Search

An adult male underwent a bowel transplant for tufting enteropathy, receiving alemtuzumab, tacrolimus, and steroids as immunosuppressants. Five years later, he developed an autoimmune hemolytic anemia (AIHA), anti-IgG positive, with reduced reticulocyte count, leukopenia, and thrombocytopenia with antiplatelet antibodies. After an unsuccessful initial treatment with high dose steroids, reduction in tacrolimus dose, and intravenous immunoglobulin (IVIG), a bone marrow biopsy revealed absence of erythroid maturation with precursor hyperplasia. The patient was switched to sirolimus and received four doses of rituximab plus two courses of plasmapheresis, which decreased his transfusion requirements. After a febrile episode one month later, the AIHA relapsed with corresponding decreases in platelet and leukocyte count: cyclosporine A (CsA) was started with a second course of rituximab and IVIG without response, even though repeat bone marrow biopsy did not reveal morphology correlated to an acquired pure red cell aplasia (APRCA). Considering the similarity in his clinical and laboratory findings to APRCA, alemtuzumab was added (three doses over a week) with CsA followed by steroids. The patient was eventually discharged transfusion-independent, with increasing hemoglobin (Hb) levels and normal platelet and leukocyte count. One year later he is still disease-free with functioning graft.

Cyclosporine A is an immunosuppressive agent that is used clinically in the prevention of transplant rejection and development of graft-versus-host disease. Recently, cyclosporine A has been shown to possess anti-inflammatory properties and is capable of inhibiting lipopolysaccharide-induced NF-kappaB activation. Ubiquitin-mediated proteasomal proteolysis plays a critical role in signal-induced NF-kappaB activation since it regulates both IkappaB degradation and p105 processing, it is also involved in the production of peptides for the assembly of MHC class I molecules. We report here that cylcosporine A acts as an uncompetitive inhibitor of the chymotrypsin-like activity of the 20S proteasome in vitro and that it suppresses lipopolysaccharide-induced IkappaB degradation and p105 processing in vivo demonstrating that inhibition of proteasome proteolysis is the mechanism by which cyclosporine A prevents NF-kappaB activation. A structurally unrelated immunosuppressant, rapamycin, did not inhibit the 20S proteasome in vitro.

Primary Sjögren's syndrome (pSS) is a common autoimmune disease involving abnormal Th17 activation. The aim of the current study was to investigate the immunosuppression effect of Cyclosporine A (Cys A), a potent immunosuppressor on the proliferation and activation of T cells, on the activation of Th17 cells. Blood samples from both inactive and active pSS patients as well as healthy controls were collected and serum and peripheral blood mononuclear cells (PBMCs) were collected and tested for IL-17 and RORγt expression. Subsequently, PBMCs were treated in vitro with Cys A in a series of doses and incubation time and the effect of Cys A on inhibiting Th17 activation was tested by measuring IL-17 and RORγt expression. IL-17 in both serum and PBMCs as well as RORγt in PBMCs from active pSS patients were significantly elevated on both the mRNA and protein levels comparing to those from both inactive pSS patients and healthy controlCys A in the final concentration of 80ng/ml and the treatment time of 24h showed strong inhibition effect on the expression of IL-17 and RORγt in PBMCs from active pSS patients. However, Cys A in various doses and incubation times did not show much impact on inhibiting IL-17 as well as RORγt expression in PBMCs from healthy donors and inactive pSS patients. Cys A possesses the capability in immunosuppressing the activation of Th17 cells, suggesting that Cys A may be a potential treatment for pSS and maybe other autoimmune diseases.