Richard T. Smith

Immunological Tolerance of Nonliving Antigens

Publisher Summary This chapter focuses on immunological tolerance of nonliving antigens, describes various individual experimental models depending on the mode of induction, including tolerance induced by exposure in prenatal period of life and tolerance induction in mature animals, analyzes the various experimental models, and presents the common features of each model. It is demonstrated that certain features of the various models are consistent for different antigens within the species, for the same antigen in most species studied, and to a lesser extent, for the tolerant state in general. General consistencies justifying an assumption of similar mechanisms are examined. Comparison of the features of the models in which the response to simple antigens has been most extensively investigated shows the evidence of many similarities of the tolerant state once induced . Therefore, it appears that the features of each can, with merit, be examined for tentative generalizations about the tolerant state. The chapter concludes that the data derived primarily from more completely characterized experimental models of tolerance of nonliving antigens appear to provide grounds for some tentative statements regarding the nature of the tolerant state, particularly the role of antigen in its induction and maintenance and the conditions permitting induction of tolerance rather than of an immune response.

Immunologic properties of mouse thymus cells: Membrane antigen patterns: Associated with various cell subpopulations☆

Abstract The membrane antigen components of mouse thymus cells and fractions derived from BSA density gradient centrifugation were assayed by quantitative cytotoxicity tests. Two subpopulations were identified on the basis of average density and antigen patterns. The major subpopulation consisted of small lymphoid cells and comprised 80%–90% of all cells, was of high relative density and rich in θ, TL, G IX , Ly-A, Ly-B, and Ly-C, but contained little or no H-2. The minor subpopulation was chiefly large lymphoid cells, comprised 10%–15% of cells, was of low relative density, was relatively rich in H-2 but low in θ and Ly antigens, and contained no detectable TL or G IX . This minor subpopulation was identical in density and antigen patterns to those cells remaining in the thymus after short-term cortisone treatment or whole-body irradiation. It could also be reproduced by treating whole thymus with anti-TL or anti-θ sera. The antigenic attributes of this minor subpopulation differed from those of spleen lymphocytes only with respect to average density.

Cancer and the immune system

Early expectations for control of cancer through immunologic intervention are still unrealized. Increased knowledge of tumor immunity has broadened the understanding of the tumor and host relationship. This article reviews the evidence for an immune response to tumors, tumor antigens, immunologic intervention in cancer, insufficiency of the immune system to eliminate tumor growth, and immunologic approaches to the diagnosis of tumors.

Selective effects of mitogens on subpopulations of mouse lymphoid cells

Abstract The mitogenic effects of phytohemagglutinin (PHA), pokeweed mitogen (PWM), staphylococcal enterotoxin B (SEB) and endotoxins upon mouse spleen cells and various subpopulations were examined. The differential responses to these mitogens by cells of varying density indicate that LPS stimulates a different subpopulation from that of PHA and SEB. The subpopulation containing cells responsive to PWM seemed to differ from both of these patterns. In contrast to the effect of PHA, PWM, and SEB, thymus cells were not stimulated by LPS. LPS- and PWM-stimulated cells taken from both neonatally thymectomized and adult-thymectomized, irradiated, and bone-marrow-reconstituted animals: SEB and PHA failed to do this. It is concluded that the subpopulation responding to SEB, like that to PHA, is thymus dependent but that the two are probably not completely overlapping. That containing PWM responsive cells involves both thymus-independent and thymus-dependent cell components. The subpopulation stimulated by LPS is contained in a low density sub-population, which appears to be completely T independent.

The effect of PHA, PPD, allogeneic cells, and sheep erythrocytes on albumin gradient-fractionated mouse spleen cell populations☆

Abstract Populations of spleen cells from immune and nonimmune mice were separated by albumin density-gradient centrifugation. Primary responsiveness to PHA, to alloantigens in mixed cell culture, and to SRBC was assayed in various fractions by tritiated thymidine incorporation. Changes in the antigen-sensitive cell population in various gradient fractions were also examined in BCG-, alloantigen-, and SRBC-immunized animals. Primary reactivities to PHA, SRBC, and alloantigens are properties of a small, dense lymphocyte population. The antigen-sensitive cell population from immune mice is augmented chiefly in the less dense, large lymphocyte populations of the spleen in the cases of alloantigen and SRBC immunizations. In contrast only the denser, small lymphocytes showed increased antigen sensitivity after BCG immunization. These data suggest that immunity to alloantigens involves augmentation of a second population of antigen-sensitive cells which may produce antibody whereas immunity to BCG under these conditions is limited to an antigenreactive small lymphocyte population.

