One recently introduced drug manipulates immune responses by regulating the migration of immune effector cells to the sites of a graft or of autoimmune disease. In Section 9-7, we described how emigration of lymphocytes out of the lymphoid tissues requires recognition of the lipid molecule sphingosine 1-phosphate (S1P) by the G-protein-coupled receptor S1PR1. Fingolimod (FTY720), a sphingosine 1-phosphate analog, is a relatively newer drug that causes the retention of effector lymphocytes in lymphoid organs, thus preventing these cells from mediating their effector activities in target tissues. Fingolimod was approved in 2010 for treatment of the autoimmune disease multiple sclerosis, and has shown promise in the treatment of kidney graft rejection and asthma.
Cytokines activate many aspects of the immune response, and many cytokine receptors use Janus kinases (JAKs) in signal transduction (see Section 3-16). The four JAK family members, JAK1, JAK2, JAK3, and TYK2, bind and phosphorylate the cytoplasmic regions of cytokine receptors and initiate the activation of different STAT transcription factors. Selective JAK inhibitors have been developed over the last decade that can block the kinase activity of one or more members of this family. Since different JAKs binds to different cytokine receptors, JAK inhibitors, or Jakinibs, can therefore exert potentially specific effects on the quality of T-cell development. Two Jakinibs are now approved for use in treating inflammatory diseases and are being investigated for their application in cancer. For example, tofacitinib inhibits JAK3, interfering with signaling by IL-2 and IL-4, and somewhat more weakly JAK1, interfering with signaling by IL-6. Tofacitinib is approved for treatment of rheumatoid arthritis. Ruxolitinib inhibits JAK1 and JAK2 and has been approved for treating myelofibrosis, an abnormal proliferation of bone marrow progenitor cells that causes fibrosis.
used to eliminate lymphocyte subsets or to inhibit lymphocyte function.
All the drugs discussed so far exert a general inhibition on immune responses and can have severe side effects, but antibodies can act in a more specific manner and with less direct toxicity. The initial therapeutic use of antibodies extends back to the late 1800s with the development of equine sera for treatment of diphtheria and tetanus. Today, intravenous immunoglobulin (IVIG), a collection of polyvalent IgG antibodies pooled from many blood donors, is still widely used as a treatment for various primary and acquired immune deficiencies. It is also used in some acute infections, where it likely works by providing antibodies that may neutralize certain pathogens or their toxins. Finally, IVIG is also used to treat certain autoimmune and inflammatory diseases, such as immune thrombocytopenia and Kawasaki disease. In these cases, IVIG exerts an immunomodulatory effect that seems to operate through interactions with inhibitory Fc receptors that inhibit immune-cell activation.