LPS regulation of the immune response: suppression of immune responses to orally administered T-independent antigen

The regulation of immune responses to gastrically administered TI antigens has been investigated, and the characterization of a regulatory cell population has been performed. Intragastric administration of TNP-haptenated homologous erythrocytes (TNP-MRBC) induced splenic IgM anti-TNP PFC responses in LPS nonresponsive C3H/HeJ mice that were higher than those in LPS-responsive C3H/HeN mice and similar to those noted in athymic (nu/nu) C3H/HeN animals. The simultaneous intragastric administration of LPS with TNP-MRBC augmented immune responses in a manner similar to that previously reported for parenterally administered LPS and antigen. Further, LPS-induced augmentation of TNP-MRBC responses was greater in athymic mice. These findings were substantiated using in vitro spleen cultures. Intragastric challenge with a 2nd TI antigen, TNP-LPS, induced approximately 8-fold higher splenic anti-TNP PFC responses in athymic C3H/HeN mice compared with those in euthymic littermates. By admixture of B and T cell populations, it was demonstrated that the host responsiveness to TNP-LPS was negatively regulated by suppressor cells. Suppressive activity resided in a Thy 1.2-bearing, irradiation-resistant, nylon wool-nonadherent cell population. These cells could be demonstrated in spleen and Peyer's patches from young or old LPS-responsive C3H/HeN mice, but not in tissues from LPS nonresponsive C3H/HeJ mice. The specificity of the regulator cells was not limited to TNP-LPS responses, since immune responsiveness to another TI antigen, TNP-dextran, was also under the control of this cell population. These studies confirm the TI nature of TNP-MRBC and indicate that immune responses to gastrically administered antigens such as TNP-LPS, TNP-dextran, and possibly TNP-MRBC are negatively regulated by a suppressor T cell population. A role for endogenous LPS in the generation of regulator cells and the effect of these cells on host responses to gut-derived antigens is discussed.     

Measles virus-induced suppression of lymphocyte proliferation

The mechanism by which measles virus induces immunosuppression was investigated using an in vitro system employing phytohemagglutinin (PHA)-induced human peripheral mononuclear cell (PBMC) proliferation. At a multiplicity of infection of 1.0 or greater measles virus significantly inhibited (45%) the proliferation of PBMC. This inhibition was not due to an alteration in the kinetics of proliferation. PHA-stimulated PBMC were then infected with measles virus for 72 hr and irradiated (3200 rad) to prevent further proliferation. These infected, irradiated PBMC when added to fresh autologous PBMC caused significant inhibition of lymphoproliferation over a wide range of infected:fresh cell ratios (maximum inhibition seen at a 1:1 ratio, 85% inhibition). Virus recovered from the irradiated, infected cells was 100-fold lower than the virus titer needed to cause inhibition by direct addition of measles virus. However, antibody to measles virus reversed the inhibition. Virus-free supernatant fluids from the infected irradiated cells caused immunosuppression of the PHA response. This immunosuppressive material induced by the measles virus was maximally produced after 72 hr and did not appear to require viral replication. This factor was not prostaglandin E or interferon-alpha or -gamma. The production of such suppressive factors during viral infection may explain some of the profound immunosuppression seen in situations in which little or no infectious virus can be detected.     

Chronic bacterial osteomyelitis suppression of tumor growth requires innate immune responses

Clinical studies over the past several years have reported that metastasis-free survival times in humans and dogs with osteosarcoma are significantly increased in patients that develop chronic bacterial osteomyelitis at their surgical site. However, the immunological mechanism by which osteomyelitis may suppress tumor growth has not been investigated. Therefore, we used a mouse model of osteomyelitis to assess the effects of bone infection on innate immunity and tumor growth. A chronic Staphylococcal osteomyelitis model was established in C3H mice and the effects of infection on tumor growth of syngeneic DLM8 osteosarcoma were assessed. The effects of infection on tumor angiogenesis and innate immunity, including NK cell and monocyte responses, were assessed. We found that osteomyelitis significantly inhibited the growth of tumors in mice, and that the effect was independent of the infecting bacterial type, tumor type, or mouse strain. Depletion of NK cells or monocytes reversed the antitumor activity elicited by infection. Moreover, infected mice had a significant increase in circulating monocytes and numbers of tumor associated macrophages. Infection suppressed tumor angiogenesis but did not affect the numbers of circulating endothelial cells. Therefore, we concluded that chronic localized bacterial infection could elicit significant systemic antitumor activity dependent on NK cells and macrophages.     

