Immunological surveillance versus immunological stimulation of oncogenesis--a formal proof of the stimulation hypothesis.
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Current immunologic theory defines a role for HLA-A, -B, -C proteins in cells presenting foreign antigens to cytotoxic T lymphocytes. No clear function, however, is assigned to the prominently represented HLA molecules on the T cells themselves. To investigate this question, the synthesis and turnover of HLA-A, -B, -C molecules in human peripheral lymphocytes was studied. Newly synthesized HLA-A, -B, -C and beta 2-microglobulin molecules were identified among total lymphocyte proteins by two-dimensional gel electrophoresis and specific immunoselection. In resting T lymphocytes, the polymorphic set of HLA-A, -B, -C proteins was among the most prominently synthesized and rapidly turned over of total cell proteins. Its half-life was 6 to 7 hr, which is considerably shorter than that of total cell protein. HLA and beta 2M were the major proteins of the plasma membrane undergoing active synthesis and turnover in resting T lymphocytes. After growth stimulation, the rate of HLA synthesis increased to a lesser degree than total protein synthesis. Survival of newly synthesized HLA was increased, however, indicating reduction in HLA turnover. The result was the accumulation of HLA in the plasma membrane. It is suggested that continuous degradation and replacement reflects the biochemical nature of the participation of HLA molecules in immunologic surveillance by quiescent lymphocytes. Cessation of HLA turnover, with accumulation of surface HLA molecules, is a biochemical adjustment related to T cell activation.
Immunological endeavor in recent years calls for a reappraisal of the concept of immunosurveillance against neoplasia. This concept proposes an immunological policing system capable of aborting tumor growth by the recognition of "nonself" tumor associated antigens on neoplastic cells. The model is supported by evidence of tumor induction in the immunosuppressed host and the demonstration of an immune response to tumors in animals. The occurrence of tumor, regarded as a failure of immunosurveillance, is attributed to selection of neoplastic cells for immunological or other reasons or abnormal humoral or cellular antitumor immune responses. However protagonists of the postulate are faced with mounting evidence that fails to support the surveillance hypothesis. These observations include, inter alia, the monoclonality of certain tumors, the low incidence of spontaneous tumors in genetically immunodeficient mice and immunological privileged sites, and new ideas about the pathogenesis of lymphoproliferative neoplasms. However, contradictory arguments are not sufficiently substantiated to prosecute the case against surveillance conclusively. In citing highlights of the evolving quandary, both the pros and cons of immunological surveillance are presented here.
The immunological surveillance hypothesis was formulated prior to the realization of the fact that an individual's effector T cells generally only see neoantigen if it is appropriately presented in the context of self MHC glycoproteins. The biological consequence of this mechanism is that T lymphocytes are focused onto modified cell-surface rather than onto free antigen. The discovery of MHC-restricted T cell recognition, and the realization that T cell-mediated immunity is of prime importance in promoting recovery from infectious processes, has thus changed the whole emphasis of the surveillance argument. Though the immunological surveillance hypothesis generated considerable discussion and many good experiments, there is no point in continuing the debate in the intellectual context that seemed reasonable in 1970. It is now much more sensible to think of "natural surveillance" and "T cell surveillance," without excluding the probability that these two systems have elements in common. We can now see that T cell surveillance probably operates well in some situations, but is quite ineffective in many others. Part of the reason for this may be that the host response selects tumor clones that are modified so as to be no longer recognized by cytotoxic T cells. The possibility that this reflects changes in MHC phenotype has been investigated, and found to be the case, for some experimental tumors. In this regard, it is worth remembering that many "mutations" in MHC genes that completely change the spectrum of T cell recognition are serologically silent. The availability of molecular probes for investigating the status of MHC genes in tumor cells, together with the capacity to develop cloned T cell lines, monoclonal antibodies to putative tumor antigens, and cell lines transfected with genes coding for these molecules, indicates how T cell surveillance may profitably be explored further in both experimental and human situations.
