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The production of autoantibodies to erythrocytes by immunization with rat red blood cells (RRBC) is significantly retarded in X-linked immune deficient (Xid) mice. We have attempted to further explore this relationship by characterizing RRBC-induced erythrocyte autoantibodies in high responder New Zealand Black (NZB) and congenic NZB.Xid mice. NZB.Xid animals, immunized with RRBC, readily produce anti-RRBC antibodies and cross-reactive antiautologous erythrocyte antibody (CR anti-MRBC) as well as anti-HB antibodies. The autoantibody response of NZB.Xid mice to RRBC appears similar to NZB controls with respect to both the time of onset and subclass diversity; the anti-HB antibody cannot be absorbed with RRBC. Moreover, there are no alterations in the spectrotype of antierythrocyte antibodies found in NZB.Xid mice. Nonetheless, NZB.Xid, but not NZB mice, fail to produce splenic plaque-forming responses against bromelase-treated mouse red blood cells. Lyb 5+ cells are not required for the production of RRBC-induced antierythrocyte autoantibodies. These results, when discussed in light of the low but significant incidence of spontaneous DAT in NZB.Xid mice, suggest that given the appropriate genetic repertoire, the influence of the Xid gene on autoantibody production can be bypassed.

NZB mice bearing the CBA/N X chromosome linked defect were generated by repetitive backcrossing and selection of the Xid gene. The male offspring resulting from the cross of NZB with CBA/N were selected as being XidY on the basis of sera IgM and IgG3 levels and responsiveness to DNP-Lys-Ficoll. Following this inbreeding protocol, 6th generation backcross NZB XidY mice were compared to littermate controls with respect to B cell function. Sera immunoglobulin levels of IgG1, IgG2b and IgA were similar in XidY and XY mice. In contrast, levels of IgM and IgG3, from XidY mice were approximately 15% and 50%, respectively, of values found in littermates. Furthermore, XidY mice failed to respond to DNP-Lys-Ficoll and had less than 3% splenic Lyb 5.1-bearing cells. Splenic immunoglobulin cell surface profiles, obtained by the fluorescent activated cell sorter, indicated a significant reduction in the frequency of Ig bearing cells in Xid animals. Such profiles were similar to those obtained for spleen cells from reference control CBA/N mice. Finally, an elevated number of splenic, lymph node and bone marrow background and lipopolysaccharide-induced B cell clones in semi-solid phase agar was found in NZB but not C57BL/6, C3H, BALB/c and DBA/2 controls. In contrast, NZB XidY mice had virtually no detectable B cell colonies. This data, obtained on significantly inbred XidY NZB mice, suggests that the Xid gene is dominant over several aspects of polyclonal B cell activation in NZB mice and indicates that serial observation of these mice will be valuable in understanding the interactions of genetic immunologic mutations and cellular function in autoimmunity.

A newly synthesized agent, disodium 4-chloro-2,2'-iminodibenzoate (CCA; Lobenzarit disodium), which prevents the development of autoimmune disease in B/W mice, and inhibits adjuvant arthritis in rats, was investigated to clarify its mode of action in B/W mice. CCA protected against the age-related decline of the suppressor T cell activity which played an important role in the regulation of both humoral and cell-mediated immunity. CCA also decreased the production of naturally occurring thymocytotoxic autoantibody (NTA) preferentially cytotoxic against the thymocytes and suppressor T cells, and inhibited both the antibody production to double-stranded DNA and the appearance of ANA in B/W mice.

The immunoregulatory effect of 1 alpha-hydroxyvitamin D3, a precursor form of active vitamin D3 (1,25-dihydroxyvitamin D3), was examined in three different kinds of experimental systems in mice. Oral administration of 0.05 and 0.2 micrograms/kg of 1 alpha-hydroxyvitamin D3 augmented the primary immune response induced by immunization with 1 X 10(7) sheep erythrocytes, although it did not influence a maximal level of antibody formation induced by immunization with 5 X 10(8) sheep erythrocytes. The same treatment also restored the immune response depressed by restraint-stress. Furthermore, 1 alpha-hydroxyvitamin D3 suppressed the anti-dinitrophenyl plaque-forming cell response enhanced by colchicine injection to near the normal level. These results suggest that 1 alpha-hydroxyvitamin D3 enhanced or suppressed the immune response through activating helper and suppressor cells in dependence on the magnitude of the response.

OK-432 (a streptococcal preparation) has been widely used for cancer immunotherapy in Japan. It is a potent immunostimulator, activating macrophages and T lymphocytes, and increasing the production of TNF and several other cytokines in both humans and animals. In the present study, we evaluated the prophylactic effect of OK-432 on the development of autoimmune kidney disease in NZB/W F1 (BWF1) mice. The mice were given 0.5 or 2.0 KE ('klinische Einheit'; clinical unit) of OK-432 intraperitoneally every week from 21 weeks of age to the time of death. The control group received the same volume of saline (vehicle). OK-432 delayed the development of proteinuria and prolonged the survival of these mice dose dependently. At 49 weeks, 33.3% of control mice were alive, whereas 55.6% in the 0.5-KE- and 75% in the 2.0-KE-treated mice were alive. In the control group, the serum cholesterol level increased due to the development of glomerulonephritis. In contrast, mice treated with OK-432 had significantly lower levels of serum cholesterol. The serum levels of anti-DNA and anti-TNP antibodies were not affected by OK-432 administration. OK-432 induced the production of tumor necrosis factor (TNF)-alpha in the peritoneal fluid in the BWF1 mice. These results indicate that the effect of OK-432 in preventing the development of autoimmune disease in the mice may result from the stimulation of the endogenous TNF-alpha production.

Thirth-three derivatives of mycophenolic acid obtained by modifying phenolic hydroxyl and/or carboxyl groups were examined for antitumor and immunosuppressive activities. Some compounds showed more potent antitumor activities to L1210 leukemia and Ehrlich solid tumor than did mycophenolic acid. Most of these suppressed the production of antibody against sheep red blood cells in mice as strongly as did the parent substance. Correlation between antitumor and immunosuppressive activities was generally observed. However, a few compounds possessed a potent antitumor activity with less or no immunosuppressive activity.

In this study, we examined the effect of an immunoregulatory antirheumatic agent, lobenzarit disodium (CCA), on spontaneously developing glomerulonephritis in MRL/Mp-lpr/lpr (MRL/l) mice. Starting from 6 weeks of age, mice were given CCA orally 5 days a week at a dose of 2 or 10 mg/kg. A control group was given the same volume of distilled water. The CCA treatment suppressed the excretion of protein in the urine. At 40 weeks of age, the incidence of proteinuria was 10/10 in the controls, 6/10 in the 2-mg/kg treatment group, and 5/10 in the 10 mg/kg group. The life span was prolonged dose dependently. The 50% survival time was 33 weeks for the controls, 35.5 weeks for the 2-mg/kg group, and 41 weeks for the 10-mg/kg group. The serum levels of anti-ssDNA antibody, anti-TNP antibody, and rheumatoid factor (RF) of the Ig G isotype and immune complex were reduced compared with control group. But the antibodies of Ig M isotype were not reduced. The serum Ig G1, Ig G2, and Ig G3 were significantly lower in the CCA-treated mice than in the controls. But again the serum level of Ig M was unchanged. These effects of CCA may be based on the suppression of lymphadenopathy. CCA may correct abnormal B-cell growth and differentiation factor release by the MRL/l abnormal T cells. These results show that CCA inhibits the development of lupus nephritis in MRL/l mice through the amelioration of the abnormal immune response, polyclonal B-cell activation.