Modulation of nonspecific defence mechanisms and specific immune responses after suppression induced by xenobiotics

Summary In the present study the possible modulation of nonspecific defence mechanisms and specific immune responses after suppression induced by oxytetracycline, oxolinic acid, and lindane – an organochlorine pesticide, were analysed in carp. Modulation was attempted using a natural immunostimulant, dimerized lysozyme (KLP-602, Nika Health Products, USA). Five groups of fish were given intraperitoneal injections of selected doses of the drugs on days 7, 6 and 4 before immunization with Yersinia ruckeri vaccine. At each injection, group I was also given 10 mg kg⁻¹ oxytetracycline, group II 10 mg kg⁻¹ oxolinic acid, group III 10 mg kg⁻¹ lindane, group IV was only immunized, and group V was injected with PBS. The immunostimulant was added in food before and after immunization. The study showed the immunotoxic effects of oxytetracycline, oxolinic acid and lindane; dimerized lysozyme corrected the defence mechanisms suppressed by these drugs and chemicals. The immunostimulatory effects of dimerized lysozyme were better when added before rather than after fish immunization.     

Measles virus, immune control, and persistence

Measles remains one of the most important causes of child morbidity and mortality worldwide with the greatest burden in the youngest children. Most acute measles deaths are owing to secondary infections that result from a poorly understood measles-induced suppression of immune responses. Young children are also vulnerable to late development of subacute sclerosing panencephalitis, a progressive, uniformly fatal neurologic disease caused by persistent measles virus (MeV) infection. During acute infection, the rash marks the appearance of the adaptive immune response and CD8(+) T cell-mediated clearance of infectious virus. However, after clearance of infectious virus, MeV RNA persists and can be detected in blood, respiratory secretions, urine, and lymphoid tissue for many weeks to months. This prolonged period of virus clearance may help to explain measles immunosuppression and the development of lifelong immunity to re-infection, as well as occasional infection of the nervous system. Once MeV infects neurons, the virus can spread trans-synaptically and the envelope proteins needed to form infectious virus are unnecessary, accumulate mutations, and can establish persistent infection. Identification of the immune mechanisms required for the clearance of MeV RNA from multiple sites will enlighten our understanding of the development of disease owing to persistent infection.     

Measles virus-induced suppression of lymphocyte reactivity in vitro

Measles virus (Edmonston strain B), in various multiplicities of infection, was added to human lymphocytes which were cultured in medium containing fetal bovine serum. Live measles virus was found to cause an almost complete inhibition of [³H]-thymidine incorporation in lymphocytes cultured in the presence of phytohemagglutinin, pokeweed mitogen, tuberculin purified protein derivate (PPD), or allogeneic lymphocytes. Analysis of cell size in the lymphocyte cultures revealed that blast transformation was inhibited as well. Measles virus, inactivated by heat or ultraviolet irradiation, did not cause inhibition. The inhibitory effect of measles virus was only measurable in the initial stages of culture; when added later, i.e., 24 hr before measuring [³H]-thymidine incorporation, it had no effect. The diminished reactivity of measles virus-infected lymphocytes cannot be explained by cytopathologic effects or by altered kinetics of lymphocyte transformation. When lymphocytes were cultured at 39 °C the extent of virus-induced suppression was significantly reduced. Very small amounts of pooled normal human serum, as well as IgG, prepared from the serum of a patient with subacute sclerosing panencephalitis, were able to prevent the inhibitory effect of measles virus.     

