A - Human Necessities – 61 – K
Patent
A - Human Necessities
61
K
A61K 35/14 (2006.01) C12N 5/08 (2006.01) C12N 5/12 (2006.01)
Patent
CA 2446391
Naturally occurring CD4+CD25+T regulatory cells (Treg) activily participate to the mechanisms of peripheral tolerance by negatively regulating autoimmunity. However, the molecular mechanisms of in vivo induction of T reg remain largely unknown. Regulatory T cells (Tr1) can be generated in vitro from human naive T cells by repetitive stimulation with immature or IL-10-treated DC. We previously reported that CD47 ligation by either CD47 mAb or a peptide of its natural ligand, i.c thrombospondin, induced naïve T cell anergy. Herein, we demonstrate that the CD47 mAb- induced anergic T cells were actively suppressing the proliferation and cytokine production of syngeneic effector T cells. T anergic/suppressors cells (Tas) produced little or no cytokine. The suppressive function required physical contact with the responder T cells and was IL-10 and TGF-.beta. independent. Tas displayed :1) increased expression of CTLA-4, OX40 and GITR; 2) decreased levels of CD40L and CD28 and 3) similar levels of FAS, FASL, CCR4 and CCR7 and CD25 compared to effector T cells. Both CD4+ and CD8+Tas suppressed effector T cells proliferation and none of them regulated DC maturation. Our findings demonstrate that ligation of an endogenous receptor, i.e CD47, on naive cells generates a distinct type of regulatory T cells (Tas) which produce no IL-10 but share phenotypic and functional features with both Treg and Tr1 described in human and mice. TAS may be re- infused to patients suffering from a large variety of chronic inflammatory diseases, graft versus host disease, graft rejection and allergic diseases. Compounds inducing in vivo the activity of TAS may be used to treat the same patients.
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