Publisher Summary The term “cell-mediated cytotoxicity” applies to lytic reactions that require the participation of lymphoid or non-lymphoid cells but not of added complement. It has been clearly established that several pathways, including different cell types, are involved in cytotoxic reactions in vitro. With membrane-associated antigens, such as transplantation, and tumor-associated antigens, the cytotoxic effect of effector cells on adequate target cells is most often highly specific and requires intimate contact rather than release of diffusible toxic factors. Specific cell-mediated cytotoxicity in vitro can be divided into three categories according to the nature of the effector cells.

Cell-Mediated Cytotoxicity, Allograft Rejection, and Tumor Immunity

Publisher Summary An individual's immunological response to some of the antigens can result in protection against tumor growth. However, it has been found that the generation of antitumor immunity is not always effective and may at times even lead to the acceleration of tumor growth. This chapter reviews the information on the role of the immune system in limiting tumor growth and discusses the concept of immunological surveillance. It discusses the types of antigens that have been associated with tumors, their specificity, and their potential significance. It also presents the evidence for the existence of specific, cell-mediated immunity, both in vivo and in vitro , against tumor-associated cell surface antigens. There is considerable evidence for the role of immune cells in the resistance of the host to tumor growth. The chapter discusses the possible role of assays in the diagnosis, prognosis, and therapy of cancer.

Cell-Mediated Immunity to Tumor Cells

Publisher Summary This chapter reviews the role of macrophages in defense against neoplastic disease. Macrophages do exert both natural and adjuvant-stimulated, afferent and efferent antineoplastic activities. Macrophages appear to be essential for the uptake and processing of tumor antigens preceding the initiation of an effective immune response. Additionally, the macrophage alteration of antigen may promote successful immunization as opposed to the induction of tolerance or production of enhancing or blocking factors. The macrophage might further enhance the immune response by stimulating the proliferation of immunocompetent cells through the production of lymphocyte-activating factor (LAF) or the delivery of macrophage-contained adjuvant. Aided by cytophilic antibody, specific macrophage arming factor (SMAF), macrophage migration inhibitory factor (MIF), interferon, nonspecific opsonins, or nonspecific activation, macrophages, either alone or in concert with other immune cells, can exert both immune and nonimmune cytotoxicity toward neoplastic cells. This antitumor activity is most likely mediated through a nonphagocytic, contact-dependent mechanism, associated in only a few systems with the release of soluble toxic substances. Such direct macrophage-mediated antitumor activity, as well as macrophage-mediated induction and the amplification of antitumor immune responses, appear to contribute significantly to host survival and deserve careful consideration in both the experimental and clinical study of animal and human neoplastic disease.

The role of macrophages in defense against neoplastic disease.

The antitumor effect of lentinan in syngeneic and autochthonous tumor-host systems and its suppressive effect on 3-methylcholanthrene (MC)-induced carcinogenesis were confirmed using DBA/2 and SWM/Ms hosts. The regressive activity of lentinan against the solid form of Sarcoma 180 was the most effective in DBA/2, SWM/Ms, or A/J mice and less effective in C3H/He or C57BL/6 mice. The growth of a syngeneic MC-induced DBA/2.MC.CS-1 fibrosarcoma (native and trypsinized) was markedly inhibited, and the regression of tumors was detected by the i.p. injection of minute amounts of lentinan into DBA/2 mice, which were the most suitable host in lentinan treatment. When DBA/2 mice were used, lentinan was also effective for even autochthonous primary tumors induced within 15 weeks after MC inoculation, but less effective for tumors induced during the 16 to 36 weeks after MC treatment. Lentinan showed a prominent suppressive effect in MC-induced carcinogenesis using DBA/2 and SWM/Ms mice but not effect when BALB/c, C57BL/6, or C3H/He mice were used. The timing of lentinan administration in the latter result was examined using SWM/Ms mice, and lentinan, when it was given daily for 10 days after the third week of MC inoculation, was strikingly effective (33%), but not so effective (63%) when lentinan was given after the sixth week of MC treatment, compared with tumor-occurrence rate in the control group (88%). The reason why DBA/2, SWM/Ms, or A/J mice were suitable hosts for lentinan treatment is not clear, but the natural killer capability or phagocytic macrophage function in these strains seems to have no relation to lentinan action, because A/J mice are deficient in natural killer function, and in these strains of mice the phagocytic function of macrophages is weak. It may be quite possible that these strains of mice are most sensitive to delayed-type hypersensitivity and/or cytotoxic T-cell response in which T-cells and lentinan play important roles. The tumor-host systems presented here provide a good model in which lentinan retains an inhibitory capacity in syngeneic and autochthonous hosts, and such a model offers the possibility for further study of the host defense mechanism against cancer.

https://cancerres.aacrjournals.org/content/canres/44/11/5132.full.pdf

Antitumor Activity of Lentinan in Murine Syngeneic and Autochthonous Hosts and Its Suppressive Effect on 3-Methylcholanthrene-induced Carcinogenesis

Publisher Summary
This chapter discusses the role of macrophages at the effector arm of the immune response. The nature of the effector cell responsible for the killing in cell-mediated destruction in transplantation and tumor immunity is variable according to the circumstances. The mechanism of destruction is not identical in all cases and may involve rapid lytic events or slower and initially cytostatic events. The recognition of cell-mediated cytotoxicity is frequently obscured by equating cytotoxicity with lysis. By definition, toxicity refers to the extent of virulence of a poison, and a poison is any substance or agent that by its action causes destruction or modification of function. Thus, cell-mediated cytotoxicity refers to the extent of damage or modification of function induced by an effector cell on a target cell and may be measured by different assay systems, depending on the nature of the change induced in the target cell.

Mechanisms of extracellular killing of nucleated mammalian cells by macrophages.

Studies on cytophilic antibodies. V. Alloantibodies cytophilic for mouse macrophages.

ALLOGRAFT rejection is usually grouped with delayed hypersensitivity, acquired cellular resistance to infection and some types of auto-immune disease as a form of cell-mediated immunity, implying that all these phenomena may share a common immunological mechanism. The rejection of skin allografts is generally accompanied by the development of delayed-type hypersensitivity to graft antigens. Reactions having the time-course and macroscopic and microscopic features of skin reactions in delayed-type hypersensitivity have been elicited by injecting donor antigen (in the form of lymphoid cells or extracts thereof) into sensitized humans, guinea-pigs, hamsters, dogs and rats1–3. Similar reactions could not be elicited in mice1. Here we describe the induction of delayed hypersensitivity reactions in the footpads of mice. Because resistance to isografts of chemically induced tumours in mice may also be a form of cell mediated immunity4, we have also tested whether similar reactions can be elicited after tumour isografting in mice.

D. S. Nelson

Papers

Studies on cytophilic antibodies. V. Alloantibodies cytophilic for mouse macrophages.

Delayed-type Hypersensitivity in Mice after Skin and Tumour Allografts and Tumour Isografts