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Modulation of Immunological Competence in 1,2-Dimethylhydrazinesensitive SWR/J Mice during Colorectal Carcinogenesis¹

Department of Anatomy, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298 [A. K. S.], and Meloy Laboratories, Inc., Springfield, Virginia 22151 [B. A. D., K. E. B.]

Morphologically defined stages of 1,2-dimethylhydrazine (DMH)-induced colorectal carcinogenesis were correlated with concomitant changes in the immunological competence of susceptible SWR/J mice. The morphogenesis of colorectal tumors and the cellular changes occurring in the spleen, draining (mesenteric) lymph node, thymus, liver, and lung of mice were studied during and after chronic s.c. administration of the carcinogen (15 mg DMH per kg body weight per week for 20 weeks). The immunological competence of T- and B-lymphocytes of spleens and draining lymph nodes was measured biweekly by tritiated thymidine incorporation in response to in vitro stimulation with concanavalin A and bacterial endotoxin.

A triphasic modulation of the regional (draining lymph node) and systemic (splenic) immunocompetence was demonstrated in DMH-treated mice during colorectal carcinogenesis. The three phases of modulation correlated with the latency of appearance of colorectal lesions, tumor progression, and the development of invasive adenocarcinomas. Cellular changes in the draining lymph node and the spleen reflected the mitogen reactivity of T- and B-lymphocytes in Phases I and III. In Phase II, however, splenic mitogen reactivity did not reflect the morphologically detectable enhancement of the splenic immune response due to the dilution effect of the extensive myeloid metaplasia in the red pulp.

In Phase I, a depression of the regional immunocompetence and an enhancement of the systemic immunocompetence initiated by DMH preceded the development of the initial colorectal lesions. In Phase II, an enhanced regional and systemic immunity corresponded to morphogenetic changes in the colorectal epithelium representing a transition from hyperplasia to neoplasia. In Phase III, a reduction in both regional and systemic immunocompetence was associated with the growth of adenocarcinomas. Subsequently, systemic immunity, as indicated by the continued depression of mitogen reactivity and the depletion of the splenic white pulp, was abrogated concomitantly with the increase in tumor burden. Regional immunity, however, recovered and became enhanced simultaneously with the appearance of invasive adenocarcinomas.

The observations indicated a DMH-initiated, tumor development-mediated modulation of immunocompetence. This modulation resulted in a compromise, a dynamic tumor-host interaction which favors the ultimate development of invasive colorectal adenocarcinomas.

¹ Research conducted at Meloy Laboratories, Inc.

² To whom requests for reprints should be addressed, at Meloy Laboratories, Inc., 6715 Electronic Drive, Springfield, Va. 22151.

Received 8/24/79. Accepted 4/15/80.