Publisher Summary The recognition of the existence of natural cell-mediated immunity, particularly natural cell-mediated cytotoxicity, has significantly altered the concepts concerning the potential mechanisms for in vivo resistance against tumor growth and for in vitro cell-mediated immune reactions. When cytotoxic reactions are measured, the evaluation of the role of natural killer (NK) cells and other more well-known mechanisms of cytotoxicity must be done carefully. This chapter focuses on natural cell-mediated cytotoxicity. It summarizes the known information on the expression of natural cytotoxicity in rodents and in man, its specificity, the nature of the effector cells and their relationship to other immune mechanisms, and the possible in vivo relevance of natural cytotoxicity, particularly in regard to resistance against tumor growth. The basic observation that initiated the studies of natural cell mediated cytotoxicity includes that lymphoid cells from some normal mice, rats, and human donors, which are not inoculated with tumor cells or other sources of antigen, exhibit significant levels of cytotoxic reactivity against certain syngeneic or allogeneic tumor cells.

Natural Cell-Mediated Immunity

A polypeptide of 8500 molecular weight is described that induces the differentiation of T (thymus-derived) cell and B (bone-marrow-derived) cell immunocytes in vitro, apparently via beta-adrenergic receptors and adenylate cyclase activation. This polypeptide shows a high degree of evolutionary conservation, exhibiting close structural, functional, and immunological similarity when isolated from such diverse origins as cells of mammals and higher plants. This polypeptide was detected in animal cells, yeast, bacteria, and higher plants, and so may well be a universal constituent of living cells.

http://www.pnas.org/content/72/1/11.full.pdf

Isolation of a polypeptide that has lymphocyte-differentiating properties and is probably represented universally in living cells

Publisher Summary This chapter discusses the nature of endotoxins and their interactions with cells of the immune system. The direct interaction of endotoxin with B lymphocytes leading to the formation of antibodies to endotoxin as well as a spectrum of other immunoglobulin molecules is discussed. In addition, the interactions of endotoxins with T cells and macrophages and the associated immunoregulatory effects are discussed. The central role of the lipid A portion of the endotoxin molecule in cellular activation and the molecular events occurring at the cell surface in the course of stimulation are presented. The potential of endotoxins as therapeutic manipulators of the immune response in man is also evaluated. Major direct interactions of endotoxins with B lymphocytes have been documented, leading to synthesis and secretion of antibody directed not only against antigenic determinants on the endotoxin molecules themselves, but also with specificities characteristic of the complete repertoire of variable region gene products. Knowledge of the immunobiology of endotoxins has prompted investigations in their therapeutic uses in man as both antigenically distinct and cross-reactive immunogens in protection against gram-negative infections.

Bacterial endotoxins and host immune responses

Immunity to intracellular bacteria.

Ubiquitin is the ATP-dependent proteolysis factor I of rabbit reticulocytes.

Major advances in our understanding of the role of the thymus gland and its endocrine secretions in the ontogenesis and homeostasis of the lymphoid system and in the mechanisms of immunological surveillance have been made in the past decade. The physiological consequences of experimental thymectomy in animals or the failure of the thymus to develop normally in man have demonstrated that this organ has an important influence on organ and tissue

Purification and properties of bovine thymosin.

Summary of Experiments Showing Generation of T Cells from Precursor Cells under the Influence of Thymic and Nonthymlc Agents Material tested for inducer activity Criterion of T cell induction Source Mouse thymus Mouse spleen Description* Expression of TL or Thy-1 antigen Fr 2 (KK) Fr 2 (KK) Medium II: in I: in vitro~ nu/nu mice§ Induced cells % 20 <10 20,40 Mouse thymus Calf thymus Calf thymus Calf thymus Calf thymus Calf spleen Calf muscle Rat thymus Chicken thymus Human thymus Fr 3 Fr 2 Ft 3 5 6 Ft 3 Fr 3 Ft 2 Fr 2 Ft 3 20-23 <10 <10 m Calf thymus¶ (AG) 40-45 (KK) 20-25 (AG) 40-45 (AG) 25-30 (AG) 18-22 (AG) 40-45 (AG) 40-45 (KK) 20-25 (KK) 25-30 (AG) 25-30 20 25 20-25 15-19 < 10, < l0 25 10 30 <10 Appearance of helper effect in vitroll cAMP DB-cAMP Poly A:U Endotoxin BSA, Medium Ft 2 (KK) + Aminophylline Fr 2 (KK) + Insulin Fr 2 (KK) + Medium PFC/culture 5th exp 24 ~10 Because of space limitations, details of materials and methods can be indicated for the most part only by key references to where full descriptions can be found * Fr = fraction (KK) = fraction prepared by Dr K Komuro according to Goldstein

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Differentiation of t cells induced by preparations from thymus and by nonthymic agents : the determined state of the precursor cell

A modified purification procedure has been developed for bovine thymosin, and chemical characterization studies have been initiated. Amino acid analyses of acid hydrolysates reveal that thymosin fraction 8 contains approximately 108 residues of which half are aspartic and glutamic acid. The molecule contains one histidine, one cysteine, one tyrosine, and no tryptophan. Nucleotides are completely absent. From the composition and from electrophoretic studies using SDS-polyacrylamide gels, fraction 8 has an estimated molecular weight of 12,200. Preliminary studies suggest the presence of subunits. Partially purified thymosine (fraction 5) contains several heat-stable acidic proteins with molecular weights that range from 1,200 to 14,000. It is not yet known whether all of the biological activity ascribed to thymosin fraction 5 resides within a single molecular species (fraction 8) or whether multiple thymic factors must act in concert to endow the host with its normal complement of immunity. The low specific activity of thymosin fraction 8 in some of the bioassays could reflect the removal of one or more active components that must be present for full expression of biological activity. Other studies using a radioimmunoassay and a rosette bioassay indicate that thymosin is present in the blood of animals and man and thatmore » thymosin levels are altered in patients with known (or suspected) immunodeficiency disease and with age.« less

John A. Hooper

Papers

Purification and properties of bovine thymosin.

Differentiation of t cells induced by preparations from thymus and by nonthymic agents : the determined state of the precursor cell

Thymosin-induced differentiation of murine thymocytes in allogeneic mixed lymphocyte cultures.

Thymosin and the immunopathology of aging.

The role of thymosin and the endocrine thymus on the ontogenesis and function of t-cells*