Protective effects of monoclonal antibodies and immunopurified glycoproteins in primary HSV-1 infection.
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Animals↗
Biomedical subjects
F Y Liew
Publications and source records attributed to F Y Liew.
Role of T cells in the unusual cutaneous responses to Leishmania in BALB/c mice.
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Animals↗
An H-11-linked gene has a parallel effect on Leishmania major and L. donovani infections in mice.
The courses of visceral infection following intravenous injection of Leishmania donovani amastigotes, or lesion growth following subcutaneous injection of L. major promastigotes, were examined in B10.129(10M) (H-2b, H-11b) mice and compared with disease profiles observed in congenic C57BL/10ScSn(= B10) (H-2b, H-11a) and B10.D2/n (H-2d, H-11a) mice, and in BALB/mice. Possession of alternative alleles at H-11 and closely linked loci transformed the normal curing/healing phenotype of B10 mice into a characteristically different noncuring/nonhealing phenotype affecting both visceral and subcutaneous infections in B10.129(10M) mice. In reciprocal radiation bone marrow chimeras made between the congenic B10 and B10.129(10M) strains, both cure and noncure phenotypes were transferable with the donor hematopoietic system. Although it was possible to demonstrate transfer of suppression with T-enriched spleen cells from day 61 L. donovani-infected B10.129(10M) donor mice into 550 rad syngeneic recipients, the pretreatment of mice with sublethal irradiation did not, as in the earlier studies of Scl-controlled L. major nonhealing or H-2-controlled L. donovani noncure phenotypes, have a clear or consistent prophylactic effect. Together with the progressive disease profile observed even for L. donovani at low parasite doses this suggests that, despite their ability to develop initial delayed-type hypersensitivity reactions to parasite antigen early in L. major infection, B10.129(10M) mice possess some inherent defect in ability to mount a cell-mediated response effective at the level of macrophage antileishmanial activity in vivo even when suppressor T cells are not generated. Further elucidation of this characteristically different noncuring/nonhealing phenotype may provide important insight into common events involved in the development of the cell-mediated immune response to both visceral and subcutaneous forms of leishmaniasis.
Animals↗
Host antigens associated with haemagglutinin.
A delayed-type hypersensitivity (DTH) test has been used to detect the presence of host-specific antigen(s) is highly purified egg-grown influenza virus, virus components and isolated haemagglutinin. Cyclophosphamide-treated mice, primed with an extract from allantoic fluid, showed DTH reactions when challenged with preparations containing envelope lipid or polymer-type subunits, whereas lipid-free derivatives such as internal virus protein complexes and monomer haemagglutinin preparations lacked the activity. This approach has been extended to demonstrate the presence of associated host antigens in SV40-vector expressed haemagglutinin produced in simian cells.
Allantois↗
Specific suppressor T cells for delayed-type hypersensitivity in susceptible mice immunized against cutaneous leishmaniasis.
BALB/c mice injected intravenously with 10(6) or higher doses of formaldehyde-fixed promastigotes (ffp) of Leishmania major developed significantly lower levels of delayed-type hypersensitivity (DTH) compared with uninjected control mice when they were subsequently immunized intradermally with ffp. The suppression of DTH was antigen specific and was also inducible with lethally irradiated promastigotes or soluble parasite antigens. The suppressive effect was adoptively transferable with splenic T cells which express the Lyt-1+2+ and L3T4+ phenotypes. These specific suppressor T cells were active against both the inductive and expressive phases of DTH. They were sensitive to 200 rads of gamma-irradiation in vitro and appeared to manifest the suppressive activity via soluble factors. In spite of this profound suppression of DTH, BALB/c mice injected intravenously with 4 X 10(7) ffp were substantially protected against a challenge infection with L. major promastigotes. The possible relationship between the suppressor T cells for DTH and prophylactic immunization against fatal cutaneous leishmanial infection in susceptible BALB/c mice is discussed.
Animals↗
New aspects of vaccine development.
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Adjuvants, Immunologic↗
Prophylactic immunization against experimental leishmaniasis. V. Mechanism of the anti-protective blocking effect induced by subcutaneous immunization against Leishmania major infection.
