Abraham White

Is the Thymus an Endocrine Gland?: Old Problem, New Data

It seems appropriate in a volume honoring Dr. Gregory Pincus, a distinguished endocrinologist, to have a contribution that will consider briefly the history of a gland studied by pioneers in experimental physiology and medicine and to indicate more recent developments which not only have attracted renewed attention to this anatomical structure but suggest it should be added to the established list of endocrine glands. It is the purpose of this essay to examine some of the evidence for a possible role ofthe thymus as an endocrine organ. This will be approached by assessing the extent to which studies of the thymus have provided data confirming the postulates generally agreed necessary to establish that a given anatomical structure is an endocrine organ. These data are generally sought in the following experimental stages: (i) extirpation of the tissue or organ with subsequent evidence ofphysiological or biochemical alterations and deficiencies; (2) replacement therapy, that is, efforts to replace the extirpated structure by transplantation of the organ and by administration of suitable extracts of the removed tissue; (3) administration of excessive amounts of an extract of the gland to normal animals in order to study alterations which may result from an exaggerated supply of the

The thymus as an endocrine gland: properties of thymosin, a new thymus hormone.

Publisher Summary This chapter discusses recently assembled evidence that unequivocally establishes a role of major significance for the thymus in both the development and the maturation of the lymphoid system. It presents evidence in support of the thesis that this influence of thymus on the lymphoid system is endocrine in nature and that the thymus gland should be added to the established list of endocrine organs. The chapter focuses primarily on modern concepts of the thymus as an endocrine gland, including effects of extirpation of the thymus, and studies of replacement therapy, the chemistry of thymic fractions, and the biological effects of thymic fractions, both in normal and thymectomized animals. The initial assessment of lymphocytopoietic activity has been based upon an assay developed utilizing adult CBA/W mice. The mechanism by which thymus exerts its endocrine role and the number of hormones secreted by the thymus are in early stages of exploration.

The Thymus Gland: Experimental and Clinical Studies of Its Role in the Development and Expression of Immune Functions

Publisher Summary The mechanism by which the thymus gland exerts its vital influence over the lymphoid system is, at present, largely formulated by hypotheses that are based on rapidly accumulating experimental data. The most primitive vertebrate to possess a thymus-like structure is the lamprey. In most mammals, the thymus is similar to the gland of lower vertebrates. The thymus gland exerts a cardinal role in the regulation of the development and expression of host immunological competence, notably phenomena reflecting cell-mediated immunity. The thymus exerts its regulatory influences by at least two mechanisms: (1) secretion of thymosin, a thymic humoral principle, and (2) functioning as a primary site for the production of classes of lymphoid cells which contribute to host immunity. The increased interest in experimental and clinical studies of the thymus provide a clearer understanding of the chemical nature of thymic secretions and of the processes basic to the contributions of the thymus to normal and pathological states.

Effects of glucocorticoids on thymocytes in vitro.

Abstract 1. Exposure of thymocytes to cortisol in vivo or in vitro resulted in the following metabolic alterations in these cells, incubated in vitro. (a) Inhibition of RNA, DNA and protein synthesis. (b) Decreased transport of nucleic acid and protein precursors into the cells. These two effects were apparently dissociable. 2. The inhibitory effects of cortisol were manifest only in the presence of an energy source in the medium and required intact cellular protein and nucleic acid synthetic capacities. 3. Good correlation was obtained between the relative in vitro potencies of various steroids in inhibiting uridine incorporation by thymocytes into an acid-insoluble form and their known thymolytic potency in vivo. 4. Progesterone, while not influencing precursor incorporation by thymocytes in vitro, appeared to inhibit competitively the action of cortisol.

Effects of an Antiserum to Calf Thymosin on Lymphoid Cells in Vitro

Summary A lymphocytopoietic fraction of calf thymic tissue, thymosin, has been utilized to prepare an antiserum in rabbits. The antiserum contained antibodies to at least two of the several components of the thymosin fraction. One of these precipitable antibodies was shown to be specific for a constituent of the thymosin preparation; the other was directed to bovine serum albumin. The antithymosin serum, after removal of antibody to BSA, was markedly cytotoxic to thymus cells but not to lymph node or spleen cells from calves, mice, and rabbits. The antithymosin serum agglutinated thymus cells of calves and cross-reacted with thymus cells of mice and rabbits. These activities of the antiserum to thymosin were not due to a Forssman antigen. The results support the concept of an antigenic difference between thymocytes and lymph node cells and provide evidence for the presence of a cellfree, soluble thymic antigen in thymosin.

Decreased activity of a soluble DNA-dependent RNA polymerase from thymus of rats injected with a thymolytic steroid

Abstract The Mg 2+ - and Mn 2+ - catalyzed DNA-dependent RNA polymerase activity of rat thymic nuclei has been solubilized by three procedures. The soluble preparation required addition of DNA for activity, indicating that endogenous DNA had been separated from the enzyme. Enzymatic activity solubilized from thymocytes of rats injected with either cortisol or fluocinolone acetonide 3 hr prior to sacrifice was significantly lower than that from cells of control rats. This decreased DNA-dependent RNA polymerase activity is due, at least in part, to an alteration in the enzymatic component of the DNA-RNA polymerase complex.

