Natural immunity and graft-vs-host disease.
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Antibody-Dependent Cell Cytotoxicity↗
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[Indices of the natural immunity system in patients with rectal cancer undergoing radiation treatment].
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Cytotoxicity Tests, Immunologic↗
Natural immunity. History, present, and future.
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Allergy and Immunology↗
Natural immunity in recurrent aphthous ulceration.
In the present study we investigated immunophenotypes of peripheral blood lymphocytes, natural killer (NK) cell activity as well as spontaneous migration, ingestion, digestion and antibody-dependent cell-mediated cytotoxicity (ADCC) as effector functions of polymorphonuclear neutrophil granulocytes (PMNs) in 51 patients with acute stage recurrent aphthous ulceration (RAU), during remission, and 47 age-matched healthy individuals. Statistically significant lower B-lymphocyte (CD19) values were found between patients with acute RAU, and those during the remission period (P<0.001), when compared with those of the controls. Total T-lymphocyte (CD3) percentages were lower in patients with RAU, and also during the remission period, when compared with the controls (P<0.001). The percentages of CD4 lymphocytes were significantly lower in patients with RAU in comparison with those of the controls (P<0.001). T-suppressor cells (CD8) were unchanged in all three groups of participants. Significantly lower spontaneous migration and ingestion values were found in patients with acute RAU, when compared with those of the controls, and during the remission period (P<0.001). Digestion values differed insignificantly between the patients with acute RAU and during the remission period. During the remission period, digestion values were significantly elevated when compared with those of the controls (P<0.05). ADCC values were lower during the remission period (P<0.001), when compared with the values during acute RAU and with those of the controls. Significantly depressed NK activity (P<0.001) was observed in patients with acute RAU, when compared with that of the controls. During the remission period, values of NK activity were also lower (P<0.001) when compared with those of the controls. These results suggest either a specific or nonspecific immunological disorder in patients with RAU.
Adolescent↗
Characterization of the natural immune response of rhesus monkey CD4+ve T cells to the bacterial antigen streptolysin O (SLO).
Rhesus monkeys show a high proliferative T cell response to the bacterial exotoxin SLO without prior immunization. The present study was undertaken to characterize this naturally present SLO-responsiveness with particular emphasis on CD4+ve reactive T cells. It is demonstrated that the frequency of SLO-reactive cells in the circulation.ranges between 1 in 75 and 1 in 610 CD4+ve T cells as determined with limiting dilution analysis. It is also shown that induction of a good proliferative response requires Mhc-DR matching between T cell and the antigen presenting cells (APC). Stable and DR-restricted SLO-specific CD4+ve T cell lines were generated from CD8 depleted peripheral blood mononuclear cells (PBMC). The SLO-reactive CD4+ve cell lines are tentatively characterized as Th1-like based on the predominant production of interferon-gamma (IFN-gamma) over IL-4, although this seems contradicted by the IL-4 dependent growth of the lines.
Animals↗
Natural immunity in mice to structural polypeptides of endogenous type C RNA viruses.
The immunological responses of inbred mice to structural components of one class of endogenous virus were investigated by means of radioimmunoassays utilizing highly purified viral proteins. Naturally occurring antiviral antibodies were demonstrated only in those strains possessing information for induction of a mouse cell-tropic endogenous virus. Moreover, these antibodies invariably appeared subsequent to the detection of spontaneous replication of this virus in the same animal. The immune responses elicited were much stronger against endogenous viral gp70 than p30, consistent with previous findings of tolerance in the mouse to the major structural antigen of its endogenous virus. However, the demonstration of an immune response to p30 under conditions of both natural and experimental immunization establishes that tolerance to this viral antigen can be overcome.
AKR murine leukemia virus↗
[Augmentation of murine organ-associated natural immune responses by cepharanthin].
Oral administration of cepharanthin (bisbenzylisoquinoline alkaloid) to mice was effective in the organ-associated immune responses. Cepharanthin, as a biological response modifier (BRM), augmented natural killer (NK) activity of leukocytes isolated from the spleen, lymph node, lung, and liver. The degree of NK augmentation was almost the same in these organs without lymph node, and reached to the maximum levels 3 days after cepharanthin administration. In addition, adherent leukocytes (greater than 95% macrophages) isolated from the lung or liver following cepharanthin administration also exhibited an augmented macrophage-mediated cytotoxicity. These results suggest that such organ-associated immune responses may play an important role in the antitumor and/or antimetastatic effects mediated by cepharanthin.