The responsiveness of BALB/c mice to protective i.v. immunization with 150,000-rad irradiated or heat-killed Leishmania major promastigotes can be totally suppressed by prior subcutaneous (s.c.) injection of the same "vaccine." Induction of this effect is leishmania specific for although prevention of protection against L. major infection can be obtained with either homologous or Leishmania donovani promastigotes, it does not follow s.c. administration of an immunogenic Trypanosoma cruzi epimastigote preparation. Multiple s.c. injections of irradiated L. major promastigotes do not inhibit the subsequent antibody response of any major isotype to i.v. immunization, but rather induce some priming. The same s.c. injections induced delayed-type hypersensitivity (DTH) reactivity that could be transferred locally or systemically, although it was weaker than in mice with cured infections. Parallel cell-mediated immunity (CMI) responses were also reflected in vitro in specific lymphocyte transformation assays. Despite this evidence of a DTH/helper type of T cell response, transfer of 5 X 10(7) viable T cell-enriched spleen cells from 4 X s.c. immunized donors to normal recipients completely abrogated the protective response to i.v. immunization. Conversely, T cell-depleted (anti-Thy-1.2 + C treated) cells were without effect. The inhibitory T cells were defined by monoclonal antibody pretreatment as possessing an Lyt-1+2-,L3T4+ phenotype. T cells from s.c. immunized donors were also shown, by mixed transfer experiments, to counteract completely the protective effect of T cells from i.v. immunized donors in 550-rad irradiated recipients. They were as potent as suppressor T cells from donors with progressive disease both in this capacity and in abrogating the prophylactic effect of sublethal irradiation itself. The similarities and differences between suppressor and immune effector T cells induced by s.c. or i.v. immunization and those arising in response to leishmanial infection itself are discussed.
Animals↗
Prophylactic immunization against experimental leishmaniasis. IV. Subcutaneous immunization prevents the induction of protective immunity against fatal Leishmania major infection.
Durable immunity against fatal L. major infection in genetically susceptible mice can be induced by immunization with 150,000-rad irradiated or heat-killed promastigotes administered i.v. or to a lesser extent i.p. Conversely, subcutaneous (s.c.) and intramuscular (i.m.) injections are not only totally ineffective but generally increase susceptibility to and enhance the progression of the disease, leading to earlier mortality. This detrimental effect is particularly evident with lower infecting challenge doses. Disease exacerbation is apparent in mice given 4 X s.c. injections of as few as 2 X 10(4) irradiated promastigotes, but it appears most potent after doses of 2 X 10(7). When mice given 4 X s.c. injections were subsequently immunized i.v. with 2 X 10(7) irradiated promastigotes, they failed to develop any evidence of protection against infection with 2 X 10(5) promastigotes, whereas mice given i.v. immunization alone were strongly protected. Thus, s.c. injections are capable of blocking the prophylactic effect of i.v. immunization with irradiated parasites. This inhibitory effect can be achieved with a single s.c. injection, although rather less potently than with four, and is even effective against four repeated weekly i.v. immunizations. Once induced, the effect persists undiminished after 100 days. A weaker effect is also inducible by s.c. injection given after i.v. immunization. The blocking effect of s.c. injection is not dependent on continuing viability of the promastigotes, as it can be induced equally readily with heat-killed, formalin-fixed, or sonicated parasites. The phenomenon extends to mouse strains genetically resistant as well as susceptible to L. major infection and, in congenic mice of BALB background, is independent of the major histocompatibility (H-2) gene complex.
Animals↗
Mechanisms of acquired immunity in leishmaniasis.
Self-curing cutaneous leishmaniasis depends on T cell-mediated immune activation of infected macrophages. Failure of immune control in inbred mouse models of metastasizing mucocutaneous and visceralizing forms of the disease involves, respectively, insusceptibility of the parasite and the generation of T cells that suppress a potentially curative response. Prophylactic immunization in man has so far been restricted to cutaneous leishmaniasis and based on inducing infection under controlled conditions with virulent Leishmania tropica major promastigotes. The feasibility of immunization against visceral leishmaniasis merits reconsideration. BALB/c mice are genetically vulnerable to L. tropica major, which produces a fatal visceralizing type of disease involving specific suppression of cell-mediated immunity. Potent and lasting protection can be induced by repeated intravenous immunization with irradiated promastigotes. The efficacy of this 'vaccine' is relatively heat-stable (1 h at 56 degrees C). Immunity is not attributable to antibody but to the generation of Lyt-1+2- T cells which, although possessing helper and macrophage-activating functions, do not express classical delayed-type hypersensitivity. The immunological features of this system and its relevance to the possibility of protection against human Leishmania donovani infection are considered.
Animals↗
Cross-protection in mice infected with influenza A virus by the respiratory route is correlated with local IgA antibody rather than serum antibody or cytotoxic T cell reactivity.
