Background and Aims

Self-specific B and T cells play a main role in pathogenesis of Systemic lupus erythematosus (SLE) and are a logical target for selective therapy. The complement receptor type 1 (CR1) on human B-lymphocytes has suppressive activity and engagement of this receptor inhibits B cell activation.

The protein Annexin A1 (Anx A1), is a modulator of the immune system and abnormal expression was found on activated B and T cells during human autoimmunity.

We hypothesize that it may be possible to down-modulate the activity of autoreactive T and B cells from SLE patients in humanized NOD/SCID model by treating them with a neutralizing antibody against Anx A1 or by protein engineered molecules, which co-crosslink the BCR and CR1.

Methods

Protein chimeric molecules construction, Immunodeficient NOD/SCID mice transfer with human PBMC from SLE patients, ELISA for dsDNA antibodies and cytokines, flow cytometry for apoptosis and activation markers, ELISpot and MTT assays, protein array.

Results

Reconstituted NOD/SCID mice showed presence of several auto-antibodies, proteinuria, as well as immunoglobulin deposition in the renal glomeruli. Treatment of the transferred NOD/SCID mice either with DNA-like chimera and anti-Anx A1 antibody prevented appearance of anti-DNA antibodies and proteinuria, while the PBS-injected animals had high levels after the transfer. The treatment reduced the levels of disease-associated cytokines also.

Conclusions

It is possible to down-regulate the activity of pathogenic human T and B cells in humanized NOD/SCID mouse model of SLE by targeting Anx A1 or CR1 with a specific monoclonal antibody or chimeric molecule.