Studies of defective tolerance in murine lupus

Non-autoimmune strains of mice are easily made tolerant to subsequent challenge with BGG in adjuvant by pretreatment with large amounts of deaggregated BGG. In contrast, autoimmune-prone NZB and (NZB x NZW)F₁ strains fail to become tolerant when studied as young adults. In the present study, 2 newer autoimmune strains, MRL/Mp-Ipr/Ipr and BXSB/Mp were shown also to fail to become tolerant to BGG. Thus, all these autoimmune mice have in common not only B cell hyperactivity but also a tolerance defect. The cellular basis for the NZB tolerance defect was further studied in an adoptive transfer system. Neonatally thymectomized (NZB x DBA/2)F₁ mice were lethally irradiated at 3 mo of age, reconstituted with DBA/2 or NZB marrow cells (T cell depleted) and DBA/2 or NZB thymocytes, and studie for BGG tolerance. Whether tolerance developed was determined both by the strain of the donor cells and by the sex of the recipient mice. The latter factor was studied in detail by using sexually altered recipients of NZB thymocytes and DBA/2 marrow cells. Three major factors were found to determine whether tolerance would occur: 1) NZB thymocytes were found to be necessary for the tolerance defect. 2) Androgens protected against the tolerance defect imposed by NZB thymocytes and promoted the development of tolerance, in the presence of normal marrow. 3) NZB marrow, by itself, was not sufficient to prevent tolerance in association with normal thymocytes. However, NZB marrow prevented androgen-mediated tolerance in the presence of NZB thymocytes. Thus, the thymic defect was sufficient to prevent normal tolerance in females; however, an additional marrow defect was necessary to prevent tolerance in males.