Search PubMed⌕ Search

Biomedical subjects

G L Ada

Publications and source records attributed to G L Ada.

At least 55 records · Page 3Linked to original sources
PubMed1985

Influenza virus-specific T cells fail to reduce lung virus titres in cyclosporin-treated, infected mice.

Cyclosporin A (CsA) inhibited the function(s) of transferred influenza-specific K,D-restricted cytotoxic T cells, which led to clearance of virus in the lungs of influenza virus-infected mice. CsA had no effect on the migration of the transferred cells to the lungs. The pattern of migration and the number of cells recovered from the lungs were similar when cells were transferred into normal, untreated, infected or CsA-treated, infected mice. CsA had no effect on the in vitro expression of cytotoxic activity by the K,D-restricted cytotoxic T cells. These findings strongly suggest that the in vivo clearance of influenza virus by K,D-restricted cytotoxic T cells involves a lymphokine mechanism.

Animals↗
PubMed1985

Sensitization of mice with wild-type and cold-adapted influenza virus variants: immune response to two H1N1 and H3N2 viruses.

Two A strain influenza viruses, A/Hong Kong/123/77 (A/HK/123/77) (H1N1) and A/Queensland/6/72 (A/Qld/6/72) (H3N2), and the two cold-adapted reassortants which possess the surface antigens of these strains (CR35 and CR6, respectively) were tested for their ability both to induce primary cytotoxic T-cell (Tc cell) responses in mice and to sensitize mice for a second Tc cell response when challenged with a distantly related A strain virus, A/Shearwater/72 (H6N5). After intranasal inoculation, A/Qld/6/72 replicated to higher titers in the lung (1 to 2 log10 50% egg infective doses) than did A/HK/123/77 or either of the reassortants. A/Qld/6/72 induced higher Tc cell responses in the lung than did CR6, and both were more effective than either A/HK/123/77 or CR35 in this respect. When similar doses (10 or 10(3) hemagglutinin units) of each virus were injected intravenously into mice and the spleens were tested for Tc cell activity 6 days later, both A/Qld/6/72 and CR6 were ca. 100-fold better at inducing a primary Tc cell response than A/HK/123/77 or CR35. In contrast, the H1N1 and H3N2 viruses gave rather similar anti-hemagglutinin antibody titers (after intravenous injection) and delayed-type hypersensitivity reactions (after subcutaneous injection). If mice were primed with a low dose of these viruses (10(4) 50% egg infective doses intranasally), A/Qld/6/72 and CR6 were more effective than A/HK/123/77 or CR35 at sensitizing for a secondary Tc cell response when challenged with A/Shearwater/72, but if larger doses were given either intranasally (10(6) 50% egg infective doses) or intravenously (10 to 10(3) hemagglutinin units), all viruses sensitized the mice equally well, despite the fact the A/Shearwater/72 gives a poor primary Tc cell response in mice. Thus, the viral glycoprotein antigens can be important in determining the immunogenicity of the virus and, particularly, the class I antigen-restricted Tc cell response of the host.

Animals↗
PubMed1984

Macrophage procoagulant-inducing activity of influenza-specific effector T cells.

Three different types of immune mouse T cells raised against influenza virus were tested for their ability to induce the formation of macrophage procoagulant activity (MPCA) by a macrophage cell line PU5-1.8. They were primary spleen cells, taken 6 days after iv injection of virus, spleen cells from sensitized mice challenged with virus and cultured in vitro for 5 days (secondary cultured cells), and cloned T cells. With the last two preparations, some samples were K,D region restricted, Lyt 2+, and had cytotoxic activity; other samples were I region restricted, Lyt 2-, and were not cytotoxic. Samples of a concanavalin A-activated T-cell supernatant which regularly induced MPCA with PU5-1.8 cells were included as controls in all assays. A few batches of T-cell preparations failed to induce MPCA production, however, most batches were active. Two sources of variation were detected: first, the number of cells (5- to 150-fold) needed to induce a certain level of MPCA, as measured by the decrease in clotting time; and second, the value of the gradient of the cell dose response. Both K,D- and I-region-restricted cells, either as cloned or secondary cultured cells, could induce MPCA but with the latter preparation, I-region-restricted cells were the better inducers by about eightfold. T cells tested in this way were also injected into mouse hind footpads and their ability to mediate delayed-type hypersensitivity (DTH) reactions was measured. A positive but not proportional correlation between the abilities to induce MPCA and mediate DTH activity for primary spleen cells was found, but this was not generally observed with cultured or cloned T cells.