Role of Thymosin and other Thymic Factors in the Development, Maturation, and Functions of Lymphoid Tissue*

Publisher Summary This chapter discusses the role of thymosin and other thymic factors in the development, maturation, and functions of lymphoid tissue. The thymus is the central organ in regulating the development and expression of cell-mediated immunity and general host resistance. The present evidence supports the concept that the thymus functions as both a donor of cell to the peripheral lymphoid system and by the production and secretion of one or more humoral factors. The mechanism by which the thymus exerts this apparent endocrine role and the number of hormones secreted by the thymus is in the early stages of exploration. The responses to partially purified thymic fractions of those functions of lymphoid tissue which are fundamental to host immunological competence suggests that several of the diverse crude thymic fractions may contain a single biologically active substance similar to or identical with thymosin. It is also established that the thymus is a major source of lymphocytes for the peripheral lymphoid tissues and circulation. Thus, the thymus exerts a dual function, namely, as an endocrine gland and as a progenitor of lymphoid cells.

DEVELOPMENT OF A NEW MEDICAL SCHOOL: PAST EXPERIENCES AND CONSIDERATIONS FOR THE FUTURE

This presentation can properly begin by paraphrasing both a preamble appearing at the beginning of most movies and a footnote sometimes found on the first page of papers published by government employees. One of these introductory comments would be as follows: “Any resemblance of the remarks that follow to individuals living or dead, or to past events, may be considered to be purely accidental, but perhaps not wholly unintended.” The second introductory comment would be: “The opinions expressed in this paper are solely those of the author and not the responsibility of the administrations, faculties, or student bodies of medical schools in which the author has functioned or is presently functioning.” The material that has been assembled for this paper represents a preliminary attempt to begin to assess information, experiences, and impressions derived, and generally recorded, during the past thirty years of activity as a member of medical school faculties, including the administrative level. If what follows Seems overly autobiographical and subjective, it is due in part to my attempt to present a background for that portion of this paper subtitled: “Considerations for the Future.” This latter section stems not only from my own experience, but is obviously greatly influenced by the writings of many others, as well as by numerous discussions with colleagues, with faculty members of other medical schools and by participation in several of the Institutes sponsored by the Association of American Medical Colleges. I also wish particularly to acknowledge the stimulation and influence provided me over the course of a number of years by Drs. Lester J. Evans, Allan Gregg, Henry Siegerist and Milton C. Winternitz. It should also be noted that certain of the criticisms implied in what follows are often not directed toward individuals and what they did, or did not, accomplish, but are frequently a reflection of factors beyond the control of the individuals concerned. One cannot have had the unusual opportunity to particibate in the development of two new medical schools without being exposed to a wide spectrum of experiences. These provide the background for this presentation, supplemented by a period of fifteen years as a member of the faculty of the Yale University School of Medicine, including functioning for four years during that period as Chairman of the Curriculum Committee. In the case of the mentioned two new medical schools, namely, the University of California School of Medicine at Los Angeles and the Albert Einstein College of Medicine of Yeshiva University, it was my good fortune to have been present during all phases of the planning and programming of the initial years. At Los Angeles, my appointment as Chairman of the Department of Physiological Chemistry came at a time when, in addition to the Dean, only three other chairmen had been selected. At the Albert Einstein College of Medicine, my appointment as Professor and Chairman of the Department of Biochemistry and Associate Dean was the first to be made to the faculty of the then unnamed, new medical school. In the first nine manths of this activity, I was associated with Dr. Harry Zimmerman, Acting Director of the new medical school, on leave of absence from Monteflore Hospital. Eighteen

Reaction of cortisol and cortisol 21-aldehyde with pyridoxamine.

Abstract A yellow product was isolated when pyridoxamine was heated with cupric ions and cortisol or other 17-hydroxy- or 17-deoxyketol steroids. Oxygen was necessary for the reaction. Copper, which could not be replaced by other metal ions, oxidized the 21-alcohol function of cortisol to the 21-aldehyde. When cortisol 21-aldehyde was substituted for cortisol, an identical product was formed in the absence of oxygen at room temperature. The yellow product contained one pyridoxylidine and two steroid residues, and copper. Pyridoxal and ammonia did not substitute for pyridoxamine. Primary amino groups and 21-aldehyde function were absent from the product. In the absence of metal ions, cortisol 21-aldehyde and pyridoxamine condensed to form a yellow product containing two steroid and one pyridoxylidine residues. One mole of steroid is bound to pyridoxamine as a Schiff base; a second mole is linked as a hemiacetal to the hydroxymethyl group of pyridoxamine. This compound chelated reversibly with cupric ions to yield one resembling that prepared in the presence of copper salts.

Inhibition of the Lymphopenic Effect of Cortisol by Puromycin Injection in Mice.

Summary In acute experiments, administration of puromycin to adrenalectomized or intact mice inhibited the lymphopenic action of cortisol, whereas injection of 6-dimethylaminopurine, a puromycin analogue, did not prevent this response to cortisol. It is suggested that protein synthesis is an essential preliminary or accompanying process for the manifestation of the lymphopenic activity of glucocorticoids.