Pernicious anemia with neurologic involvement in childhood: Report of a case with emphasis on dangers of folic acid therapy**

A child with pernicious anemia had onset of anemia in the first year of life. Prolonged treatment with folic acid was given and hematologic remissions were obtained. At 32 months of age severe neurologic involvement was manifested by ataxia and coma. After vitamin B 12 therapy was instituted, dramatic and immediate improvement of his neurologic status was seen. However, the child has partial deafness and mental retardation as probable sequelae to prolonged vitamin B 12 deficiency which was masked by folic acid therapy. The administration of physiologic doses of folic acid (25 to 100 μg per day) may be used as both a diagnostic and therapeutic measure in cases of megaloblastic anemia in children. Such doses of folic acid will not be effective in P.A. while anemia secondary to folic acid deficiency will rapidly respond.

The interactions of mitogens with lymphoid cells and the effect of neuraminidase on the cells' responsiveness to stimulation☆

Abstract Early events in the interaction between mouse spleen cell populations and two mitogenic agents, phytohemagglutinin and bacterial lipopolysaccharide, have been examined. Qualitative assessment by a fluorescent antibody technique indicated that these mitogens are first bound to cell surface membranes, then internalized. This process was maximal 30 min after PHA contact; a similar effect required up to 1 hr in the case of LPS. Internalization, but not binding, was essentially blocked by low temperature or by pretreatment of the cells with neuraminidase. More quantitative data were obtained through an absorption technique which assayed the amount of mitogen removed by cells through binding and internalization. Neuraminidase treatment almost completely blocked the PHA-absorptive capacity of such cells; however, recovery from this block occurred 4–6 hr after incubation without the enzyme. Similar treatment with neuraminidase also blocked the mitogenic effects of PHA. Prolonged incubation of cells alone in vitro resulted in progressive partial loss of their absorptive capacity; when they had been stimulatd by PHA and incubated for 24 hr or more, absorptive capacity for both mitogens was entirely lost. These studies show that binding and internalization of mitogens precede transformation and mitosis, and that both absorptive capacity and mitogenic effects are correlated with the capacity to internalize these mitogens.

Identification of mouse thymus antigen recognition function in a minor, low-density, low-Θ cell subpopulation

Abstract Using a one- or two-step syngeneic transfer system in bone marrow-restored, lethally irradiated mice, the anti-SRBC cooperative cell function of the thymus was identified as being in low-density cell subpopulations constituting less than 10% of total thymus cells. This “B layer” population consisted of about 30% small lymphocytes and 70% large lymphoid cells and blasts, which have an average Θ-antigen content more characteristic of peripheral lymphocytes than of thymocytes. The origin of these cells and some possible implications of these findings are discussed.

Studies of the Epstein--Barr virus--host relationship: autochthonous and allogeneic lymphocyte stimulation by lymphoblast cell lines in mixed cell culture

Abstract The capacity of 21 established human lymphoblast cell lines to stimulate DNA synthesis in peripheral blood leukocyte populations of autochthonous or allogeneic origin was compared in one-way mixed lymphocyte cultures. Strong stimulation in the autochthonous combination was found in 20 out of 21 pairs, and weak but significant stimulation was observed in the exceptional pair. Allogeneic pairs gave additional increments of stimulation over that of the autochthonous pair in 21 out of 31 pairs tested. The observed stimulation was shown not to be due to a secreted blastogenic agent. The data support but do not prove that EBV-related antigens are responsible for the observed stimulation. This implies the existence of an EBV-immune cell population recognizing specific antigens in the target cell membrane.

Specific Recognition Reactions at the Cellular Level in Mouse Lymphoreticular Cell Subpopulations

2. Primary responses to alloantigens the MLC 182 a. Recognition of antigens determined at the H-2 locus 184 b. Recognition of minor locus antigens 185 c. Reactions between Fi and parent 186 d. Inhibitory effect of irradiation on target cell recognition in MLC ,., 188 3. Effects of immunization on in vitro reactivity lo antigens 189 a. Alloantigens 190 b. Xenogeneic antigens 191 c. Bacterial antigens PPD 192