Therapeutic hotline. Abatacept: our experience of use in two patients with refractory psoriasis and psoriatic arthritis.

The B7 family of molecules on antigen presenting cells (APCs) regulate T cell activation. They deliver stimulatory signals through CD28 and inhibitory signals through CD152, or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). CTLA4Ig (abatacept) is a soluble chimeric protein consisting of the extracellular domain of human CD152 linked to the modified Fc portion of human IgG1. By binding to B7-1 (CD80) and B7-2 (CD86) molecules on APCs, CTLA4Ig blocks the CD28-mediated costimulatory signal for T cell activation. Success with abatacept has been noted in psoriasis. Abatacept was administered to two patients with refractory psoriasis and psoriatic arthritis after the patients had failed all conventional treatment methods. Both patients experienced very brief improvement in disease. The improvement, however, was not continued, and both patients were taken off the medication. The small patient population limits the extrapolation of the present authors' results to the larger population. Furthermore, the present authors' patients have very severe, refractory disease and do not adequately represent the majority of psoriasis patients. Although the present authors' patients demonstrated brief response to drug, this response was not sustained. No adverse events were reported in the present authors' patients.

Increased apoptosis in cystinotic fibroblasts and renal proximal tubule epithelial cells results from cysteinylation of protein kinase Cdelta.

Cystinosis is a rare genetic disease characterized by defective lysosomal cystine transport and increased lysosomal cystine. How lysosomal cystine causes the lethal nephropathic phenotype is unknown. It was shown recently that cultured fibroblasts and renal proximal tubule epithelial cells whose lysosomes are cystine-loaded display a two-fold or greater increase in apoptosis after both intrinsic and extrinsic stimuli. The mechanism for the increased apoptosis is unknown. Protein kinase Cdelta (PKCdelta) is a proapoptotic protein kinase that has been shown in vitro to be activated via cysteinylation. This report now shows that PKCdelta forms disulfide bonds specifically with cystine that is released from lysosomes in cultured fibroblasts and renal proximal tubule epithelial cells during apoptosis. PKCdelta in cystinotic fibroblasts and renal proximal tubule epithelial cells have a four- to six-fold greater association with its substrate, lamin B, and a 2.5-fold increase in specific activity after TNF-alpha exposure. Both RNA inhibition and chemical inhibition of PKCdelta resulted in a significant decrease in apoptosis in cystinotic cells but not in normal cells. It is proposed that abnormally increased apoptosis plays a role in evolution of the cystinotic phenotype.