Rheumatoid Arthritis: Cohen Y

Cohen Y, Nagler A. · Departments of Hematology and Bone Marrow Transplantation, Chaim Sheba Medical Center, Tel Hashomer, Ramat-Gan 52621, Israel. · Autoimmun Rev. · Pubmed #15003184 No free full text.

Abstract: Immunological manipulations are the basis of modern therapy for refractory autoimmune diseases (AID). Ablative chemotherapy with stem cell support (autotransplant) as well as targeted immunotherapy using specific monoclonal antibodies, such as rituximab and campath 1-H have become acceptable second line therapy for severe refractory AID. Until now, more than 500 autotransplants have been performed worldwide for various autoimmune disorders, including multiple sclerosis (MS), systemic sclerosis (SSc), systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA) with encouraging results, although transplant related mortality (TRM) in the range between 2 and 17% still remains one of the major limitations of the procedure. Immunotherapy is a relatively safe approach associating with sustained remissions in a considerable proportion of treated patients. Better selection of patients and earlier immunotherapy, preceded an irreversible organ damage might further improve the clinical outcome of patients with AID.

Cohen Y, Polliack A, Nagler A. · Department of Hematology, Chaim Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel. · Curr Pharm Des. · Pubmed #12570832 No free full text.

Abstract: Immunological manipulations are the basis for modern treatments of autoimmune diseases (AID). Targeted immune suppression with lymphopenic based chemotherapy, and monoclonal anti B or T lymphocytic antibodies, are integral part of the conditioning for stem cell transplantation (SCT). Immune manipulation by Cyclophosphamide (Cy), ATG, Campath and recently rituximab (RI), with or without stem cell support are the basis for emerging therapeutic modalities aiming to eradicate the autoreactive clone in various autoimmune disorders. Couple of hundreds of SCTs have been recently performed in various autoimmune disorders, mainly multiple sclerosis (MS), progressive systemic sclerosis (PSS), systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA). Preliminary results are encouraging. Better selection of patients and earlier treatment, before irreversible organ failure develops will probably improve results. Current ongoing multicenter studies are evaluating the role of SCT in MS, RA, SLE, and PSS.

Nagar M, Vernitsky H, Cohen Y, Dominissini D, Berkun Y, Rechavi G, Amariglio N, Goldstein I. · Sheba Cancer Research Center, The Chaim Sheba Medical Center, Tel Hashomer and Tel Aviv University-Sackler Faculty of Medicine, Israel. · Int Immunol. · Pubmed #18567616 No free full text.

Abstract: The transcription factor forkhead box P3 (FOXP3 in humans; Foxp3 in mice) controls the development and function of regulatory T cells (Treg). In mice, CD4(+)CD25(-) T cells do not express Foxp3 following TCR activation. Whether FOXP3 is a common activation-induced molecule in human T cells--hence not Treg restricted--is currently a controversial issue. As FOXP3 can significantly modulate the function of T cells, understanding the mode (and regulation) of FOXP3 expression in human T cells is vital. Here we show that in conventional CD4(+)CD25(-) T cells, the induction of FOXP3 expression following TCR activation is both restricted to a fraction of the progeny and transient. Moreover, FOXP3 expression in vivo is particularly infrequent in activated effector CD4(+) T cells that accumulate within inflamed joints. We next demonstrate that the repression of FOXP3 transcription in resting conventional human CD25(-) T cells is linked to complete methylation of an evolutionarily conserved intronic CpG island. The dense methylation pattern is furthermore inherited after activation by progeny. This intronic CpG island, on the other hand, is frequently unmethylated in CD4(+)CD25(+) T cells. Importantly, blocking maintenance DNA methylation, by pharmacological inhibition of DNA methyltransferase-1, induced significant and stable activation-dependent FOXP3 expression in cycling conventional T cells, which was further amplified by co-treatment with transforming growth factor beta. In contrast to natural Treg, such induced CD4(+)FOXP3(+) T cells could produce pro-inflammatory cytokines upon activation. These results indicate that DNA methylation normally restricts FOXP3 transcription in conventional human T cells.