ABSTRACT
Low-dose interleukin (IL)-2 has shown clinical benefits in patients with autoimmune and inflammatory diseases. Both regulatory T cells (Tregs ) and natural killer (NK) cells are increased in response to low-dose IL-2 immunotherapy. The role of regulatory T cells in autoimmune diseases has been extensively studied; however, NK cells have not been as thoroughly explored. It has not been well reported whether the increase in NK cells is purely an epiphenomenon or carries actual benefits for patients with autoimmune diseases. We demonstrate that low-dose IL-2 expands the primary human CD56bright NK cells resulting in a contact-dependent cell cycle arrest of effector T cells (Teffs ) via retention of the cycle inhibitor p21. We further show that NK cells respond via IL-2R-ß, which has been shown to be significant for immunity by regulating T cell expansion. Moreover, we demonstrate that blocking NK receptors NKp44 and NKp46 but not NKp30 could abrogate the regulation of proliferation associated with low-dose IL-2. The increase in NK cells was also accompanied by an increase in Treg cells, which is dependent on the presence of CD56bright NK cells. These results not only heighten the importance of NK cells in low-dose IL-2 therapy but also identify key human NK targets, which may provide further insights into the therapeutic mechanisms of low-dose IL-2 in autoimmunity.
Subject(s)
CD56 Antigen/immunology , Interleukin-2/pharmacology , Killer Cells, Natural/immunology , Natural Cytotoxicity Triggering Receptor 1/immunology , Natural Cytotoxicity Triggering Receptor 2/immunology , T-Lymphocytes, Regulatory/immunology , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Humans , Interleukin-2/immunology , Killer Cells, Natural/pathology , T-Lymphocytes, Regulatory/pathologyABSTRACT
Considerable controversy has recently arisen regarding the patenting of medical and surgical processes in the United States. One such patent, viz. for a "chevron" incision used in ophthalmologic surgery, has especially occasioned heated response including a major, condemnatory ethics policy statement from the American Medical Association as well as federal legislation denying patent protection for most uses of a patented medical or surgical procedure. This article identifies and discusses the major legal, ethical and public policy considerations offered by proponents and opponents of such patents. The existing literature divides up into those who favor such patents essentially without qualification, and those who condemn and wish to outlaw them. We advance a compromise position where administrative and legislative action is called for to provide more specific guidelines regarding the patentability of such processes by the Patent and Trademark Office. Our position, in sum, will be that too much is at stake in this complicated area for either the blanket prohibition, or wholesale, uncritical acceptance, of the patenting of medical and surgical processes or techniques.