Mice previously infected with an aerosol of A/Rec 31 influenza virus were strongly protected against an aerosol challenge with A/Vic influenza as judged by lung virus titers recovered 2 days after the challenge infection. Such complete homotypic immunity was not achieved by priming with live Rec 31 virus injected i.v. or UV-inactivated Rec 31 virus administered s.c. together with Al(OH)3 and saponin. The reason for the superior protective effect of the natural infection was investigated. The protection induced by respiratory infection with Rec 31 virus was specific for influenza A viruses. It was not correlated with specific serum hemagglutination inhibition antibody titer or cross-reactive cytotoxic T (Tc) cell reactivity. Moreover, the transfer of splenic and lymphoid T cell populations with strong secondary Tc activity did not significantly reduce lung virus titers in recipient mice 3 days after infection. The protection however occurred in parallel with the presence of cross-reactive IgA antibody in the lung washings. It thus appears that local secretory IgA plays a causal role in the prevention of cross-infection by influenza A virus. Serum antibody and Tc cells, on the other hand, may be crucial for recovery from such infection. All mice primed with live Rec 31 virus, administered i.v. or by aerosol and expressing equally high levels of Tc reactivity, survived a lethal challenge with A/PR8 virus. The same challenge, however, killed half of the mice immunized s.c. with inactivated Rec 31 virus which induced only a low level of Tc reactivity.
Aerosols↗
Prophylactic immunization against experimental leishmaniasis. II. Further characterization of the protective immunity against fatal Leishmania tropica infection induced by irradiated promastigotes.
The genetic vulnerability of BALB/c mice to Leishmania tropica (L. major) infection renders them incapable of controlling a primary cutaneous lesion that leads to uniformly fatal visceral disease. Potent, long-lasting protection involving both lesion healing and survival can be induced by repeated prophylactic i.v. immunization with gamma-irradiated (150K rad) L. tropica promastigotes. The effect is not dependent on continuing viability or cellular invasiveness of the irradiated parasites because their effective immunogenicity withstands heating at 56 degrees C for 1 hr. Immunity is not stage specific and encompasses both amastigote and promastigote challenges. Similar prophylaxis can be induced by immunization with heterologous irradiated L. donovani promastigotes. Repeated i.v. immunization with irradiated L. tropica promastigotes induces an antibody response in the isotype sequence M leads to G1/G3 leads to G2a/G2b leads to A with substantially higher titres than are found in response to the infection itself. Splenectomy before immunization drastically reduces this antibody response without incurring any impairment of the extent of protection. Passive transfer of large amounts (up to 10 ml) of hyperimmune serum (or isotype fractions thereof) throughout the first 8 wk of infection fails to arrest disease progression during this period. Despite the previously described lack of any detectable cutaneous DTH reactivity, which has hitherto correlated with protective cell-mediated immunity, the results obtained do not support attribution of an alternative causal role to the humoral response.
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Prophylactic immunization against experimental leishmaniasis. III. Protection against fatal Leishmania tropica infection induced by irradiated promastigotes involves Lyt-1+2- T cells that do not mediate cutaneous DTH.
Protective immunity against fatal L. tropica infection in genetically vulnerable BALB/c mice can be induced by prophylactic immunization with irradiated promastigotes even when heat-killed. Such immunity is adoptively transferable transiently into intact or durably into sub-lethally irradiated (200 or 550 rad) syngeneic recipients by splenic T but not B cells. The effector T cells are of the Lyt-1+2- phenotype, devoid of demonstrable cytotoxic activity. The immune splenic T cell population expresses specific helper activity for antibody synthesis. A causal role for helper T cells in this capacity, however, seems unlikely, because it was shown in the accompanying paper that antibody does not determine the protective immunity against L. tropica. The immunized donors show no detectable cutaneous DTH or its early memory recall in response to live or killed promastigotes or a soluble L. tropica antigen preparation. Spleen, lymph node, and peritoneal exudate cells from protectively immunized donors similarly fail to transfer DTH locally or systemically. These cells also lack demonstrable suppressive activity against the expression or induction of DTH to L. tropica. Thus, protection against L. tropica induced by prophylactic i.v. immunization with irradiated promastigotes appears to be conferred by Lyt-1+2- T cells that are distinguishable from T cells mediating either both DTH and T help, or cytotoxicity.
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Effect of irradiation on the precursor, activated and memory suppressor T cells for delayed-type hypersensitivity to sheep erythrocytes in mice.
