Biomedical subjects
Publications and source records attributed to K L Yap.
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Infection of mice with dengue-4 virus produced a significant, transient immunosuppression of the delayed-type hypersensitivity (DTH) response to sheep red blood cells (SRBC). Suppression was noted on day 3 after infection, was maximal on day 5 and was no longer evident on day 13 after infection. The suppressive effect was transferable to normal mice by viable spleen cells from immune mice but not by immune serum. These cells appeared to be present in the spleens of infected mice as early as day 1 after infection and were still detectable on day 7. No evidence was obtained that suppression was mediated by a soluble factor. Further characterization of the cells which could transfer suppression showed them to be T cells possessing both Ly-1 and Ly-2 surface antigens. These data suggest that there may exist two types of T suppressor cells or that, alternatively, an interaction between Ly-1+ and Ly-2+ cells was required to produce suppression. The significance and implications of these findings are discussed.
This study was designed to determine the role of the sensitization route and the spleen in the development of delayed-type hypersensitivity (DTH) to dengue virus in mice. DTH was measured by footpad swelling response. Strong but transient DTH was produced in cyclophosphamide (CY) pretreated mice sensitized subcutaneously (s.c.) or intravenously (i.v.) with dengue virus type 4. Subcutaneous inoculation of virus in incomplete Freund's adjuvant (IFA) further enhanced the DTH elicited. The time course of DTH generated by s.c. and i.v. sensitization were similar with the peak reactivity seen on day 6 after sensitization. Poor DTH was observed in mice given an i.p. inoculation even when CY and/or IFA were used. Intracerebral (i.c.) inoculation also sensitized mice poorly. Splenectomized mice showed enhanced DTH response when compared to intact mice. In contrast to intact mice, pretreatment of splenectomized mice with CY did not alter the DTH level. Splenectomized mice inoculated s.c. with virus in IFA showed poorer DTH than mice sensitized with virus alone.
The prevalence of human rotavirus enteritis in children admitted to the gastroenteritis ward of the Kuala Lumpur General Hospital was studied in 1982. Human rotavirus in the stool of the patients was detected by enzyme-linked immunosorbent assay. The survey showed that rotavirus enteritis in children were observed throughout the year, with two broad peaks of rotavirus infection occurring around March and September. The lowest incidence was recorded in July, however, no prolonged period of low prevalence of rotavirus enteritis was observed. The average prevalence for the whole of 1982 was 40% of the total diarrhoeal cases. No significant relationship was noted between the prevalence of the disease and rainfall.
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A thermodynamic approach has been used to measure the amount of haemagglutinin and matrix protein expressed at the surface of P815 cells infected for periods between 4.5 and 11 h with either WSN (H0N1) or JAP (H2N2) strains of type A influenza virus. This involved measuring the interaction of different concentrations of labelled (Fab)2 preparations of specific antibody with normal and infected cells. Assuming that one molecule of (Fab)2 bound to one molecule of antigen, values for the number of molecules of antigen/infected cell ranged from 7.6 X 10(5) to 1.7 X 10(7) for haemagglutinin and 1.3 X 10(5) to 1.1 X 10(6) for matrix protein. The ratio of haemagglutinin/matrix protein was lower for WSN-infected cells (1.7) than for JAP-infected cells (10). The same reagents were reacted with three purified A type virions; WSN, JAP and Port Chalmers (H3N2). Each preparation bound anti-matrix protein (Fab)2 though the value for haemagglutinin/matrix protein was much higher (66) than for infected cells and suggested that a virion may have a small number (about 12) of matrix protein molecules exposed though it was not excluded that the matrix protein detected was exposed only on damaged virions. Pre-treatment of infected cells with unlabelled reagent (anti-haemagglutinin) reduced the subsequent binding of the same labelled reagent but not the binding of the labelled matrix protein reagent and vice versa, suggesting that the haemagglutinin and matrix protein were not very close to each other on the cell surface.
A study has been made of the effect of humoral antibody on the generation of specific cytotoxic T cells (Tc) in the spleen or lungs after intravenous injection or intranasal inoculation of infectious influenza virus. Antibody injected before or at the same time as virus inhibited completely the generation of Tc in the spleen. If injected 1 h after virus, the inhibition was reduced by 50%, and little inhibition occurred if antibody was injected 6 h after virus. This suggested that antibody failed to influence Tc generation once infection of stimulating cells had occurred. Antibody injected intravenously 24 h after intranasal inoculation of virus into normal mice did not affect the level of cytotoxic activity present in the lungs, and trace amounts only (less than 1 log10 EID50) could be recovered from the lungs at 6 days. As there is a high titre (greater than 6 log10 EID50) of infectious virus in the lungs of mice 24 h after infection, this represents a very efficient control mechanism. The same protocol carried out with athymic mice gave only a partial clearance (c. 3 log10 EID50) of virus in the lungs. It was suggested that a major role of humoral antibody was to limit infection by the virus, and in this respect it complemented the action of Tc.
