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The effects of passive immunization with tumor-specific antiserum on the active immune response of mice to sublines of leukemia L1210.

In vivo, tumor cell killing was monitored with 131I-IUdR-labeled tumor cells and whole-body measurement of retained radioactivity. Treatment with antiserum in quantities that were not sufficient to kill the total leukemia cell inoculum (i.e., antigen excess) caused an immunopotentiation of the active immune responses; this was manifested by an accelerated rate of tumor cell killing beginning between days 10 and 11. The results obtained in vivo were confirmed by in vitro quantitation; both the cytotoxic antibody and cell-mediated immune responses were potentiated by the injection of antiserum. Immunosuppression was also observed in passively immunized mice. Whether potentiation or suppression occurred was dependent on the relative amounts of antiserum and leukemic cells injected and the innate immunogenicity (and/or antigenicity) of the leukemic cells; antibody excess and high immunogenicity favored suppression.

Animals↗

Cell-mediated immune responsiveness to measles. Its occurrence as a result of naturally acquired or vaccine-induced infection and in infants of immune mothers.

Studies of cell-mediated immunity (CMI) to measles were carried out in patients with natural measles infection, in recipients of live measles vaccine, and in umbilical cord blood specimens from infants of mothers who were seropositive for measles. Evidence of CMI to measles was found in 100% of patients with natural infection but in only 62% of vaccine recipients and, interestingly, in 40% of umbilical cord blood specimens. Eight of these infants were subsequently studied at 4 to 5 months of age, at which time evidence of measles CMI was still detectable in three. Sufficient stimulation of cell-mediated immune mechanisms may be a prerequisite for the development of life-long immunity to measles. The effect of congenitally acquired CMI to measles on the outcome of immunization or of exposure to natural measles during the first year of life remains to be determined.

Adolescent↗

Costs of polio immunization days in China: implications for mass immunization campaign strategies.

Ten provinces of China were selected to estimate the cost per immunization of the 1994-95 national immunization days (NIDs) at five levels (e.g. province, prefecture, county, township and village). Personnel costs accounted for the largest overall share of costs (39 per cent), followed by publicity and promotion costs (27 per cent), and logistic costs (15 per cent). Without consideration of vaccine costs, the major part of NID expenses were shouldered at the township level, which paid for 47 per cent of all incremental costs, while county and village level covered 28 per cent and 18 per cent respectively. Estimation of average costs per immunization was 2.86 RMB yuan, or $0.34, including vaccine costs, buildings and equipment amortization and salaries at all levels. The factors affecting average cost of NID included the output volume, socio-economic development and geographic features. Various approaches were recommended: to intensify the productivity of time and staff, to employ alternative inexpensive manpower resources, to make the best use of publicity and social promotion, the expansion of the age groups and utilization of multi-intervention strategies. Good planning at township level was a decisive factor to ensure an effective NID conducted in an efficient manner. The average cost of China's NID was the lowest among all mass immunization campaigns ever documented. Much of the reduced average cost was attributable to economies of scale.

Catchment Area, Health↗

Primary in situ immune response in popliteal lymph nodes and spleen of mice after subcutaneous immunization with thymus-dependent or thymus-independent (type 1 and 2) antigens.

Mice were immunized subcutaneously with thymus-independent (TI)-type 1 antigen trinitrophenylated lipopolysaccharide (TNP-LPS), TI-type 2 antigen TNP-Ficoll or thymus-dependent (TD) antigen TNP-keyhole limpet haemocyanin (TNP-KLH) in order to study the primary in situ immune response in popliteal lymph nodes (PLN) and spleen. The spleen responded more rapidly in developing specific antibody-forming cells (AFC) than the lymph nodes did, in spite of the fact that antigens reach the spleen only after passing several lymph node stations. This difference between lymph nodes and spleen in developing AFC was particularly significant with respect to the responses to TI (both type 1 and type 2) antigens. No differences in the distribution of specific AFC in PLN and spleen were observed after immunization with TI and TD antigens. Results are discussed with respect to the relative contributions of lymph nodes and spleen to immune responses to antigens injected subcutaneously.

Animals↗

Regulation of the immune response. I. Suppression of delayed-type hypersensitivity by T cells from mice expressing humoral immunity.

The ability of horse red blood cell (HRBC)-specific T cells from mice expressing humoral immunity to suppress the induction of HRBC-specific delayed-type hypersensitivity (DTH) was investigated. The transfer of Ig-negative spleen cells, from mice injected 4 days previously with HRBC, completely suppressed the development of DTH in mice treated with cyclophosphamide and sensitized with HRBC. The suppressor cell was found to be lysed by treatment with anti-theta serum and complement. Furthermore, hemocyanin-specific immune T cells were able to suppress the DTH induced to HRBC, provided these two antigens were coupled together. These studies suggest that T cells present under conditions were humoral immunity is induced can suppress DTH and that such cells play an important role in the regulation of the immune response.