Measles virus-induced immune suppression in the cotton rat (Sigmodon hispidus) model depends on viral glycoproteins.

Immune suppression during measles accounts for most of the morbidity and mortality associated with the virus infection. Experimental study of this phenomenon has been hampered by the lack of a suitable animal model. We have used the cotton rat to demonstrate that mitogen-induced proliferation of spleen cells from measles virus-infected animals is impaired. Proliferation inhibition is seen in all lymphocyte subsets and is not dependent on viral replication. Cells which express the viral glycoproteins (hemagglutinin and fusion protein) transiently by transfection induce proliferation inhibition after intraperitoneal inoculation, whereas application of a recombinant measles virus in which measles virus glycoproteins are replaced with the vesicular stomatitis virus G protein does not have an antiproliferative effect. Therefore, in vivo expression of measles virus glycoproteins is sufficient and necessary to induce inhibition of lymphocyte proliferation.     

Macrophage-mediated suppression of immune responses in Toxoplasma-infected mice. III. Suppression of antibody responses to parasite itself

In acute Toxoplasma infection, anti-sheep erythrocytes (SRBC) antibody responses were strongly suppressed in the infected C57BL/6 mice, and the mice produced low titers of only 2-mercaptoethanol (2-ME)-sensitive antibodies but not 2-ME-resistant antibodies. By contrast, the infected BALB/c mice produced much higher titers of both 2-ME-sensitive and -resistant anti-SRBC antibodies than the infected C57BL/6 mice. In anti-Toxoplasma antibody responses, the 2-ME-resistant antibody titers were significantly lower in the infected C57BL/6 mice than in the BALB/c mice in the early phase of infection, suggesting that the suppressive effect of Toxoplasma infection affects antibody responses to Toxoplasma itself as well as to the unrelated antigen, SRBC. A histological study revealed that in the infected C57BL/6 mice, a large number of acid phosphatase-positive, macrophage-like cells infiltrated into the follicles of their spleens, and an involution of follicles occurred in the acute phase of infection. This histological change was not observed in the infected BALB/c mice. The infected C57BL/6 mice, which had the suppressed anti-Toxoplasma antibody responses, made five times as many as cysts in their brains as compared with the BALB/c mice at the fifth week of infection.     

Inhibition of specific immune responses by feeding protein antigens. IV. Evidence for tolerance and specific active suppression of cell-mediated immune responses to ovalbumin.

We studied the effect of a single intragastric administration of ovalbumin (OVA) on the subsequent development of OVA-specific cell-mediated immune (CMI) responses in BDF1 mice. In animals fed OVA 7 days before subcutaneous sensitization with OVA-CFA, we observed a concomitant dose-dependent decrease in both the humoral and CMI responses specific for OVA. The CMI tolerance was found to be antigen-specific when assayed in vivo by ear swelling or in vitro by an antigen-induced T cell proliferation assay because OVA-fed mice responded normally to sensitization with horse gamma-globulin. It was also shown that either spleen or lymph node cells, but not serum, from OVA-fed donors transferred suppression to normal recipients. The transfer was mediated by antigen-specific suppressor T cells (Ts) that appeared to inhibit the induction phase (afferent limb) of the CMI response, since the Ts were only effective when transferred before or shortly after the onset of sensitization.     

Nutrition and immune responses

Clinical and epidemiologic data suggest a causal relationship between nutritional deficiency and infection. Among other factors, impaired immune responses secondary to malnutrition increase susceptibility to infectious illness. Protein-energy undernutrition and deficiencies of iron, zinc, pyridoxine, and other nutrients depress a variety of immunity functions. Cell-mediated immunity, complement system, microbicidal activity of phagocytes, secretory antibody response, and antibody affinity are often decreased. Recent studies have revealed many metabolic and hormone alterations as well as changes in the number and function of lymphocyte subpopulations. Obesity also is associated with impaired cellular immune functions. Dietary factors may play a critical role in host resistance to disease.     