Animals↗
PubMed1984

The acquisition of anti-influenza virus activity by macrophages.

Exposure of resident peritoneal macrophages or thioglycollate-induced macrophages (TG-Mø) to influenza or Sendai virus-infected spleen cell culture supernatants (MAS) resulted in macrophage activation. When normal resident macrophages were used as effector cells, both infected P815 and L929 cells were lysed in the presence of MAS. MAS-activated TG-Mø also lysed influenza virus-infected L929 cells. Histocompatibility between effector cells and target cells was not required for target cell destruction. The effector cells were plastic-adherent, phagocytic and Ia-. MAS-activated macrophages were also resistant to influenza virus infection in vitro. Both infectious and non-infectious preparations of influenza or Sendai virus preparations were effective at generating MAS. The mediator(s) which renders macrophages to become cytotoxic and resistant to infection was acid-stable, heat-labile (56 degrees C, 30 min; or 100 degrees C, 5 min), and the activity was neutralized by sheep antimouse type 1 interferon (IFN).

Animals↗
PubMed1984

Alloreactive cytotoxic T lymphocytes lyse syngeneic influenza-infected tumour cell targets.

Spleen cells from C57BL/10(H-2b) mice, when stimulated in vitro to Kk alloantigens, lysed syngeneic influenza A virus-infected tumour cell targets but not uninfected or vaccinia- or Sendai virus-infected targets. Peritoneal macrophage targets infected with influenza virus were not lysed. Lysis of H-2k targets and EL4-A influenza virus-infected targets was abrogated by treatment of effectors with anti-Thy 1.2 plus C and anti-Lyt 2 plus C but not by anti-Lyt 1 plus C or anti-GM-1, a natural killer cell-specific, monoclonal antibody plus C. Cold target inhibition experiments indicated that one and the same population of Tc cells see H-2Kk and H-2b plus influenza virus. Sensitization of C57BL/10 mice to Kk in vivo did not potentiate virus clearance from lungs. The data are discussed in relation to observed Ir gene effects and variation and modulation of H-2 antigens on tumour cells.

Animals↗
PubMed1984

The sensitization of mice with a wild-type and cold-adapted variant of influenza A virus. II. Secondary cytotoxic T cell responses.

Reductions in virus titres and the generation of enhanced cytotoxic T cell (Tc) activity in the lungs of mice primed either with a wild-type, parental (H2N2) influenza virus, A/AA/6/60, or a cold-adapted variant A/AA/6/60-ca and challenged 6 weeks later with a H1N1 A/WSN virus showed that both H2N2 viruses could sensitize the mice. A comparison of graded sensitizing doses of each virus showed that inocula of 10(6) tissue culture infective doses (TCID50) of the ca-variant or 10(3) TCID50 of the wild-type virus gave similar results. The spleens and lungs of normal mice were found to contain similar levels (circa 1/10(5) cells) of precursor Tc cells and the level in the lung did not increase 2 days after intranasal (i.n.) inoculation of A/WSN virus. Two and 6 weeks after priming mice with 10(5) TCID50 of either virus, the lungs contained about a 20-fold increase in the precursor Tc cell frequency. In contrast, sensitization with a sub-lethal dose of a mouse-adapted A/WSN virus caused a 100-fold or greater increase. Sensitization of mice with the parental but not the ca-variant virus caused an increase in frequency of precursor Tc cells in the spleens of the sensitized mice and this might reflect the very low level of replication of the ca-variant virus in the mouse lung.