The relative radiosensitivities of precursor (Tsp), activated (Ts) and memory (Tsm) suppressor T cells for delayed-type hypersensitivity (DTH) to sheep red blood cells (SRBC) were investigated in mice. Spleen cells from CBA mice, primed i.v. with 10(9) SRBC 3-4 days previously, contain specific Ts cells which substantially impair the induction of DTH to SRBC in normal syngeneic recipients. Exposure of mice to 400 rad irradiation 1 day before the priming completely eliminated the subsequent development of Ts cells. In contrast, 3 days after the priming injection, Ts cell activity in mice is resistant to doses higher than 600 rads. Mice primed 40 days previously with 10(9) SRBC contain Ts-cell memory which can be readily recalled by i.p. injection of 10(8) SRBC. The secondary Ts cells which specifically inhibit DTH induction can be demonstrated adoptively in normal recipients. Mice were exposed to various doses of irradiation 40 days after the priming and 1 day before the i.p. injection. Ts memory was significantly reduced by 300 rads and was completely abrogated by 400 rads. The relative radiosensitivities of the three subsets of suppressor T cells are in the order of Tsm = Tsp greater than Ts.
Animals↗
The estimation of host antigen in experimental and commercial influenza subunit preparations by delayed-type hypersensitivity reaction.
A delayed-type hypersensitivity (DTH) test has been used to detect the presence of host-specific antigen(s) in highly-purified egg-grown influenza virus and virus components. Cyclophosphamide-treated mice, primed with an extract from allantoic fluid, showed DTH reactions when challenged with whole virus, spikeless virus particles or polymer-type subunits. All commercial egg-grown influenza vaccines showed the presence of host antigen, whereas lipid-free derivatives such as internal virus protein complexes and monomer HA preparations lacked the activity. These findings are discussed in relation to vaccine application.
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The role of I-J subregion gene products in the inhibition of delayed-type hypersensitivity to major histocompatibility antigens by specific suppressor T cells.
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Animals↗
Genetically determined response mechanisms to cutaneous leishmaniasis.
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Animals↗
Immunologic regulation of experimental cutaneous leishmaniasis. V. Characterization of effector and specific suppressor T cells.
Resistant CBA mice infected with Leishmania tropica promastigotes develop concomitant and convalescent immunity against reinfection. This can be adoptively transferred by splenic and lymph node T cells with a threshold dosage of 1 to 2.5 x 10(7). The effector cells are of Thy-1+, Lyt-1+2- phenotype. The same immune cell population also adoptively transfers specific DTH to L. tropica, which is restricted by the major histocompatibility complex. On the other hand, highly susceptible BALB/c mice infected with L. tropica develop antigen-specific suppressor T (Ts) cells (previously shown to inhibit the induction and expression of DTH), which are capable, on transference, of reversing the healing of lesions induced by prior sublethal irradiation of BALB/c mice. As few as 10(6) of these T cells are effective in abrogating the potent prophylactic effect of 550 rad. The Ts cells are of Thy-1+, Lyt-1+2-, and I-J- phenotype. Sublethally irradiated and infected BALB/c mice produce antibody responses quantitatively and isotypically similar during the critical first 40 days after infection whether or not they are injected with 10(7) Ts cells (nonhealing vs healing). Thus, impairment of DTH and curative immune responses in BALB/c mice cannot be attributed to a helper function of these Thy-1+, Lyt-1+2- cells for the formation of suppressive antibody.
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Monoclonal antibodies to the murine Ly-2.1 cell surface antigen.
Six monoclonal anti-Ly-2.1 antibodies are described that arose from a single fusion using the spleen from a 129/ReJ mouse immunized with CBA/H thymus cells. The specificity was determined from the strain distribution, and testing of congenic strains where all six monoclonal antibodies detected the Ly-2.1 alloantigen. Furthermore, the antibodies fall into two groups: Group I (four antibodies) detected the expected number of Ly-2+ thymocytes and peripheral T cells, whereas Group II (two antibodies) detected 10% fewer peripheral T cells. Functional studies demonstrated that the Ly-2.1 determinant detected by a Group I antibody (49-31.1) was presented on cytotoxic T cells (Ly-1+2+), on concanavalin A (Con A)-induced suppressor T cells (Ly-1-2+), but absent from helper T cells (Ly-1+2-). One antibody (49-11.1) precipitated a 68,000-75,000 mol.wt glycoprotein, which on reduction yielded 30,000 and 35,000 mol.wt moieties. Thus, by functional, genetic and biochemical criteria these antibodies detected the Ly-2.1 specificity. In addition, a monoclonal, noncytotoxic, IgGl, anti-Thy-1.2 antibody is described.
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