Optimal immune responses: immunocompetence revisited

The function of the immune system of an animal is to provide defence against infection, in order to maximize fitness. Understanding this and, particularly, how limiting resources are traded off between costly immune responses and other physiological demands, is central to properly understanding life-history traits and their evolution. Here, we propose that functional (rather than immunological) measures of immune responses should be used when investigating this. We further suggest that optimal immune responses are context specific, rather than generic; that is, a maximum immune response is not necessarily optimal. The nature of an optimal immune response will depend on the specific circumstances and infection status of the animal. Identifying and understanding such optimality requires that the effects of different immune strategies on fitness be considered.     

Bacterial cyclic beta-(1,2)-glucan acts in systemic suppression of plant immune responses

Although cyclic glucans have been shown to be important for a number of symbiotic and pathogenic bacterium-plant interactions, their precise roles are unclear. Here, we examined the role of cyclic beta-(1,2)-glucan in the virulence of the black rot pathogen Xanthomonas campestris pv campestris (Xcc). Disruption of the Xcc nodule development B (ndvB) gene, which encodes a glycosyltransferase required for cyclic glucan synthesis, generated a mutant that failed to synthesize extracellular cyclic beta-(1,2)-glucan and was compromised in virulence in the model plants Arabidopsis thaliana and Nicotiana benthamiana. Infection of the mutant bacterium in N. benthamiana was associated with enhanced callose deposition and earlier expression of the PATHOGENESIS-RELATED1 (PR-1) gene. Application of purified cyclic beta-(1,2)-glucan prior to inoculation of the ndvB mutant suppressed the accumulation of callose deposition and the expression of PR-1 in N. benthamiana and restored virulence in both N. benthamiana and Arabidopsis plants. These effects were seen when cyclic glucan and bacteria were applied either to the same or to different leaves. Cyclic beta-(1,2)-glucan-induced systemic suppression was associated with the transport of the molecule throughout the plant. Systemic suppression is a novel counterdefensive strategy that may facilitate pathogen spread in plants and may have important implications for the understanding of plant-pathogen coevolution and for the development of phytoprotection measures.     

Genetic analysis of immune suppression

We have analyzed the genetic control of susceptibility to suppression by 1-J⁺, suppressor-T-cell derived factors (TsF) specific for the synthetic polymer L-glutamic acid⁵⁰-L-tyrosine⁵⁰ (GT). GT-TsF activity was measured as specific inhibition of proliferative responses to GT developed in cultures of lymph-node T cells from mice primed with GT complexed to methylated bovine serum albumin (GT-MBSA). These experiments demonstrated that there is no MHC-encoded genetic restriction between donors and recipients of GT-TsF in suppression of proliferative responses. We have also confirmed the observations that mice of the H-2 ^b, H-2 ^d, and H-2 ^khaplotypes can produce GT-TsF, whereas H-2 ^amice do not, and that H-2 ^b, H-2 ^d, and H-2 ^kmice are sensitive to GT-TsF from all producer strains, whereas H-2 ^bmice are not sensitive to GT-TsF from any strain. Analysis of the effect of GT-TsF on responses by mice bearing recombinant haplotypes suggests that at least two genes are required for susceptibility to GT-TsF and that these genes show coupled complementation.Abbreviations used in this paper GAT random linear terpolymer of L-glutamic acid⁶⁰-L-alanine³⁰-L-tyrosine¹⁰ - GAT-MBSA GAT complexed to methylated bovine serum albumin - GATTsF GAT-specific-T-cell derived suppressor factor - GT random linear copolymer of L-glutamic acid⁵⁰-L-tyrosine⁵⁰ - GT-MBSA GT complexed methylated bovine serum albumin - GT-TsF GT, specific, T-cell derived suppressor factor - ³H-TdR tritiated thymidine - Ir gene immune response gene - MBSA methylated bovine serum albumin - MEM minimal essential media - MHC major histocompatibility complex - PFC plaque-forming cell(s) - PPD purified protein derivative of M. tuberculosis H37Ra     

