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Susceptibility to Lymphoid Neoplasia in Immunodeficient Strains of Nonobese Diabetic Mice¹

Program in Developmental Biology, The Hospital for Sick Children Research Institute [P. P. L. C., E. I., S. M-T., J. S. D.], Departments of Surgery [P. P. L. C.] and Immunology [E. I., J. S. D.] and the Institute of Medical Science [P. P. L. C., J. S. D.], Faculty of Medicine, University of Toronto, Toronto, Ontario, M5G 1X8 Canada

Transformed lymphocytes exhibit aberrant growth potential resulting from enhanced proliferation and resistance to apoptotic stimuli. These mechanisms also influence the development of autoimmune disease, where dysregulated lymphocyte homeostasis has been implicated in expansion of autoreactive T cells. In the nonobese diabetic (NOD) mouse, a murine model of autoimmune type 1 diabetes and Sjögren’s syndrome, T cells are apoptosis resistant compared with other mouse strains, a feature thought to potentiate their autoimmune function. NOD mice congenic for the severe combined immunodeficiency scid mutation (NOD.scid) have an incidence of pro-T-cell lymphoma far in excess of scid mutants on other genetic backgrounds. This mutation arrests lymphocyte development secondary to a generalized defect in double-strand DNA break repair that compromises V(D)J recombination. To distinguish between the contributions of immunodeficiency and defective double-strand DNA break repair to lymphoma susceptibility on the NOD background, we examined the incidence, phenotype, and molecular mechanisms of lymphoma development in two immunodeficient NOD strains with normal DNA repair function. We report that NOD mice deficient in mature B cells (NOD.µMT) or mature T and B cells (NOD.RAG-2^-/-) display a high incidence of lymphoma of both T- and B-cell origin compared with these mutations on other genetic backgrounds. Strikingly, the lymphoma incidence in both strains was greater in females, mirroring the greater incidence of autoimmune type 1 diabetes in NOD females than in males. The high incidence of autoimmune diabetes and lymphoma in immunodeficiency NOD mice suggests the presence of genetic modifiers that affect lymphocyte homeostasis.

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