Cancer detection and prevention. Supplement : official publication of the International Society for Preventive Oncology, Inc最新文献

Interaction between severe malnutrition and immunity have been described in clinical and experimental studies. Effects of marginal malnutrition or deficiency of single nutrients are less well-defined and should be investigated. Studies indicate that T cell function, in particular, is sensitive to many nutritional deficits or abnormalities and may compromise clinical immunological responses.

Blood group-related antigenicity in 14 pancreatic cancer patients was examined by immunohistological method using monoclonal antibodies (MoAbs) against A, B, H, Lea, Leb, and CA 19-9 and compared with the phenotypic expression of the individuals' blood groups. MoAb-A reacted strongly with tumor tissue in four of five blood group A patients. Two of two patients with blood type B showed a weak, focal reactivity of their cancer with MoAb-B. H antigen was found in four of five patients from blood group A, while it was present in only one blood group O person and absent in B-type individuals. B antigen was inappropriately expressed in one person with type A blood and in two with type O. Lea antigen was expressed in all but two tumor tissues and Leb antigen in all tumorous tissues, irrespective of Le blood group status. MoAb 19-9 reacted with 11 of 14 cases.

The three Hodgkin disease-derived cell lines L 428, L 540, and L 591 were characterized in their carbohydrate epitope composition by a panel of lectins. Nine other human cell lines were tested in comparison to the Hodgkin (H) and Sternberg Reed (SR) cells: promyelocytic (HL 60), lymphoblastoid, myeloma, histiocytic lymphoma (U 937), and other non-Hodgkin lymphoma cell lines. Twenty-four different fluoresceinated lectins bound to the Hodgkin and other cell lines in different percentages of positive cells and with varying intensities. Lotus lectin and a monoclonal anti-Lewis blood group X antibody showed very similar binding patterns (L 428, L 540, HL 60, U 937). Soybean agglutinin stained only L 428 and L 540, although nearly all were positive after neuraminidase treatment. Cell lysis of the three H cell lines resulted in a very similar electrophoretic mobility pattern of proteins. In addition, staining of transblotted glycoproteins with biotinylated concanavalin A by avidin peroxidase reaction revealed corresponding bands. Differences were seen with Lotus staining. In summary, the origin of H cells is still unknown, but there is obviously some relationship in the glycoconjugate profile to the myelohistiocytic lineage.

Human-human hybridoma technology was used to produce human monoclonal antibodies with reactivity to colorectal cancer antigens. Two different B-lymphoma cell lines were fused with lymphocytes obtained from mesenteric lymph nodes from colorectal cancer patients. The fusion frequency was 11% with LICR-LON-HMy-2. Out of 294 growing hybridomas 26 secreted antibodies reacting with epitopes on cultured colon adenocarcinoma cells. Only one (D4213) was established and has now been in culture for 1.5 years. D4213 antibody shows a strong reaction with colon cancer tissue compared with normal colon epithelium. Using W1-L2-729-HF2 the fusion frequency was about 50%. Of 2,487 hybridomas 499 produced immunoglobulin and 44 of these reacted with colon cancer tissues or cultured cancer cells. One of the established hybridomas produces antibody reacting with cancer cell membrane antigens, and on immunoblotting a number of components were stained. The antibody from the other hybridomas reacts with cytoplasmatic antigens, and only one of these showed reactivity in immunoblotting where it bound to a component with Mr of about 60K.

Based on experimentation in animal model systems it is reasonable to expect immunomodulation by anticancer drugs and biological response modifiers to be instrumental in at least some of the antitumor effects of such agents. Even in the defined animal models, however, the immunomodulating effects of any given agent are in most cases correlated only with the therapeutic response to that agent, whereas causal relationships still evade unequivocal demonstration. The difficulties in this respect are magnified in humans, in whom the very nature and regulation of antitumor immunity, taken in a broad sense, are not yet well defined; thus at this time the basis on which to interpret the therapeutic or toxicological causative relevance of an immunomodulating effect is insufficient. Despite these limitations and uncertainties, or perhaps responding to the challenge they provide, experimentation evaluating the potential of immunomodulation is being carried out in a number of diversified areas. Salient findings from selected investigations of the actions of 1) drugs, 2) cytokines, and 3) combinations of agents or effectors are discussed as examples of the realization of the potential of this overall approach as well as to outline the requirements for future development of biological response modifiers.

