This invention relates generally to a novel method for regulating the appetite of warm-blooded vertebrates. More particularly, this invention concerns the use of interferon isolates to modulate the appetite and increase the efficiency of food utilization for animals such as cattle, swine, and chickens.
"Interferon" is a term generically comprehending a group of vertebrate glycoproteins and proteins which are known to have various biological activities, such as antiviral, antiproliferative, and immunomodulatory activity in the species of animal from which such substances are derived. The following definition for interferon has been accepted by an international committee assembled to devise a system for the orderly nomenclature of interferons: "To qualify as an interferon a factor must be a protein which exerts virus nonspecific, antiviral activity at least in homologous cells through cellular metabolic processes involving synthesis of both RNA and protein." Journal of Interferon Research, 1, pp. vi (1980).
Since the first descriptions of interferon by Isaacs and Lindeman [See, Proc. Roy. Soc. London (Ser.B), Vol. 147, pp. 258 et seq. (1957) and U.S. Pat. No. 3,699,222], interferon has been the subject of intensive research on a worldwide basis. Publications abound concerning the synthesis of interferon, its proposed molecular characterizations, its clinical applications, and proposed mechanisms of its antitumor, antiviral, and immune system activities. See, for example, DeMaeyer, et al., "Interferons" appearing as Chapter 5 in Comparative Virology, Vol. 15, pp. 205-284, Plenum Press, N.Y., N.Y. (1979); Cantrell, "Why Is Interferon Not In Clinical Use Today" appearing in Interferon 1979, I. Gresser, ed., Vol. 1, pp. 1-28, Academic Press, London (1979); Stewart, "The Interferon System" Springer-Verlag, N.Y., N.Y. (1979); and Dunnick, et al., "Clinical Trials with Exogenous Interferon", J. Infect. Diseases, 139, No. 1, pp. 109-123 (1979).
Because of the intensity and disparate origins of research concerning interferon and its characteristics and uses, there exists a substantial lack of uniformity in such matters as classification of interferon types. There are also numerous, sometimes contradictory, theories concerning the mode of action of interferon in producing clinical effects. The following brief summary of the current state of knowledge regarding interferon will aid in understanding the present invention.
Although originally isolated from cells of avian origin (chick allantoic cells), interferon production has been observed in cells of all classes of vertebrates, including mammals, amphibians, and reptiles. Interferon production by vertebrate cells is seldom spontaneous but is often readily "induced" by treatment of cells (in vivo or in vitro) with a variety of substances including viruses, nucleic acids (including those of viral origin as well as synthetic polynucleotides), lipopolysaccharides, and various antigens and mitogens.
Interferon have generally been named in terms of the species of animal cells producing the substance (e.g., human, murine, or bovine), the type of cell involved (e.g., leukocyte, lymphoblastoid, fibroblast) and, occassionally, the type of inducing material responsible for interferon production (e.g., virus, immune). Interferon has been loosely classified by some researchers according to induction mode as either Type I or Type II, with the former classification comprehending viral and nucleic acid induced interferon and the latter class including the material produced as a lymphokine through induction by antigens and mitogens. More recently, the international committee devising an orderly nomenclature system for intereferon has classified interferon into types on the basis of antigenic specificities. In this newer classification, the designations alpha (.alpha.), beta (.beta.), and gamma (.gamma.) have been used to correspond to previous designations of leukocyts, fibroblast, and type II (immune) interferons, respectively. Alpha and beta interferons are usually acid-stable and correspond to what have been called type I interferons; gamma intereferons are usually acid-labile and correspond to what has been called type II intereferons. The international committee's nomenclature recommendations apply only to human and murine interferons. Journal of Interferon Research, 1, pp. vi (1980). Therefore, the interferon employed herein is identified simply by animal species and type of cell producing the intereferon, e.g. bovine fibroblast interferon.
Determination of precise molecular structures for interferon was for some time beyond the capacities of the art. In the years since interferon was first characterized as proteinaceous on grounds of its inactivation by trypsin, attempts to purify and uniquely characterize it have been frustrated by its high specific activity as well as its apparent heterogeneity. Presently, some precision in determining molecular structure has been achieved for interferon derived from a single cell type and using a single specific inducer, e.g., human alpha interferon.
In its earliest applications, interferon was employed exclusively as an antiviral agent and the most successful clinical therapeutic applications to date have been in the treatment of viral or virus-related disease states. It became apparent, however, that exogenous interferon was sometimes capable of effecting regression or remission of various metastatic diseases. A summary of clinical trials of interferon as an antiviral and antiproliferative therapeutic agent through late 1978 is contained in Dunnick, et al. supra.
The clinical agent of choice in this work has been human leukocyte interferon, "mass-produced" by procedures involving collection and purification of vast quantities of human buffy cost leukocytes, induction with virus, and isolation from culture media. The need for interferon of human source is, of course, consistent with the long-standing conclusion that interferon is "species specific", i.e., biologically active, in vivo, only in species homologous to the source cells.
In the work described above, interferon has been administered parenterally, i.e., intramuscularly and intradermally, with some successful topical usages having been reported. It has seldom been administered intravenously because of substantial adverse effects attributable to "contaminants" in crude and even highly purified isolates. Prior to applicant's invention described in U.S. patent application, Ser. No. 180,464, filed Aug. 22, 1980, and in PCT International Application No. PCT/US 81/01103, filed Aug. 18, 1981, published Mar. 4, 1982, the disclosures of which are hereby incorporated by reference, there had been no reports of therapeutically successful oral administration of interferon. This circumstance was consistent with the widely held belief that interferon would not withstand exposure to a digestive environment such as that found in mammals.
In addition to use in antiviral and antitumor therapy, interferon has rather recently been noted to possess immunomodulatory effects, both immunopotentiating and immunosuppressive in nature. See, e.g., Sonnenfeld, et al., "A Regulatory Role For Interferon In Immunity", Annals, N.Y. Acad. Sci., Vol. 322, pp. 345-355 (1979). While no human clinical or in vivo animal work specifically directed to evaluation of immunological effects of interferon has been reported, it is proposed by some that the antitumor effects of interferon are at least in part related to immune stimulation or activation of so-called "natural killer cells," macrophages and T-lymphocytes. See, e.g., Kershner, "New Directions in Cancer Chemotherapty" A.S.M.News, Vol. 46, No. 3, pp. 102 et seq. (1980).
Further, "new" biological activities for exogenous interferon are consistently being ascertained. Cantrell, et al., New Eng. Jour. Med., Vol. 302, No. 18, P. 1032 (1980) report an effect of interferon in transiently diminishing high density lipoprotein levels and total cholesterol values, suggesting that interferon in humans, may influence cardiovascular disease.
Prior to applicant's invention described and claimed in the present application, there had been no reports of any biological activity of any form of interferon with a direct impact upon the appetite or efficiency of food utilization in vertebrates. Insofar as the possibility of using interferon to stimulate appetite is concerned, interferon has been considered in the art as possessing the opposite effect. It has been reported in the literature that human patients receiving interferon cancer therapy experience a loss of appetite as a side effect of such therapy. Marx, Science 210, p. 998 (1980); Journal of Infectious Diseases, 139, pp. 109-25 (1979). This suppression of appetite has been one of a number of side effects, such as lower white blood cell counts, nausea, fever, and hair loss, experienced by humans in clinical trials of interferon. Further, the prior art literature has not reported any effect of interferon upon appetite in nonhuman species.
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