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PubMed1992

Adaptive cellular interactions in the immune system: the tunable activation threshold and the significance of subthreshold responses.

A major challenge for immunologists is to explain how the immune system adjusts its responses to the microenvironmental context in which antigens are recognized. We propose that lymphocytes achieve this by tuning and updating their responsiveness to recurrent signals. In particular, cellular anergy in vivo is a dynamic state in which the threshold for a stereotypic mode of activation has been elevated. Anergy is associated with other forms of cellular activity, not paralysis. Cells engaged in such subthreshold interactions mediate functions such as maintenance of immunological memory and control of infections. In such interactions, patterns of signals are recognized and classified and evoke selective responses. The robust mechanism proposed for segregation of suprathreshold and subthreshold immune responses allows lymphocytes to use recognition of self-antigens in executing physiological functions. Autoreactivity is allowed where it is dissociated from uncontrolled aggression.

Animals↗
PubMed1986

Humoral antibody response to glutaraldehyde-treated antigens of Dermatophilus congolensis.

Glutaraldehyde-treated whole cell antigens (GA.WcA) of Dermatophilus congolensis induced in guinea pigs immunological memory in contrast to cell wall antigens treated similarly (GA.CwA). However, GA.WcA could not induce a secondary response in animals primed with untreated WcA while GA.CwA on the other hand did stimulate a secondary response in animals primed with untreated CwA. Primary antibody production was induced by both GA.CwA and untreated CwA to a similar level in their respective hosts but it was the secondary response that was found similar in response to GA.WcA and untreated WcA. However, both untreated WcA and CwA induced primary and secondary antibody production in their respective hosts though these responses were considerably higher in guinea pigs given untreated CwA. This study showed that both untreated and GA-treated antigens of D. congolensis are capable of stimulating antibody production in guinea pigs but they differ in their levels of stimulation.

Aldehydes↗
PubMed2003

Stress applied during primary immunization affects the secondary humoral immune response in the rat: involvement of opioid peptides.

The effect of unpredictable, inescapable and uncontrollable electric tail shocks (ES) on the humoral immune response to bovine serum albumin (BSA) was investigated in the rat. Contributions of the procedures that accompany shock delivery, such as witnessing the ES procedure (stress witnessing, SW) and exposure to the apparatus for shock delivery (apparatus control, AC) to the changes in specific immunity induced by ES were also tested. All procedures were applied during primary and/or secondary immunization. It was demonstrated that exposure to ES during primary immunization with BSA significantly suppressed specific anti-BSA antibody production after secondary and tertiary immunization with the same antigen. Exposure to the SW procedure during primary immunization with BSA enhanced the specific antibody level after secondary immunization, while exposure to the apparatus alone did not influence the development of either the primary or secondary humoral immune response to BSA. Both ES-induced suppression and SW-induced potentiation of the humoral immune response were partially inhibited by prior treatment with the opioid receptor antagonist naloxone. Additionally, treatments with the opioid peptides methionine- and leucine-enkephalin decreased anti-BSA antibody level, mimicking to some extent the effects of ES. It is suggested that ES and endogenous opioid peptides had long-term effects on humoral immunity through mechanisms involving immunologic memory.

Animals↗
PubMed1967

The immune response to sheep erythrocytes in the mouse. I. A study of the immunological events utilizing the plaque technique.

