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Hereditary Immunodeficiency and Leukemogenesis in HRS/J Mice¹

The Jackson Laboratory, Bar Harbor, Maine 04609, and Brookhaven National Laboratory, Upton, New York 11973

Adult and fetal tissues of hairless (hr/hr) and haired (hr/+, +/+) HRS/J mice contain the same or a similar amount of endogenous murine C-type RNA virus. However, the onset of leukemia is earlier and its incidence is somewhat greater in hr/hr than in haired mice. This finding raises the question of whether the hr mutation exerts a pleiotropic effect leading to immunodeficiency, thus rendering hairless mice more susceptible to the development of leukemia than normal mice. Several different experimental approaches yielded the following results. (a) A severe thymic cortical atrophy was observed in hr/hr mice beginning at about 6 months of age, with a concurrent increase in splenic lymphoid elements. (b) Whole-body DNA turnover as well as turnover of DNA, RNA, and protein in thymus, spleen, lymph nodes, and bone marrow were similar in all three genotypes, independent of age and sex. (c) In two in vivo test systems, phytohemagglutinin stimulation and plaque assays for sheep red cell hemolysis, the hr/hr mutant responded somewhat better than the +/+ and hr/+ animals. (d) In contrast, in intact mice, the ability to produce antibody to tetanus toxoid in the form of aluminum-adsorbed, fluid, and complexed toxoid (in slight antigen excess) was greatly reduced in hr/hr mutants. These findings indicate a relative functional defect in the immune system of these mutants. If a deficient "collaboration" among different lymphoid cell types or a deficiency in the proliferative capacity of immunocompetent cells occurs in mutants, it may result in an ineffective immunosurveillance against leukemogenesis.

¹ This study was conducted under Research Contract N01 CP 33255 within the Special Virus-Cancer Program of the National Cancer Institute and was supported in part by NIH Research Grant CA 01594 from the National Cancer Institute. The Jackson Laboratory and Brookhaven National Laboratory are fully accredited by the American Association for Accreditation of Laboratory Animal Care.

² Supported by the United States Atomic Energy Commission.

Received 7/ 3/73. Accepted 10/18/73.