Unlike most bodily organs, the central nervous system (CNS) exists behind a blood-tissue barrier designed to minimize the passage of cells and macromolecules into the neural parenchyma. Yet, the CNS is routinely and effectively surveyed by the immune system. This review examines the mechanisms and participants in this immunological surveillance mechanism. The nature of the healthy blood-brain barrier, factors modifying it, and its central position in determining the number and nature of leukocytes permitted to enter, are considered. In addition the role in surveillance played by lymphatic drainage, migrating T and B lymphocytes, and elements of the monocyte/macrophage/microglia family are considered. While all these participants are known to be important in responding to a CNS antigen and/or establishing a site of inflammation in the nervous system, they also are major elements in maintaining the homeostasis of the CNS and permitting the necessary immunological surveillance of that organ.
OBJECTIVE: To compare the characteristics of three- and two-color flow cytometry for immunologic surveillance of toll-like receptor 4 (TLR-4) after renal transplantation. METHOD: The expressions of CD14, TLR4 and CD80 in peripheral blood monocytes were measured in 10 patients after renal transplantation by three- and two-color fluorescent staining flow cytometry, respectively. The percentages of TLR4 and CD80 in CD14-positive monocytes were calculated, and the characteristics of two methods of flow cytometry were compared. RESULTS: The two detection methods did not significantly differ in their detection of TLR4 (P=0.198) and CD80 (P=0.872) expressions in CD14-positive monocytes, and the measurements of the two methods for the same sample showed positive correlation (r=1, P=0.000 for TLR4 and r=0.999, P=0.000 for CD80). Three-color flow cytometry was also capable of detecting monocytes positive for both TLR4 and CD80. Compared with two-color flow cytometry, three-color flow cytometry provided more information and required less blood sample and monoclonal antibody. CONCLUSIONS: Three- and two-color flow cytometry have almost the same accuracy in immunologic surveillance of TLR4 after renal transplantation. The former method also provides information of the simultaneous expression of TLR4 and its down stream molecule CD80, which could be critical for imploring the mechanisms by which TLR4 takes part in alloimmunity through modulating CD80 expression, and requires less blood sample and monoclonal antibody.
A 1,2-dimethylhydrazine dihydrochloride-induced rat gastrointestinal tract tumor model was used to study the phenomenon of immunologic surveillance. In two different sets of experiments, a properly timed administration of antithymocyte globulin resulted in earlier tumor appearance, increased numbers of tumors, and increased multiplicity of gastrointestinal tumors. Results obtained from histologic examination of the gastrointestinal tract at different times after the last dose of 1,2-dimethylhydrazine dihydrochloride suggested that a normally functioning immune system effectively suppressed the growth of some nascent tumors. However, the immunosuppression of the host with antithymocyte globulin allowed the development of foci of microtumors into grossly visible neoplasms. Our experiments supported the concept that immunologic surveillance against neoplasia depends on the thymus cell system, although other possible mechanisms were not excluded.
A precise immunological surveillance of liver graft recipients can allow the adaptation to each patient of an adequate immuno-suppressive treatment. In 11 liver-transplanted patients (7 primitive biliary cirrhoses, 2 post-hepatic cirrhoses, one bile duct atresia with one antitrypsin deficit) different lymphocyte subpopulations were tested before transplantation and at days 3, 5, 7, 15, 30, 60 and 120 after grafting using OKT3, OKT4, OKT8 (Orthoclone, France). In 6 patients presenting one or more rejections, the (T4+):(T8+) lymphocyte ratio was significantly increased during the days preceding rejection. In all cases, the (T4+):(T8+) ratio increase was linked to a (T4+) helper lymphocyte augmentation. In the 6 patients who did not present any rejection, the (T4+):(T8+) ratio did not increase at long term. A decrease of the (T4+):(T8+) ratio, along with an augmentation of (T8+) lymphocytes, was noticed at long term in patients free of chronic rejection. The evolution of T lymphocyte populations, followed using monoclonal antibodies and mainly the (T4+):(T8+) ratio, can provide a test for rejection predictability of for the prognosis of tolerance to liver allografts.