The direct and indirect plaque technique for the detection of antibody-forming cells against sheep erythrocytes was utilized for the investigation of a number of biological parameters of the primary and secondary immune response on a cellular level. The sequential pattern of 19S followed by 7S antibody formation was elicited in the primary response after a latent period of at least 1-2 days and 2-3 days respectively. The secondary response initiated 140 days after primary immunization, in contrast, was characterized by the simultaneous appearance of 19S and 7S antibody-forming cells after an observed latent period of 2-3 days. The cellular dynamics of the recruitment phase of the respective immunoglobulins in the primary and secondary response was interpreted as evidence for the derivation of the two classes of immunoglobulins from separate progenitors. The 19S antibody-forming cells were derived predominantly by a process of transformation and maturation and 7S antibody formers by a process of cellular division with a doubling time of about 12 hr. The draining lymph node exhibited maximal immunological reactivity due to its capacity to retain the particulate antigen. This capacity was considerably enhanced in the sensitized draining lymph node. Minimal cellular activity was also noted in distal lymphoid tissues which included the thymus. Focal cellular activity was observed in the draining lymph node for 60 days after immunization. Subsequently, very low level plaque-forming cellular activity was observed in association with persistence of maximal antibody activity. The appearance at 120 days of a generalized peak of cellular activity in lymphoid tissues throughout the host was considered an explanation for this discrepancy. The change in distribution of cellular antibody-forming activity, from a local to a generalized lymphatic response during the late phase of the immune response, implied a fundamental alteration in homeostatic mechanisms associated with maintenance of immune reactivity. Further manifestations of such an alteration were indicated by the appearance of 2-ME-sensitive 7S antibody nearly 3 months after primary intradermal immunization, which in the ensuing 5 months was associated with, and inversely related to, two major fluctuations in 2-ME-resistant 7S antibody. Evidence for the existence of immunological memory in the 19S system was not established in the present work. 19S anamnesis, for which evidence was derived from measurements of circulating antibody levels, was interpreted from cellular studies as the result of the substantial activity of previously uncommitted 19S lymphoid cells in distal lymphoid tissue associated with previously committed 19S cells contained in the draining lymph node.

Animals↗
PubMed1970

Synergistic interaction of macrophages and lymphocytes in antigen-induced transformation of lymphocytes.

The role of macrophages and lymphocytes in antigen-induced transformation of lymphocytes has been investigated. Lymphocytes and macrophages were obtained from inbred strain 13 guinea pigs which were either unimmunized or immunized with complete Freund's adjuvant (CFA) or tetanus toxoid in CFA. The transformation response to PPD or tetanus toxoid was assayed by tritiated thymidine incorporation. Addition of macrophages to immune lymphocytes significantly increased their response to purified protein derivative (PPD) or tetanus toxoid. This was observed if the macrophages were (a) "immune" or "nonimmune", (b) unirradiated or irradiated (3000 R), (c) 99% pure, and (d) peritoneal or alveolar in origin. Neither immune nor nonimmune macrophages were able to induce nonimmune lymphocytes to respond to PPD or tetanus toxoid. When macrophages were incubated with PPD or tetanus toxoid and then washed, they stimulated immune lymphocytes to transform. An incubation time of (1/2) hr was adequate, however, 2-4: hr was optimal. These studies indicate (a) that antigen-induced transformation of lymphocytes is greatly enhanced by macrophages; (b) that macrophage-antigen interaction can antecede lymphocyte-antigen interaction and results in macrophages which are able to stimulate lymphocyte transformation; and (c) that the immunological memory requisite to elicit specific transformation responses is a property of the lymphocyte and not the macrophage.

Animals↗
PubMed1970

Demonstration of heavy and light chain antigenic determinants on the cell-bound receptor for antigen. Similarities between membrane-attached and humoral antibodies produced by the same cell.

High-rate antibody-forming cells and immunological memory cells can be selectively retained if filtered through a column coated with relevant antigen. This trapping can be blocked if the cells are incubated with an anti-immunoglobulin serum prior to column passage. A similar blocking is not observed when cells are treated with an anti-lymphocyte serum, thereby excluding the possibility that any antibodies combining with surface structures could cause this effect. By the use of antisera specific for heavy or light chain antigens, it was possible to locate such antigens in the antigen-binding receptor areas of immune cells. Criss-cross studies using antisera specific for gamma 1 or gamma 2a heavy chains showed that the membrane receptor has the same heavy chain as will be present in the eventual product of that cell, the humoral antibody.

Animals↗
PubMed1971

Antigen-specific cells in mouse bone marrow. II. Fluctuation of the number and potential of immunocyte precursors after immunization.

