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It has been postulated that systemic cell-mediated immunity (CMI) is an important host defense mechanism against Candida infections of the vagina. However, in an estrogen-dependent murine model of experimental vaginal candidiasis, we recently showed that systemic Candida-specific Th1-type CMI induced by immunization with Candida culture filtrate antigen had no effect on vaginal Candida population levels during the course of a vaginal infection. In the present study, mice given a second vaginal inoculation in the presence of peripheral Candida-specific Th1-type CMI induced by prior vaginal infection had anamnestic-type increased delayed-type hypersensitivity (DTH) responses, concomitant with significantly fewer Candida organisms in the vagina than in primary-infected mice. In addition, organisms in secondary-infected mice were fragmented and superficial penetration into the epithelium was reduced. The systemic presence of Candida-specific T suppressor (Ts) cells that significantly suppressed the infection-derived anamnestic DTH reactivity did not abrogate the protective effect in the vagina. Additional experiments showed that vaginally immunized mice were not protected from gastrointestinal or systemic candidiasis and, in contrast to mice with a second vaginal infection, did not demonstrate anamnestic DTH reactivity. These results suggest that a moderate level of local protection against a Candida vaginal infection can be achieved by vaginal immunization but that the protective role of acquired peripheral Candida-specific Th1-type reactivity at the vaginal mucosa appears to be limited.

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Two immunomodulatory protocols were evaluated for their ability to inhibit lung colonization by mouse mammary tumor line 4T07. Preimmunization with tumor cells or pretreatment with poly I:C were equally effective at inhibiting lung colonization but a clonogenic tumor cell assay demonstrated that the treatments reduced tumor cell burden at different steps during the metastatic process. Poly I:C pretreatment accelerated tumor cell clearance based on the recovery of clonogenic tumor cells from lungs dispersed within 6 h post-arrest. Preimmunization inhibited the subsequent replication of tumor cells which survived and established in the lung, as indicated by the expansion of clonogenic cell numbers between 1 day and 7 days post-arrest. Histologic examination of serial sections of lungs demonstrated that very few (6%) of the tumor cells were extravascular 6 h post-tumor cell injection. By 24 h and 168 h the percentages of tumor cells which were extravascular had increased to 62% and 86%, respectively. Thus, poly I:C pretreatment appears to enhance killing of tumor cells prior to extravasation, whereas preimmunization appears to inhibit tumor cells after extravasation.

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T cells from genetically susceptible mice developing experimental autoimmune thyroiditis (EAT) proliferate in response to restimulation with mouse thyroglobulin (MTg) in vitro. The in vitro-activated cells adoptively transfer EAT as well as differentiate into cells cytotoxic for syngeneic thyroid monolayers. To examine the kinetics of T cell subset infiltration and distribution in situ after adoptive transfer, we applied the avidin-biotin-peroxidase labeling technique to thyroid sections, utilizing rat monoclonal antibodies followed by a biotinylated rabbit anti-rat antibody. Female CBA donor mice were immunized with MTg and lipopolysaccharide. Their spleen cells were obtained 7 days later, cultured with MTg, and transferred into recipient mice. The thyroids were removed on Days 7, 10, and 14 after transfer and serially sectioned. The early phase of transferred EAT showed a higher percentage of L3T4+ cells compared to Lyt-2+ cells, yielding a ratio of 2.3 and total T cells of about 35%. By Day 10, both T cell subsets had increased to a total of about 56%. However, the relative increase was greater in the Lyt-2+ subset; the nearly doubled percentage was statistically significant, resulting in a downward shift in the subset ratio to 1.7. Little change in the in situ distribution was seen on Day 14. The percentages of F4/80+ (macrophage) population in lesions examined on Days 10 and 14 were fairly constant and B cell involvement was minimal. These findings illustrate the pathogenic role of both T cell subsets in adoptively transferred EAT and the time-dependent changes in their relative proportions leading to thyroid gland destruction.