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7,12-dimethylbenz(a)anthracene (DMBA) is a polyaromatic hydrocarbon with potent mutagenic, carcinogenic and immunomodulatory activities. It has been postulated that the immunosuppressive effects of DMBA may contribute to the carcinogenicity of this agent. We investigated this issue by examining whether the pre-administration of DMBA at one skin site would augment its carcinogenic activity at a distant skin site. In animals placed on a cutaneous chemical carcinogenesis protocol to the skin of the back, pre-sensitization with DMBA to the abdomen augmented skin tumorigenicity whether the tumor data are considered as cumulative number of tumors, percent of mice with tumors, number of tumors per mouse, or numbers of tumors per tumor bearing mouse as a function of weeks on test. These data demonstrate that pre-treatment with DMBA augments its skin tumorigenicity by impairing immunological surveillance.
The literature analysis has shown that somatic cell hybridization is one of the mechanisms of tumour progression in vivo. This mechanism is suggested to underlie the establishment and development of human tumours, in particular of human breast cancer. Somatic hybridization of cells in human breast cancer is supposed to be one of the mechanisms responsible for the inadequacy of immunologic surveillance. The latter appears to occur in those cases when antigenic determinants of unchanged original cells predominate on the surface of hybrid formations.
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Considering the more recent physiopathogenetic advancements in neurofibromatosis (NF), we propose to employ novel instrumental and laboratory procedures for the immunological and clinical surveillance of NF. In NF the evolution of the non-self can lead to disease expansion, at times transforming into malignancy. Contemporarily, the resulting immunological reactivity can either lead to the type of fibrosis that one sees in paraneoplastic connective tissue disease or be deficient. Through interdisciplinary biohumoral analyses were carried out contemporarily so as to gain comparative insight into the eventual unfolding of immunological and fibrotic phenomena. The range of the clinical follow-up varied from one to four years with periodic day hospital admissions. We studied ten NF patients that originated from southern Italy and belonged to middle and lower middle class status; we also studied one healthy subject who had the same HLA haplotype as his NF affected twin. We performed biohumoral analyses in clinical stable patients and saw moderate variations in induces useful for monitoring the evolution of this dysplastic-neoplastic condition, e.g. procollagens, interleukin-2, NSE (assayed with radioimmunological methods) and complement these parameters proved to be of use in monitoring the fibrotic evolution of NF. The intent of our work was to complete the earlier studies on NF surveillance, especially during periods of disease evolution and immuno-fibrotic alteration.
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Adenovirus type 2 (Ad2)-transformed hamster and rat cells are susceptible to lysis by natural killer (NK) cells from the host of origin and are nontumorigenic in immunocompetent hamsters and rats, respectively. These NK-cell-susceptible, virus-transformed cells are, however, highly tumorigenic in athymic (nude) mice--animals with intact NK-cell responses. In vitro lysis of these xenogeneic, Ad2-transformed cells by nude-mouse NK cells was found to be defective. In contrast, Ad2-transformed hamster and rat cells were highly susceptible to lysis by nude-rat NK cells. Furthermore, xenogeneic, Ad2-transformed hamster cells were nontumorigenic in nude rats unless the NK-cell responses of the challenged animals were compromised. The results of the nude-rat studies show that thymus-dependent, cytotoxic T-lymphocyte-mediated, host cellular immune responses are not essential for rejection of xenogeneic cells transformed by nononcogenic Ad2. The data suggest instead that immunologically nonspecific host cellular immune responses, such as those mediated by NK cells, are sufficient for rejection of Ad2-transformed cells. These results indicate that biologically important differences exist in the NK-cell-mediated defenses mounted by nude mice and nude rats against transformed cells that may account for the different patterns of tumor induction by various neoplastic cell types in these athymic animals.