Quantitative and qualitative changes of mouse bone marrow cells were studied by limiting dilution assays 2-3.5 months after immunization of donors with sheep erythrocytes or unrelated antigens (Salmonella typhimurium, horse and chicken erythrocytes). Irradiated (C3H x C57BL/10)F(1) mice were reconstituted with an excess of nonprimed thymocytes and small graded numbers of primed bone marrow cells. Direct and indirect plaque-forming cells (PFC) were induced by secondary stimulation with SRBC and enumerated on the 9th day after cell transplantation. Marrow precursors of PFC (P-PFC) cooperated with thymocytes in the production of direct and indirect PFC after SRBC priming. The limiting dilution plots, which were not compatible with predictions of the Poisson model before immunization, changed and conformed to this model afterwards, as if the population of P-PFC had become functionally more homogeneous. The concentration of marrow P-PFC increased up to the 3rd month after priming, and decreased during the 4th, varying over two logarithms of nucleated marrow cells. The fluctuation was simultaneous and of the same order of magnitude for precursors of direct and indirect PFC, which were class restricted. A third effect of immunization was detected at 3.5 months: individual precursor units generated 3-4 times more direct and indirect PFC than at earlier intervals. Qualitative and quantitative changes of marrow P-PFC participating in anti-sheep responses were specific, since antigens unrelated to SRBC failed to induce them. The data suggested that marrow-derived cells were the major carriers of immunologic memory, but that they functioned in cooperation with thymus-derived inducer cells during secondary anti-sheep responses.

Animals↗
PubMed1972

A receptor for antibody on B lymphocytes. I. Method of detection and functional significance.

Evidence is presented for the existence on all B lymphocytes, but not on T lymphocytes, of a membrane-associated receptor for antibody. The receptor was detected by a radioautographic technique in which lymphoid cells were incubated with antibody followed by the corresponding radioiodinated antigen. The ease with which antibody eluted during washing indicated that the bond between antibody and cell was weak. The formation of an antibody-antigen complex on the cell surface, however, stabilized the bond and permitted accurate quantitation of cells with adherent antibody. The ability of several combinations of antibody and antigen to adhere to the cells demonstrated the nonspecificity of the phenomenon and emphasized the need for care in interpretation of antigen-binding studies particularly when immune cells are being used. The identity of antibody-binding lymphocytes was established by two different approaches. In the first, mouse lymphocyte populations greatly enriched for either T cells or B cells were examined. Their T cell content was assessed by means of well-established markers such as the theta C3H isoantigen. When this was compared with the number of antibody-binding cells, an inverse relationship was obtained in each instance; thus almost all thoracic duct cells from athymic mice labeled with an immune complex although none were theta positive. The striking reduction in antibody-binding cells observed in bursectomized chickens provided a second and independent line of evidence suggesting that B cells, not T cells, bind antibody. The ability of B cells from primed animals to bind antibody in vivo made it important to test whether this phenomenon was related to the carriage of immunological memory. No correlation was, however, found between membrane-bound antibody and memory. It was proposed that the existence of a receptor of this kind may provide a rational explanation for antibody-dependent killing of target cells and may prove of importance in antigen concentration particularly during the secondary response.

Animals↗
PubMed1977

The relationship between surface immunoglobulin isotype and immune function of murine B lymphocytes. I. Surface immunoglobulin isotypes on primed B cells in the spleen.

We investigated the ability of IgM-, IgD-, and IgG-bearing cells from the spleens of (BALB/c x C57BL/Ka)F1 mice primed to dinitrophenyl-bovine serum albumin (DNP-BSA) to restore the adoptive secondary anti-BSA and anti-DNP antibody responses. A rabbit anti-mouse IgD antiserum was prepared and the specificity documented by radioimmunoprecipitation, and cell surface staining. Purified populations of IgM-, IgD-, and IgG-bearing cells were prepared by immunofluorescent staining with isotype-specific reagents, and sorting on the fluorescence activated cell sorter. Bright or dull cells were transferred to irradiated syngeneic recipients which were challenged with DNP-BSA in saline. Unfractionated spleen cells restored an adoptive secondary serum antibody response which was all IgG (2-mercaptoethanol resistant). Purified IgM- or IgD-bearing cells restored both the secondary IgM and IgG antibody response. IgG-bearing cells restored only the IgG response. In addition, the IgG-bearing cells appear to suppress the adoptive secondary IgM response, since depletion of IgG-bearing cells from transferred spleen cells results in a marked increase in the adoptive IgM response.

Animals↗
PubMed1981

Contrasuppression. A novel immunoregulatory activity.