Mechanisms of virus-induced immune suppression

The recent demonstration that the acquired immune deficiency syndrome (AIDS) is caused by a retrovirus that affects humans has given rise to widespread concern about the immunosuppressive properties of viruses in general. A wide variety of viruses have been shown to be able to compromise immune function. Sometimes immunosuppression results from the pathologic processes that viruses are able to induce. In other instances virus-induced immune derangements may themselves be responsible for the onset of pathologic change. In some cases a single infectious viral agent may be able to modulate several immunologic mechanisms simultaneously. This review discusses some of the various complex mechanisms through which viral infections can alter the function of the immune system.     

Reversal of virus-induced immune suppression

We studied the immunosuppressive capacity of splenic lymphocytes from rabbits at different stages of progressive myxosarcoma induced by malignant rabbit fibroma virus (MV). Spleen cells taken from rabbits 7 days after virus inoculation proliferate poorly in response to Con A, and suppress normal responses to the mitogen. Those from animals 11 days after virus injection have recovered partially from MV-induced suppression. Further, their Con A responses are no longer suppressed by day 7 spleen cells. Supernatants from cultures of spleen cells from rabbits given MV 7 days previously suppress both antibody-producing and proliferative responses to unrelated antigens. Comparable supernatants from rabbits receiving MV 11 days before sacrifice neither suppress nor augment such responses. Mixing cells from 7 or 11 day MV rabbits with normal spleen cells gives similar results. When supernatants from spleen cell of rabbits with tumors induced 7 and 11 days previously are mixed, the supernatants from rabbits with 11-day-old tumors inhibit the suppressive capacity of those from animals with 7-day-old tumors. Similarly, mixing spleen cells from rabbits given MV 7 and 11 days previously results in culture supernatants that do not suppress normal antibody and proliferative responses. The ability of cells from rabbits given MV 11 days before to inhibit the effects of cells from rabbits given MV 7 days previously does not involve the production of interferon. Thus, despite progressive tumor burden, immunologic recovery is observed in rabbits 11 days after tumor virus inoculation. One factor in this recovery may be the generation of active inhibitors of virus-induced immunosuppression. Similar mechanisms may apply to recovery of immunologic function in other virus infections as well.     

Orientia tsutsugamushi infection: overview and immune responses

Orientia tsutsugamushi, an obligate intracellular bacterium, was isolated for the first time in 1930. Infections by virulent strains are characterized by fever, rash, eschar, pneumonia, myocarditis, and disseminated intravascular coagulation. Here we review the general aspects of O. tsutsugamushi and immune responses in terms of inflammation, protective immune mechanisms, and immunogenic antigens.     

Macrophage-mediated suppression of immune responses in Toxoplasma-infected mice. I. Inhibition of proliferation of lymphocytes in primary antibody responses

The suppressor cells induced by Toxoplasma infection were shown to be macrophages, since they adhered to plastic, and their suppressive activity in anti-sheep erythrocytes (SRBC) antibody responses was abrogated by treatment with silica or carrageenan, which are selectively cytotoxic for macrophages. The suppressor macrophages strongly inhibited the uptake of tritiated thymidine ( [3H]TdR) by normal mouse spleen cells in the responses to SRBC and Toxoplasma antigens. Supernatant fluids from the suppressor macrophages could not passively transfer the suppressive effect on anti-SRBC antibody responses. Furthermore, when the suppressor macrophages were isolated by a cell-impermeable membrane from normal mouse spleen cells, the antibody responses of normal spleen cells were not suppressed. These results indicate that suppression of antibody responses in Toxoplasma-infected mice is caused by an inhibitory effect of the suppressor macrophages upon proliferation of lymphocytes via direct contact with responder target cells. The suppressive effect of the macrophages was not counteracted by indomethacin, a potent inhibitor of prostaglandin synthesis, or catalase, a catabolic enzyme for hydrogen peroxide (H2O2).