Animals↗
PubMed1983

Protection of mice against influenza virus infection: enhancement of nonspecific cellular responses by Corynebacterium parvum.

Groups of C57BL/6J, BALB/c, BALB/c, nu+/nu+ mice, inoculated intranasally with Corynebacterium parvum (350 micrograms/mouse) were protected from death by an otherwise lethal dose of influenza virus, A/WSN (H1N1) inoculated 3 days later. The lungs of C. parvum-treated, virus-infected C57BL/6J, BALB/c, or BALB/c nu+/nu+ mice contained significantly less infectious virus than did controls, and this reduction was apparent as soon as 24 hr after virus inoculation. The maximum protective effect correlated with increased lung interferon levels. C. parvum treatment caused an increase in the lung cell number which was in part due to a large increase (ca. 10-fold) in macrophage content, and the natural killer cell activity was also enhanced, though not as markedly as occurred 3 days after infection. Most (greater than 85%) of the resident macrophages in normal lungs were susceptible to infection by virus (as indicated by hemadsorption), whereas most of those recovered from the lungs of C. parvum-treated mice resisted infection. Despite the increase in macrophage content, the level of specific immune responses to infection, such as cytotoxic T-cell activity, DTH reaction, and antihemagglutinin antibody, remained unchanged by C. parvum treatment so that the major if not only effect of this treatment was on the level of the less-specific components of the immune system.

Adjuvants, Immunologic↗
PubMed1982

The generation of 'cytotoxic' macrophages in mice during infection with influenza A or Sendai virus.

Injection of infectious but not of non-infectious influenza A virus or of infectious or non-infectious Sendai virus intraperitoneally into mice induces the generation of plastic-adherent cells that are able to effect release of 51Cr from labelled virus-infected target cells but not from labelled, uninfected cells. Their activity is greatly diminished by exposure to silica or carrageenan but not by anti-Thy 1 antibody and complement treatment. Similarly, the activity of the cell preparation cannot be explained by contamination with natural killer or 'K' cells. Thus, the effector cells were identified as macrophages and for convenience are called 'cytotoxic macrophages'. The maximum cytotoxic activity was recovered from the peritoneal cavity 5 days after virus injection and declined thereafter. Although the effector cells are cross-reactive in that cells activated by an influenza A strain virus lyse target cells infected with the same or other A strain viruses or with Sendai virus, there is preferential lysis of cells infected with the homologous virus. The action of the effector cells is not h-2-restricted. Preliminary experiments showed that similar effector cells can be recovered from the lungs of mice 5 days after intranasal inoculation of infectious influenza virus, so they may contribute to the host control of the disease.

Animals↗
PubMed1982

In vivo collaboration between precursor T cells and helper T cells in the development of delayed-type hypersensitivity reaction to influenza virus in mice.

Nude, athymic mice do not mount a delayed-type hypersensitivity (DTH) response to influenza A virus. A single injection of T helper cells (gamma-irradiated, 2-day immune spleen cells) or three injections over 3 days of a concanavalin-A-activated spleen cell supernatant to virus-sensitized nude mice resulted in a 'normal' DTH response when the mice were challenged with the virus. It was previously shown that the cells responsible for the reaction were T cells and required I-region compatibility. Injection of T helper cells into normal mice did not affect the level of the subsequent DTH response. However, injection of such cells into mice pretreated with anti-thymocyte serum (ATS) restored the ability of the mice to mount a DTH response. The results show that (1) nude mice contain precursor T cells for influenza virus antigen; (2) an I region-restricted response can be generated in the absence of a thymus; and (3) in vivo collaboration between DTH T-cell precursors and helper T cells can be shown to occur in congenitally nude mice and ATS-treated mice.

Animals↗
PubMed1982

Humoral and cellular responses of mice to infection with a cold-adapted influenza A virus variant.

