(1/1802) Advances in the biological therapy and gene therapy of malignant disease.
Biological and gene therapy of cancer have become important components of clinical cancer research. Advances in this area are based on evidence for the presence of tumor antigens, antitumor immune responses, evasion of host control by tumors, and the recognition of host defense failure in cancer patients. These mechanisms are being corrected or exploited in the development of biological and gene therapy. Over the last decade, 9 biological therapies have received Food and Drug Administration approval, and another 12 appear promising and will likely be approved in the next few years. Our approach to gene therapy has been to allogenize tumors by the direct intratumoral injection of HLA-B7/beta2-microglobulin genes as plasmid DNA in a cationic lipid into patients with malignant melanoma. In four Phase I studies, we found a 36% response by the local injected tumor and a 19% systemic antitumor response. In other cancers, gene transfer, expression, and an intratumoral T-cell response were seen, but no clinical response was seen. A variety of follow-up studies with HLA-B7 and other genes are planned. Evasion of host control is now a major target of gene therapy. Strategies to overcome this include up-regulation of MHC and introduction of cell adhesion molecules into tumor cells, suppression of transforming growth factor and interleukin 10 production by tumor cells, and blockade of the fas ligand-fas interaction between tumor cells and attacking lymphocytes. With these approaches, it seems likely that gene therapy may become the fifth major modality of cancer treatment in the next decade. (+info)
(2/1802) Characterization of the culture filtrate-specific cytotoxic T lymphocyte response induced by Bacillus Calmette-Guerin vaccination in H-2b mice.
Although CD8+ T cells are supposed to play an important role in protective immunity to mycobacteria, cytotoxic T lymphocyte (CTL) responses in this infection remain poorly characterized. We previously demonstrated that bacillus Calmette-Guerin (BCG) immunization of H-2b mice induced CTL able to recognize and kill macrophages incubated with proteins from mycobacterial culture supernatant [culture filtrate (CF) antigens]. In the present study, we have further characterized the lytic activity of these CTL and the processing pathway used for the presentation of CF proteins. We show that they use the degranulation pathway (secretion of perforins and granzymes) as the main lytic mechanism of cytotoxicity and also secrete IFN-gamma upon incubation with CF-pulsed macrophages. The in vitro presentation of CF proteins to CTL required a processing step inhibited in the cold but insensitive to Brefeldin A. Transporter-associated protein (TAP)-2-deficient RMA-S cells were efficiently recognized and killed by CF-specific CTL, demonstrating the lack of TAP requirement for this presentation. However, recognition of target cells by CTL was abolished when carried out in the presence of chloroquine. These results indicate that a non-classical MHC class I-processing pathway allows the recognition of a CF protein by CTL in BCG-vaccinated H-2b mice. (+info)
(3/1802) Influences of Kupffer cell stimulation and suppression on immunological liver injury in mice.
AIM: To study the possible involvement of Kupffer cells (KC) in immunological liver injury in mice. METHODS: Liver injury was induced by i.v. injection of Bacillus Calmette-Guerin (BCG) 5 x 10(7) viable bacilli followed by i.v. injection of lipopolysaccharides (LPS) 7.5 micrograms to each mouse. Indian ink and silica were i.v. injected to suppress KC and retinol was given po to stimulate KC in these mice. Plasma alanine aminotransferase (AlaAT), aspatate aminotransferase (AspAT), nitric oxide (NO), and liver tissue were examined. RESULTS: Injection of LPS following BCG injection resulted in a remarkable elevation of plasma NO, AlaAT, and AspAT levels, and severe liver damage. The damages were enhanced by the activation of KC with retinol and reduced by suppression of KC with silica and Indian ink. CONCLUSION: The degree of liver injury induced by BCG + LPS is closely correlated with the status of KC, and NO from KC plays an important role in the pathogenesis of the liver damage in mice. (+info)
(4/1802) Differential protective efficacy of DNA vaccines expressing secreted proteins of Mycobacterium tuberculosis.
