MECHANISM OF ACTION OF THIABENDAZOLE

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The general scientific goals of the project are to test the hypothesis that the immunomodulating agent thiabendazole (TBZ), when given in conjunction with a thymus-dependent antigen, promotes the production of ahumoral factor(s) (lymphohemopoietic stimulating factor, LHSF) which affects the proliferation and differentiation of primitive lymphopoietic and hemopoietic cells. The following progress has been made in the first year of the grant. We have initiated experiments to determine whether other thymus-dependent antigens, in addition to DNFB, can act synergistically with TBS to stimulate lymphohemopoiesis in normal mice. The results indicate that oxazolone, another skin-sensitizing antigen, is also effective, whereas KLH is not. We now plan to screen a battery of thymus-dependent antigens to determine if only those having skin-sensitizing properties are active in the generation of the LHSF. The results of these studies may have important clinical implications, if indeed skin-sensitizing antigens are required for the maximum therapeutic efficacy of TBZ and closely related compounds. We have initiated experiments to determine whether TBZ and DNFB stimulate lymphohemopoiesis in congenitally athymic (nude) mice. Thus far we have not observed any effect. This suggests that T lymphocytes may be important in the generation of the LHSF. We plan to formally test this by reciprocal cell transfer and serum transfer experiments between normal and nude mice injected with TBZ and/or DNFB. These experiments should also reveal whether LHSF is composed of two factors, one produced by antigen-stimulated T cells (and therefore absent from nude mice) and one produced by TBZ-stimulated macrophages (and therefore present in nude mice). We have improved the assay for TdT-positive cells by changing from immunofluorescence to immunoperoxidase. The results are not only more quantifiable but also the preparations are permanent and available for retrospective analysis if necessary. We have also initiated studies using 50H-TBZ, the active metabolite of TBZ. This should make the experimental system more dose-responsive by eliminating the need to work with the highly insoluble form of TBZ. (IT)