We have described an interaction between two T cells subsets that results in interference with the expression of Ly-1-, 2+ (Ly-2) T cell-mediated suppression. We refer to this novel immunoregulatory activity as contrasuppression. The T cell responsible for the induction of contrasuppression (inducer cell) expresses the phenotype Ly-1-, 2+;I-J+;Qa-1+. This phenotype distinguishes it from the suppressor effector cells which we find to be I-J-2.3. An I-J+ soluble mediator from the contrasuppressor inducer cell acts on another cell (acceptor cell) that expresses the phenotype Ly-1+, 2+; I-J+; Qa-1+. This phenotype distinguishes it from T helper cells. Both the inducer cell (or its biologically active mediator) and its acceptor cell are required for the expression of contrasuppression. Because contrasuppressor cells can block the suppressive activity of cell-free mediators released by Ly-2 suppressor T cells, the mechanism of contrasuppression is either separated from or in addition to the inactivation of suppressor cells themselves. The potential importance of contrasuppressor activity in the regulation of suppressor T cell activity in allowing immunologic memory to be expressed and in permitting microenvironmental immune regulation is discussed.

Animals↗
PubMed1990

Metabolic, humoral, and cellular responses in adult volunteers immunized with the genetically inactivated pertussis toxin mutant PT-9K/129G.

PT-9K/129G, a nontoxic mutant of pertussis toxin (PT) obtained by genetic manipulation, has been shown in animal models to be a promising candidate for new vaccines against whooping cough. To assess the safety and the immunogenicity of PT-9K/129G in humans, a pilot study has been performed in adult volunteers. The protein was found to be safe, capable of inducing high titers of toxin-neutralizing antibodies, and capable of generating immunological memory. In fact, vaccination caused an increase of cell-mediated response to PT, PT-9K/129G, S1 subunit, and B oligomer, indicating that memory T cells are induced by the vaccine. Since PT-9K/129G is mitogenic for T lymphocytes in vitro, it was investigated whether this activity is also present in vivo. No variation was observed in the proportion of T cells (CD3+), T helper cells (CD4+), and cytotoxic T cells (CD8+), as well as in that of other lymphoid populations, by FACS analysis. Interestingly, no thorough correlation was found between humoral and cellular responses. In one case, a very high cellular response was present in absence of detectable antibodies, suggesting that the antibody response, which is the only parameter measured in most clinical trials, may not give a complete picture of the response induced by a vaccine.

Adult↗
PubMed1993

Regression of bladder tumors in mice treated with interleukin 2 gene-modified tumor cells.

This study explored the use of interleukin 2 (IL-2) and interferon gamma (IFN-gamma) gene-modified tumor cells as cellular vaccines for the treatment of bladder cancer. The mouse MBT-2 tumor used is an excellent model for human bladder cancer. This carcinogen-induced tumor of bladder origin resembles human bladder cancer in its etiology and histology, and responds to treatment in a manner similar to its human counterpart. Using retroviral vectors, the human IL-2 and mouse IFN-gamma genes were introduced and expressed in MBT-2 cells. The tumor-forming capacity of the cytokine gene-modified MBT-2 cells was significantly impaired, since no tumors formed in mice injected intradermally with either IL-2- or IFN-gamma-secreting cells, using cell doses far exceeding the minimal tumorigenic dose of parental MBT-2 cells. Furthermore, mice that rejected the IL-2- or IFN-gamma-secreting tumor cells became highly resistant to a subsequent challenge with parental MBT-2 cells, but not to 38C13 cells, a B cell lymphoma of the same genetic background. To approximate the conditions as closely as possible to the conditions prevailing in the cancer patient, inactivated cytokine-secreting cells were used to treat animals bearing tumors established by orthotopic implantation of MBT-2 cells into the bladder wall of the animal. Treatment of mice carrying a significant tumor burden with IL-2-secreting MBT-2 cells had a significant inhibitory effect on tumor progression with extended survival. Moreover, in 60% of the mice the tumor regressed completely and the animals remained alive and free of detectable tumor for the duration of the observation period. Treatment of tumor-bearing animals with IL-2-secreting MBT-2 cells was superior to the use of cisplatin, a chemotherapeutic agent used in the treatment of bladder cancer. The therapeutic effect of IFN-gamma-secreting cells was minimal and treatment with unmodified MBT-2 cells had no effect on tumor growth or survival, showing that the parental MBT-2 cells were nonimmunogenic in this experimental setting. Most importantly, mice that exhibited complete tumor regression after treatment with IL-2-secreting MBT-2 cells became resistant to a subsequent challenge with a highly tumorigenic dose of parental MBT-2 cells, indicating that long-term immunological memory was established in the "cured" mice.

Animals↗
PubMed2001

Assessing efficacy of Haemophilus influenzae type b combination vaccines.

