The evolution of interferon-tau.

Thirty years ago, a novel type I interferon (IFN) was identified by molecular cloning of cDNA libraries constructed from RNA extracted from ovine and bovine pre-implantation embryos. This protein was eventually designated as IFN-tau (IFNT) to highlight its trophoblast-dependent expression. IFNT function is not immune related. Instead, it interacts with the maternal system to initiate the establishment and maintenance of pregnancy. This activity is indispensable for the continuation of pregnancy. Our review will describe how IFNT evolved from other type I IFNs to function in this new capacity. IFNT genes have only been identified in pecoran ruminants within the Artiodactyla order (e.g. cattle, sheep, goats, deer, antelope, giraffe). The ancestral IFNT gene emerged approximately 36 million years ago most likely from rearrangement and/or insertion events that combined an ancestral IFN-omega (IFNW) gene with a trophoblast-specifying promoter/enhancer. Since then, IFNT genes have duplicated, likely through conversion events, and mutations have allowed them to adapt to their new function in concert with the emergence of different species. Multiple IFNT polymorphisms have been identified in cattle, sheep and goats. These genes and gene alleles encode proteins that do not display identical antiviral, antiproliferative and antiluteolytic activities. The need for multiple IFNT genes, numerous alleles and distinct activities remains debatable, but the consensus is that this complexity in IFNT expression and biological activity must be needed to provide the best opportunity for pregnancy to be recognized by the maternal system so that gestation may continue.

Chronicling the discovery of interferon tau.

It has been 38 years since a protein, now known as interferon tau (IFNT), was discovered in ovine conceptus-conditioned culture medium. After 1979, purification and testing of native IFNT revealed its unique antiluteolyic activity to prevent the regression of corpora lutea on ovaries of nonpregnant ewes. Antiviral, antiproliferative and immunomodulatory properties of native and recombinant IFNT were demonstrated later. In addition, progesterone and IFNT were found to act cooperatively to silence expression of classical interferon stimulated genes in a cell-specific manner in ovine uterine luminal and superficial glandular epithelia. But, IFNT signaling through a STAT1/STAT2-independent pathway stimulates expression of genes, such as those for transport of glucose and amino acids, which are required for growth and development of the conceptus. Further, undefined mechanisms of action of IFNT are key to a servomechanism that allows ovine placental lactogen and placental growth hormone to affect the development of uterine glands and their expression of genes throughout gestation. IFNT also acts systemically to induce the expression of interferon stimulated genes that influence secretion of progesterone by the corpus luteum. Finally, IFNT has great potential as a therapeutic agent due to its low cytotoxicity, anti-inflammatory properties and effects to mitigate diabetes, obesity-associated syndromes and various autoimmune diseases.

The type I interferons: Basic concepts and clinical relevance in immune-mediated inflammatory diseases.

There is increasing scientific and clinical interest in elucidating the biology of type I Interferons, which began approximately 60 years ago with the concept of "viral interference", a property that reduces the ability of a virus to infect cells. Although our understanding of the multiple cellular and molecular functions of interferons has advanced significantly, much remains to be learned and type I Interferons remain an active and fascinating area of inquiry. In this review, we cover some general aspects of type I interferon genes, with emphasis on interferon-alpha, and various aspects of molecular mechanisms triggered by type I interferons and toll-like receptor signaling by the Janus activated kinase/signal transducer activation of transcription (JAK-STAT) pathway and interferon regulatory factor pathway. We will also describe the role of type I interferons in autoimmune and inflammatory diseases, and its potential use as therapeutic agent.

Interferons: the pathways of discovery. II. Immunomodulatory, in vivo and applied aspects.

This article analyzes the conceptual and technological context in which, over a period of 50 years, exploration of the biological and clinical significance of type I interferon has evolved. The elaboration of techniques for production and purification of mouse and human interferons and the establishment of laboratory-size production units have been of crucial importance in this process. Animal experiments have been invaluable for elucidation of mechanisms underlying the in vivo antiviral, anti-tumour and immunomodulatory potential of interferon, but have been of limited help to define the areas of clinical applicability. Proof of principle for applications as they are established today has come from clinical trials performed quite independently of evidence from animal experiments.

Elucidation of the basic three-dimensional structure of type I interferons and its functional and evolutionary implications.

The scientific and personal backgrounds of the crystallographic elucidation of the three-dimensional structure of murine interferon-beta (Mu-IFN-beta) are described. This structure, elucidated in 1990, is still the only experimentally determined structure for type I IFNs. Model-building studies for various type I IFNs based on the Mu-IFN-beta structure and the arguments on the receptor-binding epitopes appearing since then are reviewed. An updated set of a table and a figure demonstrating a strong correlation between the degree of amino acid sequence variation in various cytokine proteins and that in their cognate receptor proteins is given. The origin of a remarkably larger rate of evolutionary change in amino acid sequences of cytokine proteins despite their physiologic significance is discussed in view of the cytokine network and the neutral theory of evolution.

Use of interferon in the treatment of chronic myelogenous leukemia.

In a series of studies spanning 14 years, investigators from M.D. Anderson Cancer Center (Houston, TX) documented the activity of interferon-alfa (IFN-alpha) in chronic myelogenous leukemia (CML). Beginning with partially purified IFN-alpha, we demonstrated that this biologic compound has clinical activity against CML, that some malignancies are resistant to IFN-alpha, and that the effect is selective whereby the malignant clone can be restored to normalcy. These observations were confirmed by us and others when larger quantities of IFN-alpha became available through recombinant DNA technology (rIFN-alpha). In contrast with our experience with chemotherapy, myelosuppression was not required for cytogenetic remission; this dissociation may be the basis for the selectivity of IFN-alpha against CML. Recently, another group demonstrated that patients randomized to receive rIFN-alpha 2a survived longer than those treated with standard hydroxyurea chemotherapy. New tests are needed to identify the subset of patients most likely to benefit from IFN-alpha therapy and to distinguish cytogenetic responders who are truly cured from those with minimal residual disease.

The history of interferon and its use in animal therapy.

The history of the discovery and development of knowledge on interferon is reviewed in some depth. Although interferons have been considered a very exciting group of proteins for many years during which they were initially shown to have antiviral effects and lately immunomodulatory and immunoregulatory effects, attempts to use them in the therapy of animal and human disease have been disappointing. The initial problem was to obtain sufficient quantities of purified interferons for use in clinical trials. This was overcome in the 1980's by the use of biotechnological techniques which resulted in the synthesis of adequate amounts of interferons. While beneficial aspects of interferon therapy have been shown in a variety of experiments, both in animals and humans, the great potential for interferon treatment has yet to be achieved. In the body, interferon is produced in such small quantities as compared to the large quantities which have been normally used in therapy and it is well recognized that these proteins, the interferons, are particularly potent. A small group of scientists working from biological principles, originating from U.S.A. and are now being developed in Kenya, have found powerful beneficial effects when relatively low dose of IFN-alpha is applied orally to animals and humans, particularly for the treatment of AIDS and East Coast fever. It is now known that interferons are only a part of the cytokine network and indirect and direct effects of interferon can occur on cells to change their behaviour. Many of these effects are non-specific and have a general effect on the course of diseases which, hopefully, can be translated into effective broad spectrum therapy, for man and animals.