects of the immune response and to minimize the detrimental aspects.