Regulatory approval of diphtheria and tetanus toxoids and acellular pertussis (DTaP)-based combination vaccines containing Haemophilus influenzae type b (Hib) has been delayed in the US because of difficulty in assessing the effect of lower Hib immunogenicity on vaccine efficacy compared with the immunogenicity of the specific Hib component administered separately. Hib conjugate vaccines confer protection by eliciting serum anticapsular antibody and priming for immunologic memory. Therefore, compelling proof of efficacy would be demonstration that a combination vaccine primes for memory and elicits antibody responses that are not inferior to those elicited by other US-licensed Hib conjugate vaccines, not necessarily the specific Hib component used in the combination. Vaccinated infants also can be considered protected if their serum anticapsular antibody concentrations are > or =0.15 microg/mL immediately before the booster dose given in the second year of life, when antibody concentrations are lowest. These alternative serologic approaches offer a strong scientific and regulatory rationale for licensure of effective DTaP-based Hib combination vaccines.

Antibodies, Bacterial↗
PubMed2006

Serogroup C meningococcal glycoconjugate vaccine in adolescents: persistence of bactericidal antibodies and kinetics of the immune response to a booster vaccine more than 3 years after immunization.

BACKGROUND: The persistence of protection from meningococcal disease following immunization with serogroup C meningococcal (MenC) glycoconjugate vaccines in infancy is short-lived. The duration of protective immunity afforded by these vaccines in other at-risk age groups (i.e., adolescents and young adults) is not known. We evaluated the persistence of bactericidal antibodies following immunization with a MenC glycoconjugate vaccine (MenCV) in adolescents and the kinetics of immune response to a meningococcal AC plain polysaccharide vaccine (MenPS) challenge or a repeat dose of MenCV. METHODS: We conducted a randomized comparative trial of 274 healthy 13-15-year-olds from whom a total of 4 blood samples were obtained (prior to administration of a dose of MenPS or MenCV, again on 2 further occasions at varying times from days 2-7 after vaccination, and finally on day 28 after vaccination. The correlate of protection was a serum bactericidal assay titer > or = 8 (with a serum bactericidal assay using human complement). RESULTS: A serum bactericidal assay using human complement titer > or = 8 was observed in 75% of participants at baseline (mean age, 14.5 years; mean time since routine MenCV vaccination, 3.7 years). No increase in serum bactericidal assay geometric mean titers was detected until day 5 after administration of MenPS. Geometric mean titers following administration of MenCV were significantly higher than those observed following administration of MenPS, at days 5, 7, and 28. CONCLUSIONS: This study showed sustained levels of bactericidal antibodies for at least 3 years after immunization of adolescents with MenCV. After challenge of immunized adolescents with MenPS, there was no increase in serum bactericidal assay observed until day 5 after vaccination, indicating that immunological memory may be too slow to generate protection against this potentially rapidly invasive organism.

Adolescent↗
PubMed1998

Detection of Leishmania DNA by polymerase chain reaction in scars of treated human patients.

Leishmaniasis is an endemic disease in developing countries. The efficacy of therapy is usually evaluated through clinical parameters. To define the parasitologic cure, 20 patients were biopsied before and 1 month to 8 years after treatment. Paraffin-embedded tissue was used for DNA isolation. All patients had a positive polymerase chain reaction (PCR) result before therapy, except 1, for whom no histopathologic material was available. The causative agent was identified as belonging to the Leishmania (Viannia) subgenus by hybridization. Despite clinical healing and absence of reactivation or development of mucosal lesions, PCR was positive in scars of 16 patients (80%). The results suggest that parasites persist in the skin for many years despite treatment. Depending on specific pathogenetic features of the parasite and the immune status of the host, this phenomenon might result in mucosal lesions. Alternatively, it could have a role in the maintenance of immunologic memory in patients living in areas in which leishmaniasis is endemic.

Animals↗
PubMed2002

A longitudinal study of cell-mediated immunity in pigs infected with porcine parvovirus.