Administration, Oral↗
Acquired and natural immunity to gonococcal infection in chimpanzees.
Despite the fact that gonorrhea is our most common reportable infectious disease, little is known about natural and acquired resistance to Neisseria gonorrhoeae. With the chimpanzee model, which mimics human gonococcal infection in signs, symptoms, and host response, a natural resistance to gonococcal challenge was found. One aspect of this natural resistance became evident when the cervix and oral pharynx resisted more gonococci than the urethra. Natural resistance was also shown when environmental factors were found to influence resistance to gonococcal pharyngitis. In addition to natural resistance a postinfection-acquired immunity to the gonococcus was demonstrated. Following gonococcal pharyngitis, this anatomical location successfully resisted more gonococci than were initially resisted. Similarly, more gonococci were successfully resisted in rechallenging the urethra. These findings are related to the clinic situation and suggest possible new approaches to gonorrhea control.
Animals↗
Influence of conditioned natural immunity on tumor growth.
We studied the effect of classical (Pavlovian) conditioning of the natural killer cell response on survival of tumor-bearing mice. Mice were given repeated injections of poly I:C every three days paired with exposure to the odor of camphor for 4 hours. First, we investigated the possible therapeutic effect of repeated exposure to the odor of camphor on the growth of MOPC 104E murine myeloma. The results indicate that camphor alone had no therapeutic effect when the mice were exposed to the odor of camphor after tumor transplantation. We then investigated the effect of repeated exposure to camphor prior to tumor transplantation and subsequent repeated exposure to camphor following tumor transplantation. Again, we observed no therapeutic benefit. In a third experiment, we examined the effect of the conditioned poly I:C response on the growth of the murine myeloma. Animals in the conditioned group had an increase in median survival (day 43, as compared to days 34, 38, 37 of various control groups). Two of these conditioned mice lived more than 120 days and showed early tumor growth, but were free of disease at day 97. During the course of the study conditioned mice received no additional treatment other than being reexposed to camphor every third day.
Animals↗
Idiotype immunity (natural and vaccine-induced) in early stage multiple myeloma.
Idiotypic structures expressed on the myeloma immunoglobulin (Ig) protein (M-component) might be regarded as tumor-specific antigens. Naturally occurring, idiotype-specific type I T-cell immunity has been observed preferentially in patients with early stage myeloma. The idiotypic structures on the clonal myeloma B-cells (B lymphocytes and plasma cells) may serve as targets for active immunization. Vaccination using the autologous monoclonal Ig as a vaccine has conferred resistance to tumor cell challenge in murine myeloma. The autologous myeloma Ig protein was used for immunization in patients with progressive stage I and early stage II multiple myeloma. When the idiotype (emulsified in aluminium phosphate) was used alone for immunization, a weak and transient idiotype-specific T-cell response was observed with no clinical effects. In our second series, the idiotype (in alum) was combined with GM-CSF. In all five patients, a specific T-cell response was induced consisting preferentially of MHC class I restricted (CD8+) T-cells. Ig-specific CD4+ T-cells were also induced. A clinical response ( > 50% reduction of the M-component concentration) was observed in one patient. These results indicate that idiotype-specific T-cell immunity may be induced or enhanced by idiotype Ig vaccination in patients with early stage multiple myeloma, in which the tumor load is relatively low and the immune system is functionally less compromized than in patients with chemotherapy-treated, advanced stages of the disease. The use of GM-CSF seems to be mandatory for the frequency and magnitude of the induced T-cell response. The optimal route, schedule and cytokine combination for idiotype immunization remains to be established.
Clone Cells↗
Augmentation of natural immune defence mechanisms and therapeutic potential of a mismatched double-stranded polynucleotide in cutaneous herpes simplex virus type 2 infection.