The serum antibody response and four different cellular immune responses (cytotoxic T cells, delayed-type hypersensitivity T cells, natural killer cells, and cytotoxic macrophage levels) induced in CBA/H mice were measured at different times after intranasal inoculation of a cold-adapted (ca) variant of influenza A virus, influenza virus A/Ann Arbor/6/60-ca, or the parental virus, influenza virus A/Ann Arbor/6/60. At the highest dose of virus inoculated (5 log10 50% tissue culture infective doses), all four cellular responses reached high levels in the lungs of both groups of mice, and serum antibody titers were detected on day 20 after inoculation of either virus. However, whereas extensive replication of the parental virus occurred in the mouse lungs, very limited replication of the ca variant was observed. Macroscopically, infection with the parental virus caused gross lung damage, whereas such damage was almost absent in mice inoculated with the ca variant. Inoculation of 2 to 5 log10 50% tissue culture infective doses of the parental virus induced high cytotoxic T-cell responses, whereas only the highest dose of the ca variant caused a clearly significant cytotoxic T-cell response. As an inoculum of 5 log10 50% tissue culture infective doses of the ca variant caused a substantial primary immune response without appreciable lung damage, the avirulence of the ca variant may be primarily related to its limited ability to replicate productively in mouse lungs.

Animals↗
PubMed1982

Host factors important in immune surveillance against tumours.

The nonspecific and specific arms of the immune response are described. The nonspecific components consist of three cell types - macrophages, natural killer and killer cells - and the specific components are antibody produced by B lymphocytes and regulatory and effector T lymphocytes. The evidence suggests that a surveillance system does operate, since at least some tumours are contained. Malignant lesions are more common in unselected autopsies and surgical biopsies of noncancer patients compared with the observed rate of clinical cases; and spontaneous cures of cancer do occur. There is general agreement that surveillance of all types of tumours by the specific components of the immune response does not occur; but there is direct evidence from some model systems and correlations from the incidence and class of tumours which arise in germ-free athymic mice, in immunosuppressed patients with transplants and in immunodeficient patients that the specific immune response, particularly by effector T cells, may control the expression of some tumours of lymphoreticular cells. Such surveillance may be superimposed on a more general system which is mediated by the nonspecific elements. One possible way of increasing the efficiency of the system would be to provide some of the soluble mediators of activated effector cells such as macrophages and T cells. Thus, administration of interferon has had some success, and there is a case for further purification of these and other lymphokines and monokines for administration to patients.

Antibody Formation↗
PubMed1981

Effect of helper T cells on the primary in vitro production of delayed-type hypersensitivity to influenza virus.

Injection of mice with infectious or noninfectious preparations of influenza virus induces the formation of T cells which, when added to primary tissue cultures of normal spleen cells exposed to influenza virus, enhance the generation of effector T cells which mediate delayed-type hypersensitivity (DTH) reaction. The enhancing cells possess Thy-1 and Ly-1 surface antigens are radioresistant and antigen-specific. If infectious virus was used to stimulate the DTH response in vitro, help was delivered whether homologous or heterologous A strain influenza virus was used to generate the helper T cells (Th) in vivo. In contrast, only Th cells generated using homologous virus were effective if noninfectious virus was used to stimulate the DTH response in vitro. Peak helper activity occurred 2 d after virus injection and the Th cells were only effective if added to the primary cultures within 24 h after addition of the stimulating antigen. The Th cells enhanced the generation of both classes of DTH effector cells, i.e., those that are Ly-1 positive and IA-subregion restricted and those that are Ly-2,3 positive and K,D-region restricted. The activity of the Th cells was found to be IA-subregion restricted and this was shown to operate at the level of the stimulator cells so that the delivery of help to the responder cells was not H-2 restricted. The possibility that the Th cells might be a precursor to the Ly-1 positive IA subregion-restricted DTH effector cells is discussed.

Animals↗
PubMed1981

Induction of natural killer cells during murine influenza virus infection.