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L3T4+ T cells from genetically susceptible mice developing experimental autoimmune thyroiditis (EAT) were shown earlier to proliferate in response to restimulation with mouse thyroglobulin (MTg) in vitro and to mediate the adoptive transfer of EAT, whereas Lyt-2+ cells differentiated in vitro into cells cytotoxic for thyroid monolayers. Leukocyte suspensions from disrupted thyroid glands examined on Days 13-21 after immunization revealed the accumulation of both T cell subsets in the infiltrate at varying ratios. To characterize the in situ kinetics of cellular infiltration in chronic EAT, we extended the observation intervals after immunization to include Days 21 to 42. The leukocytes in thyroid sections were labeled immunohistochemically first with rat monoclonal antibodies to L3T4, Lyt-2, Thy-1, k light chain, or F4/80 macrophage antigen, then with biotinylated anti-rat IgG, utilizing the avidin-biotin-peroxidase technique. Throughout the 21- to 42-day interval, no significant variations were detected in the percentages of L3T4+ subset, but those of Lyt-2+ cells increased and then declined. The shift in the L3T4+:Lyt-2+ ratio, down from 2.4 to 1.6 and then up to 3.0, was directly related to changes in the Lyt-2+ subpopulation. The F4/80+ and B cell populations changed little during this period. These findings illustrate the changing kinetics of T cell subsets in situ in the development and perpetuation of EAT and MTg-immunized mice.

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To delineate the contribution of L3T4+ and Lyt-2+ cells in the pathogenesis of experimental autoimmune thyroiditis (EAT), synergistic pairs of monoclonal antibodies (mAb) to the T cell subsets were used in conjunction with the adoptive transfer of mouse thyroglobulin (MTg)-activated cells from immunized mice. Initial experiments verified the important role of L3T4+ cells in the transfer of EAT. Subsequent experiments pointed to the relative contribution of both L3T4+ and Lyt-2+ cells, depending on the stage and extent of disease development. Treatment during disease with L3T4, but not Lyt-2, mAb alone significantly reduced thyroiditis. However, in situ analysis of the cellular infiltrate in thyroid sections revealed that, after treatment with mAb, the appropriate subset was eliminated without altering the amount of the other subset in the remaining lesion. In addition, treatment during severe thyroiditis following the transfer of MTg-activated lymph node cells showed that Lyt-2 mAb alone also reduced thyroid infiltration. When the recipients were pretreated with either pair of mAb before transfer, disease development was only moderately affected. We conclude that (i) donor L3T4+ cells are the primary cells responsible for the initial transfer and development of thyroiditis; and (ii) previous in vitro cytotoxicity data, plus current monoclonal antibody treatment of disease and in situ analysis, further implicate a role for Lyt-2+ cells in EAT pathogenesis.

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A group of related borzoi dogs were studied over a 6-year period to ascertain the cause of primary hypothyroidism. Four generations of dogs were analyzed. Two littermates with lymphocytic thyroiditis were mated and the 10 offspring were all diagnosed, on the basis of thyroid biopsy evaluation, as having lymphocytic thyroiditis by age 2.5 years. A wide range of thyroid gland lesions was demonstrated in this litter of dogs. This report documents the occurrence of lymphocytic thyroiditis in three successive generations of an inbred group of borzoi dogs. An autosomal recessive mode of inheritance for the trait in this group of dogs is proposed.

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A six-year study of clinical data and the morphologic changes involved in lymphocytic thyroiditis in a colony of related borzoi dogs was conducted. Lesions observed included initial degenerative thyroidal parenchymal changes which progressed to subacute inflammation with subsequent fibrosis and end stage thyroid gland disease. This study encompasses three successive generations of this borzoi colony and documents the progression of the histologic changes from the initial thyroid gland degenerative lesions to the end stage parenchymal atrophy. Spontaneous, familial thyroiditis has not been reported previously in the borzoi breed.

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