The development of more-effective antituberculosis vaccines would assist in the control of the global problem of infection with Mycobacterium tuberculosis. One recently devised vaccination strategy is immunization with DNA plasmids encoding individual microbial genes. Using the genes for the M. tuberculosis secreted proteins MPT64 (23 kDa), Ag85B (30 kDa), and ESAT-6 (6 kDa) as candidate antigens, DNA vaccines were prepared and tested for immunogenicity and protective efficacy in a murine model of aerosolized tuberculosis (TB). Intramuscular immunization with DNA-64 or DNA-85B resulted in the activation of CD4(+) T cells, which produce gamma interferon (IFN-gamma), and high titers of specific immunoglobulin G antibodies. Further, DNA-64 induced major histocompatibility complex class I-restricted CD8(+) cytotoxic T cells. The addition of a eukaryotic leader sequence to mpt64 did not significantly increase the T-cell or antibody response. Each of the three DNA vectors stimulated a significant reduction in the level of M. tuberculosis infection in the lungs of mice challenged 4 weeks after immunization, but not to the levels resulting after immunization with Mycobacterium bovis BCG. The vaccines showed a consistent hierarchy of protection, with the most effective being Ag85B, followed by ESAT-6 and then MPT64. Coimmunization with the three vectors resulted in a greater degree of protection than that induced by any single vector. This protective efficacy was associated with the emergence of IFN-gamma-secreting T cells earlier than in infected animals immunized with a control vector. The efficacy of these DNA vaccines suggests that multisubunit vaccination may contribute to future vaccine strategies against TB. (+info)
(5/1802) Vaccinated mice remain more susceptible to Mycobacterium tuberculosis infection initiated via the respiratory route than via the intravenous route.
Mice given Mycobacterium tuberculosis bacilli via the respiratory route succumbed much sooner to infection than mice given 1,000 times more bacilli via the intravenous route. Vaccination provided increased protection to an M. tuberculosis challenge infection; however, mice infected via the respiratory route remained much more susceptible. (+info)
(6/1802) Skin reaction and antibody responses in guinea-pigs sensitized to human leukaemia cells or their nuclei in combination with Bacillus Calmette-Guerin.
Guinea-pigs sensitized by subcutaneous injection of chronic lymphatic leukaemia (CLL) cells combined with Bacillus Calmette-Guerin (BCG) displayed good skin reacitons 24 and 48 h after challenge with CLL cells. Equally good responses were also demonstrated using nuclei from the leukaemic cells in combination with BCG. These reactions were significantly greater than those produced in the same manner but without BCG. Sera form the animals were examined for the presence of antibodies against CLL cells by cytotoxicity and immunofluorescence techniques. Only samples from guinea-pigs innoculated with CLL cells were found to contain significant antibodies. Histological examination showed that whereas leukaemic cells persisted at the sensitizing injection site leukaemic cell nuclei could not be visualized. It is suggested that because leukaemic cell nuclei in combination with BCG are able to induce good skin reactivity without provoking a vigorous humoral antibody response they may have possible advantages over leukaemic cells when used for immunotherapy. (+info)
(7/1802) The association between CD2+ peripheral blood lymphocyte subsets and the relapse of bladder cancer in prophylactically BCG-treated patients.
We investigated the potential existence of differences in the distribution of T-lymphocyte subsets and in the proliferative response of these CD2+ cells to polyclonal mitogens in patients with transitional cell bladder carcinoma (SBTCC) treated with prophylactic intracavitary instillations of bacillus Calmette-Guerin (BCG) according to their clinical response to this treatment. Before BCG treatment, different subset distribution (CD8+ and CD3+ CD56+), activation antigen expression (CD3+ HLA- DR+) and proliferative response to mitogenic signals were found in CD2+ cells from SBTCC patients prophylactically treated with BCG who remained free of disease or those who had recurrence of tumour. Otherwise, the prophylactic intracavitary BCG instillations in SBTCC patients are associated with a transitory variation of T-lymphocyte subset distribution (CD4 and CD8) and activation antigens expression (CD25). (+info)
(8/1802) Childhood immunization coverage in zone 3 of Dhaka City: the challenge of reaching impoverished households in urban Bangladesh.
A household survey of 651 children aged 12-23 months in Zone 3 of Dhaka City carried out in 1995 revealed that 51% of them had fully completed the series of childhood immunizations. Immunization coverage in slum households was only half that in non-slum households. Apart from residence in a slum household, other characteristics strongly associated with the completion of the entire series of childhood immunizations included the following: educational level of the mother, number of children in the family household, mother's employment status, distance from the nearest immunization site, and number of home visits from family-planning field workers. The findings point to the need to improve childhood immunization promotion and service delivery among slum populations. Two promising strategies for improving coverage are to reduce the number of missed opportunities for immunization promotion during encounters between health workers and clients, and to identify through visits to households those children who need additional immunizations. In the long run, increasing the educational level of women will provide a strong stimulus for improving childhood immunization coverage in the population. (+info)