We studied the effect of an analogue of polyinosinic acid:polycytidylic acid, the mismatched poly(rI).poly(rC12U), on herpes simplex virus type 2 (HSV-2)-induced cutaneous disease in the guinea-pig. Recurrence patterns and HSV-2-induced immune responses were also defined. Intranasal administration (1.5 micrograms/g body weight, five doses at 48 h intervals) of poly(rI).poly(rC12U) during initial HSV-2 infection caused a significant (P less than 0.05) reduction in virus titres in the skin and decreased (P less than 0.01) the duration and severity of the primary cutaneous lesions. The incidence and frequency of subsequent recurrent episodes were also significantly (P less than 0.01) reduced. Titres of serum neutralizing antibody were identical in treated and untreated animals. Interferon (IFN) activity was detectable in the sera from poly(rI).poly(rC12U)-treated animals. Peripheral blood mononuclear (PBL) and spleen cells from treated animals had enhanced cytotoxic activity for HSV-2-infected and uninfected target cells. The cytotoxic activity of the PBL was enhanced by treatment in vitro with poly(rI).poly(rC12U) or IFN.
Animals↗
Immune capacity of the chicken bursectomized at 60 hours of incubation: failure to produce immune, natural, and autoantibodies in spite of immunoglobulin production.
Chickens surgically bursectomized at 60 hr of incubation were immunized at the ages of 6, 7, 8, and 9 weeks with Escherichia coli lipopolysaccharide, levan, tetanus toxoid, and dinitrophenyl-bovine serum albumin. All antigens were given on each occasion. All embryonically bursectomized (BX) chickens had detectable concentrations of serum IgM, IgG, and IgA. On the whole, the IgG level was markedly decreased and the levels of IgM and IgA were normal. Concentrations of serum immunoglobulins did not change during immunization in the BX chickens. In spite of the production of serum immunoglobulins the BX chickens were unable to respond to the immunization by production of specific antibodies, whereas the control (CO) chickens produced good antibody response to each antigen used. The BX chickens also lacked both natural antibodies to phosphorylcholine, fecal bacteria, rabbit red blood cells (RRBC), and MHC antigens and autoantibodies to the liver, kidney, and thyroidea. Neither were any antibodies to the bursal structures observed. These results support the hypothesis that the bursal influence is not necessary for isotype switch, but is essential for the production of specific antibodies.
Animals↗
Cytotoxic T-lymphocytes against malaria and tuberculosis: from natural immunity to vaccine design.
1. Mycobacterium tuberculosis and the liver stage of Plasmodium falciparum are intracellular pathogens which are potentially susceptible to cytotoxic T-lymphocytes, a crucial component of the protective immune response to viral infections. Evidence from animal models points to a protective role for cytotoxic T-lymphocytes against M. tuberculosis and P. falciparum, but cytotoxic T-lymphocytes specific for these pathogens have been difficult to identify in man.2. Using a reverse immunogenetic approach, candidate epitopes from selected antigens of P. falciparum and M. tuberculosis were used to detect peptide-specific cytotoxic T-lymphocyte responses in individuals exposed to these pathogens. Cytotoxic T-lymphocyte activity was detected by the 51Cr release cytotoxicity assay and a sensitive ELISPOT assay for single-cell interferon-gamma release.3. In naturally exposed, partially immune Africans in The Gambia, eight largely conserved cytotoxic T-lymphocyte epitopes in P. falciparum, restricted by several different HLA class I alleles, were identified. Several epitopes were also recognized in Tanzanians and cytotoxic T-lymphocytes recognized endogenously processed antigen.4. In tuberculosis patients with HLA-B52, a CD8+ cytotoxic T-lymphocyte epitope was identified in ESAT-6, a secreted antigen specific for M. tuberculosis complex but absent in BCG. Cytotoxic T-lymphocytes exhibited HLA-B52-restricted peptide-specific interferon-gamma release and lytic activity and recognized endogenously processed antigen.5. These studies demonstrate that CD8+ cytotoxic T-lymphocytes specific for mycobacterial and protozoal antigens are induced during natural infections in humans. The identification of these T-cells endorses current strategies to develop cytotoxic T-lymphocyte-inducing vaccines against P. falciparum and M. tuberculosis and highlights candidate antigens for inclusion in subunit vaccines.
Animals↗
Negative regulation of liver regeneration by innate immunity (natural killer cells/interferon-gamma).