Animals↗

Antigen detection in vivo after immunization with different presentation forms of rabies virus antigen: involvement of marginal metallophilic macrophages in the uptake of immune-stimulating complexes.

Several mechanisms have been postulated to explain the relatively high immunogenicity of antigens presented in immune-stimulating complexes (iscom). Their potency can in part be explained by the specific targeting of these structures to cells presenting antigens to the immune system. However, until now no method for the subcellular detection of iscom in situ was available. In the present study, a novel, fast and simple method for the detection of iscoms in situ is demonstrated. By making use of the lipophilic fluorescent carbocyanine dyes, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) and 3,3'-dioctadecyloxacarbocyanine perchlorate (DiO), rabies virus antigen and iscom prepared with this antigen were visualized with fluorescence microscopy. The labeled antigen and iscoms were observed in macrophages of spleen and liver of mice within 1-2 h after intravenous administration. When administered intramuscularly or in the footpad, uptake in macrophages of draining lymph nodes could be demonstrated. In the spleen, labeled inactivated virus antigen localized preferentially in the marginal zone macrophages and to a lesser extent in the red pulp macrophages. In contrast, antigen presented in iscom was taken up mainly by the marginal metallophilic macrophages and to a much lesser extend by marginal zone macrophages or follicular-dendritic and -B cells. This method enables the detection of iscom and membrane viruses and allows the analysis of their relation to antigen-presenting cells in situ. Here, we demonstrate that iscom containing rabies virus antigen are taken up by a subset of macrophages in the spleen distinct from those that take up inactivated rabies virus antigen not presented in iscom, thereby possibly explaining the observed difference in immunogenicity of these antigen preparations. Furthermore, we show a lower efficiency on the induction of humoral and cellular responses after intravenous immunization for both types of antigen when compared with subcutaneous immunization.

Animals↗

Dendritic cells engineered to express the Flt3 ligand stimulate type I immune response, and induce enhanced cytoxic T and natural killer cell cytotoxicities and antitumor immunity.

BACKGROUND: Tumor antigen presentation by dendritic cells (DCs) to T cells in lymphoid organs is crucial for induction of antitumor immune responses. Fms-like tyrosine kinase 3 ligand (Flt3L) is a regulator of hematopoietic cell development. METHODS: To investigate the potential effect of Flt3L transgene expression on DC-based cancer vaccines, we constructed a recombinant adenovirus AdVFlt3L expressing Flt3L, transfected DCs with AdVFlt3L, and investigated the efficacy of antitumor immunity by vaccination of DC(Flt3L) engineered to express Flt3L transgene. RESULTS: Our data demonstrated that AdVFlt3L transfection up-regulated the expression of cytokine IL-1beta and chemokines MIP-1alpha, MIP-1beta, IP-10, MCP-1 and MIP-2, and stimulated DC(Flt3L) cell proliferation in vitro and migration toward regional lymph nodes in vivo. Our data also demonstrated that vaccination of Mut1-pulsed DC(Flt3L) cells was able to stimulate (i). a type 1 immune response comprising CD4(+) Th1 and CD8(+) Tc1 activation and (ii). around 2- and 3-fold enhanced tumor-specific cytotoxic T lymphocyte (CTL) and non-specific NK responses (p < 0.05) than vaccination with similarly pulsed control virus-transfected and untransfected DCs, respectively. More importantly, vaccination of Mut1-pulsed DC(Flt3L) cells induced enhanced antitumor immunity in vivo, even against poorly immunogenic 3LL tumor cells. Vaccinations of Mut1-pulsed DCs, DC(pLpA) and DC(Flt3L) all protected mice from challenge of low dose (0.5 x 10(5)) tumor cells. However, only vaccination of the last one was able to protect 63% (6/8) mice from challenge of high dose (3 x 10(5)) 3LL tumor cells (p < 0.01). CONCLUSIONS: DCs engineered to secrete Flt3L may offer a new strategy in DC-based cancer vaccines.

Adenoviridae↗

Enhancement of immune response to naked DNA vaccine by immunization with transfected dendritic cells.

Immunization with plasmid DNA encoding various proteins promises to be a valuable vaccine approach especially if its immunogenicity could be optimized. In this study we show that the intramuscular delivery in dendritic cells (DC) of naked plasmid DNA encoding two proteins of herpes simplex virus (HSV) leads to the induction of significantly enhanced levels of resistance to viral challenge. Whereas DC transfected in vitro with DNA induced enhanced immunity, similarly transfected macrophage (M phi) populations lacked immunogenicity even though plasmid expression occurred in vitro. The enhanced immunity induced by DC-delivered DNA appeared to be associated mainly with an increased Th1 CD4+ T cell response. Our results add evidence that DC are the essential antigen-presenting cell types involved in immune responses to intramuscularly administered DNA vaccines.