Cells which are cytotoxic for both virus-infected and uninfected target cells can be recovered from the spleens of mice injected with either infectious or non-infectious influenza A virus. Peak activity doccurs at 1-2 days and decreases to low levels by day 6. The effector cells are insensitive to anti-Thy 1 antibody and complement treatment, are not H-2 restricted, do not adhere to plastic and are unaffected by silica or carrageenan. in this sense and in the pattern of susceptibility to lysis of a variety of cultured cell lines, these effector cells have the properties of natural killer (NK) cells and are referred to as such. They are present to an increased level of activity in nude (nu+/nu+) mice and to a low level of activity in beige (bg+/bg+) mice, but upon injection of virus there is a significant increase in activity in both hosts. Such cells were also recovered from the lungs of mice infected intranasally with a lethal or sublethal dose of virus. In the former case, maximum activity was reached 2 days post infection and the activity remained high until death; in the latter case, peak activity was reached 4 days after virus inoculation and by day 11 the activity had decreased to pre-infection levels. After intranasal inoculation of influenza virus, both beige mice and their heterozygous littermates contained similar levels of infectious virus in their lungs. However, this result does not eliminate the possibility that these cells may help to limit virus infection.

Animals↗
PubMed1981

Roles of influenza virus infectivity and glycosylation of viral antigen for recognition of target cells by cytolytic T lymphocytes.

The influenza virus strains A/JAP (H2N2) and the recombinant strain A/JAP/BEL (H2N1) were tested before and after UV-light inactivation for their ability to sensitize target cells for cytotoxic T-cell lysis (CTL). Infectious preparations were efficient sensitizers for both specific and cross-reactive CTL, exposure of the cells to even low doses of virus resulting in almost maximum susceptibility. When inactivated, however, A/JAP/BEL was about 10 times more efficient than A/JAP at sensitizing the cells for specific CTL; neither sensitized the cells for cross-reactive CTL. Thus factors other than or in addition to a cleaved haemagglutinin (HA) molecule are important in the fusion of the virus with the cell membrane. Target cells which were infected with virus and exposed to different concentrations of tunicamycin, which inhibits glycosylation, became susceptible to CTL by both specific and cross-reactive effector cells through to a lesser extent than controls. Infected cells showed both strong haemadsorption and cocapping of the HA with K, D gene products. Both of these properties were greatly diminished in the presence of even low concentrations of tunicamycin. Analysis of binding studies using labelled monoclonal anti-HA IgG showed that, in the presence of tunicamycin, the total amount of HA expressed at the cell surface was not reduced, but there was an increase in the dissociation constant of the reaction between expressed HA and antibody. This latter finding was thought to reflect a conformational change in the HA antigen, which might be the reason for the reduced susceptibility to CTL.

Animals↗
PubMed1981

The inductive requirements for the primary in vitro generation of delayed-type hypersensitivity response to influenza virus in mice.

Effector T cells (Td) which mediate delayed-type hypersensitivity reactions to influenza A virus can be generated in tissue culture using normal mouse spleen cells as the responder population. Addition of helper T cells enhances but is not essential for the production of Td cells. Both Ly 1 positive, I region restricted and Ly 2,3 positive, K,D region restricted effector cells are generated. Treating the responder cell population with anti-Ly 1 or anti-Ly 2,3 antibodies and complement prevented the generation of both classes of effector T cell, suggesting that the precursor Td cells are Ly 1,2,3 positive. Effector cells which are specific for the homologous virus or cross-reactive within the A strains of influenza virus are produced, as has been found previously in in vivo experiments. Depleting the cell population of phagocytic and plastic adherent cells resulted in a failure to produce Td cells, which showed a requirement for macrophage-like cells as accessory cells in the primary in vitro generation of Td cells. A variety of cells, such as peritoneal exudate cells, mitogen stimulated blasts or L929 fibroblast cells could serve as stimulator cells. Only Ly 2,3 positive, K,D region-restricted Td cells were produced when L929 cells were used as they lack I region-coded surface antigens. The I region-restricted DTH response was mapped to the IA sub-region of the H-2 gene complex.

Animals↗