BACKGROUND AND AIMS: Hepatic lymphocytes are composed mainly of natural killer (NK) cells and NKT cells, which play key roles in innate immune responses against pathogens and tumors in the liver. This report analyzes the effects of activation of innate immunity by viral infection or the toll-like receptor 3 (TLR3) ligand on liver regeneration. METHODS: The partial hepatectomy (PHx) method was used as a model of liver regeneration. Murine cytomegalovirus (MCMV) infection and the TLR3 ligand polyinosinic-polycytidylic acid [poly(I:C)] were used to activate innate immunity. RESULTS: NK cells are activated after PHx, as evidenced by producing interferon (IFN)-gamma. Infection with MCMV or injection of poly(I:C) further activates NK cells to produce IFN-gamma and attenuates liver regeneration in the PHx model. Depletion of NK cells or disruption of either the IFN-gamma gene or the IFN-gamma receptor gene enhances liver regeneration and partially abolishes the negative effects of MCMV and polyI:C on liver regeneration, whereas NKT cells may only play a minor role in suppression of liver regeneration. Adoptive transfer of IFN-gamma +/+ NK cells, but not IFN-gamma -/- NK cells, restores the ability of polyI:C to attenuate liver regeneration in NK-depleted mice. Finally, administration of polyI:C or IFN-gamma enhances expression of several antiproliferative proteins, including STAT1, IRF-1, and p21cip1/waf1 in the livers of partially hepatectomized mice. CONCLUSIONS: Our findings suggest that viral infection and the TLR3 ligand negatively regulate liver regeneration via activation of innate immunity (NK/IFN-gamma), which may play an important role in the pathogenesis of viral hepatitis.
Adoptive Transfer↗
Radio-detoxified endotoxin activates natural immunity: a review.
It is well demonstrated that serial endotoxin injections produce endotoxin tolerance and elevate the natural immunity/resistance. However, such injections may also have harmful effects such as high fever, hypotension and abortion. For this reason endotoxin (LPS) injections are not suitable to enhance nonspecific resistance in endotoxin-sensitive species like man. Various techniques have been designed (physical, chemical, etc.) for the detoxification of endotoxins while the beneficial effects are maintained. Perhaps one of the best detoxification techniques is the treatment with ionizing radiation. The irradiation of LPS with 60Co (150 kGy) decreased its toxicity in a dose-dependent manner. Such radio-detoxified endotoxin (RD-LPS) preparations show decreased toxicity whereas the beneficial effects were preserved. Irradiation causes marked chemical alterations in LPS, such as a decrease of glucosamine, ketodeoxyoctonic and fatty acids. A single parenteral RD-LPS injection prevents various forms of shock in experimental animals. This preparation has a membrane-stabilizing effect, and thereby it can prevent the membrane-damaging effect of LPS and of some cytostatic agents. Unlike endotoxin, RD-LPS has little hypotensive effects, and the pretreatment with this preparation can prevent practically all the hemodynamic changes induced by LPS. LPS plays an important role in the pathogenesis of intestinal syndrome of radiation disease, which may be prevented by RD-LPS pretreatment up to 70% in rats. RD-LPS retains the adjuvant activity of LPS, and it serves as a good adjuvant for inactivated virus vaccines. RD-LPS can also evoke the regeneration of the immune system in irradiated animals. The decrease of nonspecific resistance in immunodeficient or immunosuppressed patients is the most important cause of opportunistic infections that may lead to sepsis like in endotoxaemia and pneumonia. Organ transplant recipients commonly die of septicaemia. Antilymphocyte serum (ALS) is used in such patients as an immunosuppressant. The augmentation of natural resistance and the induction of endotoxin tolerance are of major significance in such patients. In ALS-treated rats RD-LPS induces also tolerance against the lethal dose of LPS. This demonstrates that in spite of the suppressive effect of ALS on T-lymphocytes the induction of LPS tolerance (the enhancement of natural resistance) remains normal. Facultative pathogenic organisms may flourish and cause disease when specific and nonspecific resistance is impaired. RD-LPS can produce a significant proliferation of lymphoid cells in germ-free animals which are immunodeficient. Many other beneficial effects are preserved by RD-LPS preparations, such as the activation of macrophages and of the reticuloendothelial system and antitumor activity. On the basis of these favorable experimental results, RD-LPS has been tested on 350 surgical patients suffering from gastrointestinal tumors, patients suffering from acquired immunodeficiency syndrome (AIDS) and cancer patients treated with CYSPLATIN. RD-LPS treatment prevented sepsis and activated the bone marrow function in these patients.
