Production of erythrocyte autoantibodies in NZB mice is inhibited by CD4 antibodies

Abstract

SUMMARYNZB mice spontaneously develop haemolytic anaemia as the result of production of erythrocyte autoantibodies. The mechanisms leading to breakdown in tolerance to erythrocyte autoantigens are unknown. Antibodies to CD4 have been successfully used to treat several murine models of autoimmune disease. In this study we injected NZB mice with non-depleting CD4 antibodies and were able to prevent and abrogate erythrocyte autoantibody production in young {Coombs" negative) and old (Coombs" positive) mice, respectively. Our data indicate the dependency of autoantibody production on CD4' T cells. However, withdrawal of anti-CD4 antibodies resulted in the appearance of erythrocyte autoantibodies, showing that under these conditions we were unable to re-establish tolerance to autoantigens on erythrocytes using anti-CD4 treatment.

Production of the effector cytokine interleukin-17, rather than interferon- , is more strongly associated with autoimmune hemolytic anemia

“…5,8 Valuable insights have been obtained from studies of both murine AIHA, particularly the spontaneous form affecting New Zealand Black (NZB) mice, and human patients. NZB IgG autoantibody production in vivo is retarded by treatment with anti-CD4 monoclonal antibody, 9 or by CD4 gene deletion, 10 with disease being modulated by the administration of peptides bearing the dominant autoreactive Th cell epitope. 11 Findings in human AIHA are also consistent with the need for T-cell help.…”

Long-term treatment of NZB mice with anti-CD4 results in wasting disease, lymphoid atrophy and chronic diarrhea

“…[20][21][22] Preliminary studies by the authors demonstrated that anti-CD4 treatment of NZB mice starting by three months of age prevents the development of anti-RBC auto-antibodies. 23 Furthermore, treatment of six-month old Coombs' positive NZB mice with anti-CD4 antibody abrogates erythrocyte autoantibodies production. During these studies, we noticed that although the anti-CD4 treatment was effective in suppressing RBC autoantibody production, the NZB mice developed a nonautoimmune-related anemia and began to lose weight.…”

“…The flow cytometry analysis was carried out as previously reported. 23 Briefly, blood samples were dispensed in 30 μL aliquots into tubes (LP3, Luckman) and washed once with PBS. Cells were incubated for 30 minutes with 10 μL anti-CD4-PE conjugate (Coulter), anti-Ly5-PE (Coulter), or a control rat MoAb IgG2b-PE, of irrelevant specificity (R-PE; Bradsure).…”

Regulatory T cells essential to prevent the loss of self-tolerance in murine models of erythrocyte-specific autoantibody responses

“…In fact, the Th-cell dependence of this response has been directly demonstrated, both in vivo and in vitro [26,27]. In actively autoimmune NZB mice, MRBC-specific AFC are found predominantly in spleen and bone marrow and rarely in the peritoneal cavity (Calkins and Esposito, unpublished results), consistent with a typical B-cell memory response.…”