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This report examines the requirement for infectious virus in the induction of influenza virus-specific cytotoxic T cells. Infectious influenza virus was found to be highly efficient at generating both primary and secondary cytotoxic T-cell response in vivo. Inactivated influenza virus however, failed to stimulate a detectable cytotoxic T-cell response in vivo even at immunizing doses 10(5)-10(6)-fold higher than the minimum stimulatory dose of infectious virus. Likewise inactivated virus failed to sensitize target cells for T cell-mediated lysis in vitro but could stimulate a specific cytotoxic response from primed cells in vitro. Possible requirements for the induction of virus-specific cytotoxic T-cell responses are discussed in light of these observations and those of other investigators.
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Cytotoxic T cells are present in the lungs and the bronchoalveolar washings of mice infected intravenously (i.v.) or intranasally (i.n.) with live influenza A/WSN virus. After i.v. injection, cytotoxic T cell activity in both spleens and lungs reaches a peak at 6 days when the level of infectious virus recovered from the lungs falls sharply and the mice do not die. If a lethal dose of virus is given intranasally, very high levels of virus appear rapidly in the lungs, and the development of lung consolidation follows slightly behind the appearance of cytotoxic T cells there. When a non-lethal dose of virus is given intranasally, lower levels of virus are found in the lung and the appearance of cytotoxic T cells is delayed. These results suggest that the cytotoxic T cells play a protective role if the level of virus in the lungs does not reach very high levels. After injection of antithymocyte serum, the subsequent level of cytotoxic T cell activity in the lungs was greatly reduced, suggesting that the T cells recovered in lungs had at an earlier stage been circulating cells. However, splenectomized mice develop high levels of cytotoxic T cell activity, after intranasal infection of mice, indicating that the spleen did not contribute substantially to the T cells recovered in the lungs.
Transfer of primary or secondary influenza-immune spleen cells to mice infected intranasally with influenza virus resulted in a significant clearance of virus from the lungs and the protection of the recipients from death. The antiviral activity was associated only with intact, viable cells and was not due to carryover of virus. The effector cell population responsible for the antiviral effect was shown to be T cells. Thus, the removal of adherent, phagocytic and Ig+ cells did not affect the antiviral activity, whereas it was destroyed with antitheta serum and complement. Antiviral activity was specific and was best expressed if the virus used to infect the recipients and to generate immune cells was the same strain. Further work will be necessary to define rigorously the role of different viral antigens in cell-mediated immune response to influenza virus infection.
Mice inoculated intranasally with infectious influenza virus of a given A strain were adoptively transferred 24 h later with preparations of secondary influenza virus-immune T cells generated either in vitro or entirely in vivo. The immune cells were raised during infection with homologous or heterologous A strain influenza viruses or with a type B virus. The greatest antiviral effect, measured by reduction in lung virus level of recipient mice, occurred if homologous viruses were used. Sharing of haemagglutinin specificity was shown to be important, but significant antiviral activity was still expressed if neither haemagglutinin nor neuraminidase antigenic specificities were shared. The antiviral effect was type-specific. Adoptive transfer of type A influenza immune T cells did not express antiviral activity against type B virus, and vice versa. On the basis of earlier work, the effector population in the transferred cells was cytotoxic T cells (Tc). Intranasal reinfection of mice with a heterologous type A virus sharing neither haemagglutinin nor neuraminidase antigenic specificity with the first infecting virus induced enhanced and earlier production of cross-reactive Tc against type A influenza viruses. This was paralleled by significantly lower virus levels in the lungs. The results of this work demonstrate heterotypic cell-mediated immunity in influenza virus infection in mice.
Cytotoxic T cells (Tc) have been shown to be important in the rejection of histoincompatible tissue grafts. They are also generated in mice during infection with viruses that are known to express viral coded antigens at the infected cell surface, although their presence is much easier to demonstrate with some viral infections than with others. Cell-mediated lysis only occurs if the Tc and virus-infected target cells share gene products coded for in the K or D region of the H-2 complex. In the case of both ectromelia and influenza virus infection of mice, transfer of specific Tc to histocompatible, infected mice has been shown to significantly lower the virus titre in target organs (spleen and lungs respectively). In experimental animals with some tumours, there is increasingly good evidence for the expression of tumour specific transplantation antigens (TSTA) in the membrane of the malignant cells, yet there is little evidence for the presence of specific Tc which might control the growth of the tumour. Possible reasons for the lack of generation or expression of Tc in these situations are discussed.
Conditions are described for the generation and detection of murine cytotoxic cells which lyse influenza virus-infected target cells. A number of criteria indicated that most and probably all of the activity was due to T cells. These criteria included the susceptibity of cytotoxic activity to treatment with anti-theta ascitic fluid plus complement and the enhancement of lysis when there was H2 compatibility between donors of effector and virus-infected target cells.