The antitumor and metastasis-inhibitory activities, mode of action, and clinical application of lentinan, a strictly purified beta-1,6:beta-1,3-glucan, are reviewed. Lentinan exerts a prominent antitumor effect and prevents chemical and viral oncogenesis. The antitumor action of lentinan is host-mediated. Compared to other well-known immunostimulants, such as bacille Calmette Guérin (BCG), Corynebacterium parvum, and lipopolysaccharide (LPS), lentinan appears to represent a unique class of immunopotentiator, a T cell-oriented adjuvant. Lentinan triggers the increased production of various kinds of bioactive serum factors associated with immunity and inflammation, such as IL-1, CSF, IL-3, vascular dilation inducer, and acute-phase protein inducer, by the direct impact of macrophages or indirectly via lentinan-stimulated T cells, which results in the induction of many immunobiological changes in the host. Augmented IL-1 production amplifies the maturation of immature effector cells to mature cells capable of responding to lymphokines such as IL-2 and T cell-replacing factors. Because of this mode of action, intact T cell compartments for antitumor activity of lentinan are required. Lentinan has little toxic side effects. Excellent results were obtained in a 4 year follow-up of the randomized control study of lentinan in phase III on patients with advanced and recurrent stomach and colorectal cancer.

The assumption that life changes and stressful events can alter host defense is based mainly on studies of changes in a variety of immune and inflammatory reactions. Whether those changes also confer an increased susceptibility to infectious agents and neoplasms, or modify the course of such diseases, is still less well substantiated. Nonetheless, psychological and neural modulation of immunity has recently been possible to approach from a mechanistic viewpoint. For instance, generation of a variety of lipid mediators from arachidonic acid may be under control of dietary and endocrine factors that can be affected by stress. Since these lipids, eg, lipoxygenase products, are potent regulators of leukocyte functional responses, their significance as one of several mechanisms is discussed. The role of various neuropeptides in leukocyte function has only recently been discovered. Since the release of, eg, substance P, enkephalins, and endorphins, which all have modulating effects on leukocyte functional responses, is under neural control and can occur in the vicinity of immunocompetent cells, they might constitute one of several links between the mind and the immune system.

Pregnancy is a natural allograft and the mechanisms for its non-rejection are obscure. Depression of maternal cellular immunity was suggested as a possible explanation. Interleukin-2(IL-2) is a lymphokine release from OKT4+ lymphocyte. This factor has a crucial role in the proliferation and differentiation of T cell subsets, and controls functions associated with immune rejection mechanisms. We therefore examined the ability of lymphocytes from women in the 3 trimesters of pregnancy to produce IL-2 in culture. Mononuclear cells were cultured with PHA for 48 h. The IL-2-containing supernatant was added to and supported the proliferation of an IL-2 dependent T cell line. Proliferation of this line indicated the IL-2 content of the added supernatant. Using this assay, IL-2 production in all 3 trimesters of pregnancy was adequate and comparable to that of lymphocytes from non-pregnant women. These results suggest that the proposed defect in cellular immunity during pregnancy is not mediated by an inability of the lymphocytes to produce IL-2.

Studies in hemophiliacs receiving factor concentrates demonstrated T-cell defects in vitro. Recently, B-cell dysfunctions were described in AIDS and pre-AIDS and in some hemophiliacs. To investigate the B-cell function in hemophiliacs in relation to factor substitution, we examined five patients with mild (substitution less than 20,000 U/year) and seven with severe (greater than 100,000 U/year) hemophilia A and compared the data with normal control individuals. The B-cell proliferative response (3H-thymidine uptake) to Staphylococcus aureus Cowan I and the differentiation response (Ig secretion into culture supernatants) to T-cell-dependent or -independent polyclonal B-cell activators (PBAs) were studied in vitro. In contrast to T-cell dysfunctions, which correlate with the amount of clotting factor concentrates, the B-cell proliferative response was not affected. Stimulation with PBAs however failed to increase elevated spontaneous IgG levels and showed a diminished increase in IgM levels in severe, but not in mild, hemophilia. Our data give evidence of a T-cell-independent B-cell dysfunction in asymptomatic hemophiliacs that correlates with factor substitution.

Secondary T-lymphocyte deficiencies are common in cancer, aging, malnutrition, chronic infection, and AIDS. Reconstitution with thymic hormones has not been successful. The various thymic hormone preparations induce prothymocyte differentiation and promote the differentiated functions of mature T cells, but they do not regulate intrathymic maturation. In contrast, interleukin 2, endotoxin, thymic epithelial cell products, but not interleukin 1 were found to promote functional maturation of immature thymocytes. Logically, thymic hormones may have synergistic interaction with inducers of intrathymic maturation, and preliminary evidence in athymic nude mice supports this notion. Two classes of drugs show thymomimetic actions. Levamisole, diethyl dithiocarbamate, and other sulfur-containing compounds restore T-cell function via induction of a thymic hormone-like factor. Isoprinosine, NPT 15392, and related hypoxanthine derivatives induce T-cell maturation directly and promote T-cell function in vitro and in vivo. An assessment of the combined actions of these drugs and biologicals should improve immunorestoration in T-cell deficiencies.