Porcine parvovirus (PPV) is an ubiquitous pathogen causing reproductive failure in swine. Protection against reproductive failure caused by acute PPV infection has commonly been related to the presence of specific antibodies in the dam. However, the role of cell-mediated immunity during chronic PPV infection remains to be elucidated, and may be relevant to the pathogenesis of novel diseases such as postweaning multisystemic wasting syndrome (PMWS), which may be triggered by coinfection with PPV and porcine circovirus type 2 (PCV2). To investigate whether pigs infected with PPV generate a cell-mediated immune response, a longitudinal infection experiment was performed, using swine leukocyte antigens (SLA) class I characterized growing pigs (haplotype H7/H7). Pigs were intranasally inoculated with PPV at 0, 80, and 136 days. At predetermined time points, peripheral blood mononuclear cells (PBMC) were isolated, and virus-specific lymphoproliferative responses and the cytolytic activities of cytotoxic T-lymphocytes (CTL) and natural killer (NK) cells were examined. Cytolytic assays were performed by the chromium release method, using as targets a syngeneic porcine kidney cell line established for the purpose (CTL assays) and K562 cells (NK assays). A specific proliferative response of PBMC from virus-infected pigs to PPV was observed from day 101 onwards. In contrast, PBMC from mock-infected pigs did not proliferate in response to PPV. Flow cytometric analysis indicated that the CD4+CD8+ T-cell subset of PBMC proliferated in response to virus antigen, in keeping with the assumed role for these cells in immunological memory. This is, to our knowledge, the first indication of a cellular immune response following PPV infection. A weak CTL activity, which peaked on days 80 and 87, was observed in PPV-infected pigs. In vitro restimulation of PBMC with live PPV did not induce further CTL activity. A pronounced NK cell activity was detected in both virus-infected and control pigs throughout the experiment, and may have negatively affected the sensitivity of the CTL assay. In conclusion, the findings of a late lymphoproliferative response together with weak CTL activity are in keeping with an effective control of acute PPV infection by humoral immunity, but open the possibility that cellular immunity may play a role in controlling PPV reinfection. Finally, we find that the established experimental model using SLA characterized pigs may constitute a valuable tool for future studies of CTL activity in pigs.

Animals↗
PubMed2002

Use of surrogate antigens as vaccines against cancer.

Tumor cells may evade immune surveillance by possessing polysaccharides or carbohydrates on their surface. This evasive strategy is effective because glycans are poorly immunogenic and fail to elicit immunological memory responses due to an absence of T-cell processing. Induction of an immune response to cell surface carbohydrate antigens is considered as an important strategy to fight cancer. As carbohydrates per se are poor immunogens, alternative approaches are being evaluated to induce functional cross-reactive responses. We are focusing on the use of peptide mimotopes of tumor-associated carbohydrate antigens to challenge cancer, as we would manipulate the immune system to establish protective immunity based on carbohydrate cross-reactive humoral and cellular responses.

Animals↗
PubMed1997

A family of bicistronic vectors to enhance both local and systemic antitumor effects of HSVtk or cytokine expression in a murine melanoma model.

The herpes simplex virus-thymidine kinase/ganciclovir (HSVtk/GCV) system produces both direct and immune-mediated tumor cell killing. Here, we compare the efficacy of HSVtk/GCV with cytokines, alone and in combination, on the tumorigenicity and immunogenicity of B16 cells. With respect to single gene modifications, only HSVtk/GCV, or high-level interleukin-2 (IL-2) secretion, completely prevented tumor growth, whereas granulocyte-macrophage colony-stimulating factor (GM-CSF) generated the best levels of long-term systemic protection. To augment both local killing and immune activation, we constructed bicistronic constructs that express HSVtk and a cytokine within the same cell. Co-expression of HSVtk with IL-2 or GM-CSF enhanced the local antitumor activity of any gene alone. In a tumor-prevention model, HSVtk killing, in an environment preprimed with GM-CSF, generated the best long-term immune protection. However, in a short-term therapy model, continued IL-2 expression was most effective against 3-day established tumors. This probably reflects differences in the activities of IL-2 and GM-CSF in generating short-term, nonspecific immune stimulation compared to long-term immunological memory, respectively. As a prelude to in vivo delivery experiments, we also demonstrated that these bicistronic cassettes can be packaged normally into retroviral (5 x 10(5) virus/ml from pooled populations) and adenoviral vectors (5 x 10(9) virus/ml) and function as predicted within virally infected cells. This family of bicistronic vectors can be used to stimulate synergy between suicide and cytokine genes, overcomes the problems of delivering two genes on separate vectors, and should allow easier preparation of vectors for the delivery of multiple genes to patients' tumor cells.

Adenoviridae↗