Journal Article↗
Quantitative studies of natural immunity to solid tumours in rats. NK activity in animals with primary or transplanted spontaneous tumours.
Natural killer (NK) cell activity was measured in a quantitative 6 h chromium release assay using sarcoma MC7 cells as targets. The total NK lytic activity present in the spleen and blood of tumour-bearing animals was compared with the corresponding values for age/sex/parity-matched animals. Rats with primary spontaneous tumours in the breast or subcutaneous sites showed normal levels of NK activity, while rats with primary spontaneous kidney tumours had elevated NK activity, the degree of augmentation being greater with increasing tumour size. A similar elevation of NK activity was generally found in animals with large, transplanted, spontaneous or chemically-induced tumours. This augmentation could only detected when total lytic activity was considered: when NK activity was measured merely on a cell-for-cell basis, it often appeared to be depressed in such animals, in agreement with previous reports. However, with one rapidly metastasizing spontaneous tumour, a real depression of both spleen and blood NK activity was found. Small inocula of cells from non-immunogenic spontaneous mammary tumours or from other non-immunogenic spontaneous tumours caused no early increase in systemic NK activity when injected into the mammary pad, a site where spontaneous tumours frequently arise. However, cells from one immunogenic spontaneous tumour and 2/3 immunogenic chemically-induced tumours did occasionally stimulate significant early increases in NK activity when placed at this site. Early changes in peritoneal exudate NK activity were also investigated using small inocula of these tumours injected intraperitoneally. Augmentation of NK activity occurred with a 3-fold greater frequency following inoculation with immunogenic tumour cells than with non-immunogenic cells in this system. It can be concluded from these studies that: (1) spontaneous tumours do not selectively arise in members of an inbred strain with subnormal NK activity; (2) most large tumours in rats stimulate rather than depress NK activity; (3) early boosting of NK activity by small inocula of tumour cells placed in the mammary pad does not occur with non-immunogenic spontaneous tumours; (4) early boosting of NK activity in the peritoneal site does occur with non-immunogenic tumours, but with a very low frequency. The latter findings suggest that developing spontaneous tumours are unlikely to stimulate the NK system, and emphasize the importance of using syngeneic, spontaneous tumours for studying tumour-host relationships in animals.
Animals↗
Hypothalamic control of certain aspects of natural immunity in the mouse.
Electrothermocoagulation (ETC) of the individual nuclei of the median region of the hypothalamus (MH) in the C57BL/6 mouse leads to a significant reduction in the cytotoxic activity of natural killer cells (NK) and the number of large granular lymphocytes (LGL) compared with intact or sham-operated controls. This effect, however, is less than that observed after simultaneous destruction of all MH nuclei. By contrast, no significant change in NK activity was noted after ETC of the anterior (AH) or posterior (PH) regions. Diminution of NK activity due to nuclear MH destruction is not an outcome of the change in adenohypophysis secretion provoked by hypothalamic lesion. Natural cytotoxic activity was markedly increased after ETG located either in AH, or MH, or PH. These results indicate that NK- and NC-mediated immunity is governed by a control mechanism situated in the hypothalamus.
Animals↗
Genetic control of natural immunity to ecotropic mouse leukemia viruses: production of endogenous immunogen.
Mice of the AKR and C57L strains naturally produced low titers of antibody against ecotropic murine leukemia viruses (MuLV). The F1 hybrid of these strains produced anti-MuLV antibody in higher titer than mice of either of the parental strains. Progeny of the genetic backcross C57L X (AKR X C57L)F1 segregated for the production of infectious ecotropic MuLV (according to the Akv-1 and Akv-2 loci) and for the production of antibody against MuLV. All mice that contained infectious MuLV produced anti-MuLV antibodies. Thus, the persistent production of high-titered MuLV in these mice did not result in immunological tolerance towards viral antigens. In contrast, mice that did not contain infectious MuLV could be separated into antibody-producing and -nonproducing classes. The absence of detectable antibody to MuLV in an individual mouse was invariably associated with a virus-free phenotype. Antibody against MuLV reacted primarily with p15 and gp70 proteins of the viral envelope. It was concluded that overt production of endogenous ecotropic MuLV served as a major immunogenic stimulus for the production of anti-MuLV antibody in these mice.
Animals↗