Key Peptides Found That Stop -- Even Reverse -- Kidney Disease In Lupus

In an article in the May 15 issue of the Journal of Immunology, Syamal Datta, M.D., the Solovy Arthritis Research Society Professor, and colleagues at Northwestern reported that brief therapy with the peptides in young, lupus-prone mice markedly delayed the onset of severe, lupus-related kidney disease. Long-term therapy with the peptides in adult mice with established kidney disease prolonged survival and even stopped progression of their disease.

Remarkably, one of the peptides, called H4 16-39, not only arrested but reversed kidney disease in the mice and allowed them to live almost a normal lifespan.

Datta's group used a special method of administering the peptides in a soluble, high-dose form -- a technique called tolerization -- to induce tolerance or inactivate disease-causing T helper cells and B cells. T helper and B cells are the mediators of the body's immune response.

Interestingly, the most effective peptide, H4 16-39, inhibited function of lupus nephritis-causing T helper and B cells because it contains molecules (epitopes) on its surface that are "recognized" by both cell types.

The normal immune system produces antibodies and T helper cells in response to invading antigens, e.g., toxins, foreign proteins or whole organisms, such as bacteria or viruses. Portions of the foreign protein molecules are recognized by the antibody receptor and the T helper cell receptor molecules on infection-fighting T and B cells. In response, B cells -- with the help of the T cells -- produce antibodies to wipe out the invaders.

Datta had earlier discovered that in lupus, specific T helper cells react to nucleosomes, a complex of DNA and histone proteins that forms a cell's nuclear material. Nucleosomes are a natural byproduct of cell death and are normally cleared by the system without causing immune response. But in lupus, the immune system "sees" nucleosomes as an antigen, causing T helper cells to drive B cells to produce antibodies against the body's own genetic material.

Datta also found that the disease-causing T helper cells and B cells of lupus have a regulatory defect in the expression of a molecule called CD40 ligand, which results in abnormal costimulatory signals that sustain production of autoantibodies. This discovery has led to another type of therapy for lupus using anti-CD40 ligand antibody.

The Northwestern investigators currently are conducting research to find peptides similar to those used in the mouse models for treating human lupus.

Datta is a professor of medicine and of microbiology-immunology at the Medical School and director of the biomedical research component of the Northwestern Multipurpose Arthritis Center. His co-investigators on this study were Arunan Kaliyaperumal, assistant research professor, and Marissa A. Michaels, also of Northwestern.