Murine mercury-induced autoimmunity: the role of T-helper cells.

ABSTRACT

Genetically mercury-susceptible (H-2s) mice in which the nude (athymic) mutation had been introduced, and euthymic (H-2s) mice treated with anti-CD4 monoclonal antibodies were used to determine the importance of T-helper (CD4+) cells for induction of autoimmunity by mercury, and to study the possibility of using anti-CD4 MAb for treatment of manifest autoimmunity. SJL/N and (A.SW x SJL-nu) F1 x SJL-nu BC (H-2s) mice homozygous for the nude mutation (nu/nu) were treated with 10 mg HgCl2/litre drinking water for 6 weeks. These mice developed neither the antinucleolar antibodies (ANoA) nor the systemic immune-complex (IC) deposits seen in mercury-treated littermates heterozygous for the nude mutation (nu/+). The nu/nu mice showed a significant and substantial reduction of splenocytes with pan-T-(CD3+), T-helper-(CD4+) and T-cytotoxic/suppressor (CD8+) markers, which was accompanied by a severe reduction of the proliferative response to Concanavalin A. Euthymic SJL/N mice given an initial intravenous (i.v.) injection of 100 micrograms anti-CD4 MAb (clone GK 1.5, rat IgG2b), followed by 6 weeks treatment with 100 micrograms anti-CD4 MAb intraperitoneally (i.p.) every third day in combination with 10 mg HgCl2/litre drinking water, did not develop ANoA or systemic IC-deposits. These features were seen in controls i.p. injected with rat IgG2b and given HgCl2 in the drinking water. The anti-CD4 MAb-treated mice showed very few CD4+ splenocytes, but a significant increase of CD8+ cells and severely impaired T-cell function. The possibility of treating longstanding autoimmune conditions with anti-CD4 MAb was examined by giving euthymic SJL mice HgCl2 for 3 months, followed by a mercury-free interval of 3 months and finally 7 weekly injections of 1 mg anti-CD4 MAb. This therapy caused a severe reduction of CD4+ cells, but there was no decline in the ANoA titre. In conclusion, induction of systemic autoimmunity by mercury was strictly dependent on T cells, specifically T-helper (CD4+) cells, and mercury-induced ANoA persisted for a long time after stopping mercury treatment. At this late stage, the autoimmune condition was no longer amenable for anti-CD4 MAb therapy.