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.

Specificity, Ly phenotype, and H-2 compatibility requirements of effector cells in delayed-type hypersensitivity responses to murine influenza virus infection.

Delayed-type hypersensitivity (DTH) to infectious and to noninfectious (UV-irradiated) influenza A viral preparations was measured in mice by the increase in footpad swelling 24 h after injection of the eliciting virus. DTH mice sensitized with noninfectious virus was elicited only by virus that shared hemagglutinin specificity with the sensitizing virus, whereas footpad injection of a given A-strain virus (A/WSN) could elicit DTH in mice sensitized with a variety of infectious A-strain viruses, including some not sharing hemagglutinin or neuraminidase specificities. The effector T cells generated in mice sensitized with either form of virus were sensitive to anti-Ly 1.1 serum and complement, but not to anti-Ly 2.1 serum and complement. Adoptive transfer of DTH was H-2 restricted. With spleen cells from mice sensitized subcutaneously with either infectious or noninfectious virus, sharing of the IA region was both necessary and sufficient for successful transfer to occur. Cells recovered from infected mouse lungs, and secondary effector cells generated in vitro transferred DTH if injected into the footpad with the eliciting virus. The effector cells had the Ly 1 phenotype, and, in both cases, the cells were I restricted. These results contrast with earlier findings that transfer of DTH to lymphocytic choriomeningitis virus infection required K- or D-region sharing between donor and recipient. Thus, the earlier hypothesis that multiplying infectious agents such as viruses would "alter" K- or D-coded, rather than I-coded, structures is not generally correct.

Antibody-mediated enhancement of hormone activity.

The enhancement of hormone activity by antibodies has been known for many years; however, investigation into the molecular basis of the phenomenon has only recently begun. A number of mechanisms for this enhancement, including "buffering" or slow release, bivalency and Fc region, and conformational and receptor "restriction" effects, have been documented or proposed. The availability of panels of monoclonal antibodies of distinct combining site specificity have aided in these studies and contributed substantially to our understanding of hormone-receptor interactions.

Prospects for HIV vaccines.

This article initially discusses the types of responses elicited by infectious agents, such as viruses and the role of each response in preventing, limiting, and clearing the infection. An important response is the generation of immunological memory, in both the B and T cell compartments. Generally, attenuated viral vaccines have been highly successful at inducing long-lived immunity but our understanding of the reasons for this comes from the study of model systems, such as murine influenza virus infections. Specific antibody may largely prevent infection and specific cytotoxic T cells and antibody-dependent cell cytotoxic reactions are the main mechanisms for clearing viral infections. Recent evidence shows that for some months after infection by HIV, a strong cytotoxic T (Tc) cell response occurs in infected, asymptomatic individuals; these cells are continuously generated by HIV-infected stimulator cells that most likely also serve as target cells in vivo. A low level of specific antibody is also formed and a number of reasons are listed to explain why HIV escapes antibody-mediated neutralization and infects cells expressing CD4 receptors. Cells of the macrophage/monocyte lineage are also infected and these express Fc and complement receptors; there is the strong possibility that infection of these cells occurred following the formation of complexes of infectious HIV with antibody to the surface antigen and attachment of complement components. The continuous presence of activated Tc cells that, in contrast to many other viral diseases, does not clear the infection strongly suggests that foci of infected cells sequestered from or resistant to immune control become established. These secrete virus that infects other (stimulator) cells.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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).

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.

Modern approaches to vaccine development with special reference to the needs of developing countries.

Vaccination has proved to be one of the most effective public health measures to control infectious diseases. The eradication of smallpox by world-wide vaccination represents one of mankind's greatest achievements. Despite the availability of vaccines to control many diseases, they are generally under-used in many developing and some developed countries. However, there are many diseases for which current vaccines are inadequate or vaccines cannot be prepared using conventional approaches. This article describes the new approaches which are now available and are being used extensively to develop new vaccines against viral, bacterial and parasitic diseases. Success has already been achieved in a few cases and the prospect for others is encouraging. In addition, progress is being made to develop vaccines to control human fertility as this development is seen to complement the control of infectious diseases.

The ideal vaccine.

The ideal vaccine is discussed under three headings. 1. The major requirements of the vaccine. This includes primarlly safety and efficacy and a number of other desirable features if the vaccine is to control a disease of global importance. These include cost, easy administration (e.g. orally), thermal stability, multivalency and long-lived immunlty 2. The nature and persistence of the immune responses which, as judged by model systems, are probably generated by the most effective viral vaccines in current human usage. 3. Approaches for developing future 'simplified" vaccines with similar levels of safety and efficacy so that these objectives are achieved.