Animals↗

Immune responses to influenza immunization in children receiving maintenance chemotherapy for acute lymphoblastic leukemia.

PURPOSE: To compare the immune responses to influenza vaccine in children with acute lymphoblastic leukemia (ALL) receiving maintenance chemotherapy with those in healthy children. METHODS: Hemagglutinin-inhibition (HAI) antibody titers were determined before and after influenza vaccination in children with ALL and healthy controls. Immune responses were measured as geometric mean titers (GMT) and 4-fold rises in HAI titers. RESULTS: Although post-immunization GMT were lower in children with ALL compared to healthy children for the H1N1 antigen (P<0.001), the H3N2 antigen (P=0.03), and for the influenza B antigen (P=0.003), at least 60% of children with ALL had at least a 4-fold rise in HAI titers to each of the influenza antigens. CONCLUSIONS: While the GMT after trivalent influenza immunization in children with ALL were significantly lower than those seen in healthy children, the majority of children with ALL had 4-fold rises in HAI titers. Children receiving maintenance chemotherapy for ALL should receive yearly influenza vaccine.

Antibodies, Viral↗

Long-term effect of primary immunization on subsequent immune responsiveness.

Specific antigen/adjuvant combinations preferentially induce type 1 or type 2 cytokine responses. For example, BALB/c mice primed with TNP-ovalbumin in complete Freund's adjuvant (TNP-OVA/CFA) produce a type 2-dominated response characterized by the activation of IL-4-secreting cells and the production of IgG1 and IgE anti-TNP antibodies. In contrast, mice primed with TNP conjugated to Brucella abortus (TNP-BA) produce a type 1 response dominated by the secretion of IFN-gamma and IgG2a anti-TNP antibodies. We examined whether treating young mice with these antigen/adjuvant combinations altered the cytokine profile of their subsequent immune responses. Mice immunized with TNP-BA and boosted several months later with TNP-OVA/CFA developed a cytokine and antibody profile similar to the priming rather than boosting antigen. This was also observed in mice immunized with TNP-OVA/CFA and boosted with TNP-BA. Both the ratio of IL-4:IFN-gamma-secreting cells and the isotype of antibodies produced by these mice were altered by primary immunization. Analysis of Con A-responsive cells from these animals showed that long-lived changes in the frequency of T lymphocytes available to secrete type 1 versus type 2 cytokines were induced by strong primary immunogens.

Animals↗

Combined DNA immunization with the glycoprotein gene of viral hemorrhagic septicemia virus and infectious hematopoietic necrosis virus induces double-specific protective immunity and nonspecific response in rainbow trout.

Glycoprotein (G) of viral hemorrhagic septicemia virus (VHSV) and infectious hematopoietic necrosis virus (IHNV) contains several neutralizing epitopes. However, recombinant G protein never matches intact viral particles for immunogenicity. DNA immunization offers the possibility to deliver the antigen through the cellular machinery, thus mimicking natural infection. We constructed pCDNA gVHS and pCDNA gIHN plasmids with the G gene of VHSV and IHNV under the control of the CMV promoter, and we tested the plasmids for the accurate G protein expression prior to their use in fish immunization. Following intramuscular injection to adult rainbow trout, plasmid DNA was found inside the muscle cells shortly after injection and was still present 45 days later. mRNA of the G protein was detected in muscle tissue extracts, and the G protein was found within muscle cells at the site of injection. This resulted in the synthesis of high levels of specific neutralizing and protective antibodies. Fish injected with pCDNA gVHS and pCDNA gIHN in combination responded similarly to fish receiving one recombinant plasmid. In addition to the elicitation of a strong humoral response, DNA immunization was able to activate specialized cells of the immune system as well as nonspecific defense mechanisms, since mRNAs of MHC class II and Mx were strongly activated at the site of injection.

Animals↗

The therapeutic significance of concomitant antitumor immunity. II. Passive transfer of concomitant immunity with Ly-1+2- T cells primes established tumors in T cell-deficient recipients for endotoxin-induced regression.

Intravenous injection of 50 micrograms bacterial endotoxin can cause complete regression of an established SA1 sarcoma, but not if the tumor ir growing in mice that are incapable of generating concomitant immunity because they have been made T cell-deficient by thymectomy and gamma-radiation (TXB mice). It also was shown that endotoxin fails to cause complete regression of a tumor that is either too large or too small. Only when administered on day 9 of tumor growth, at the time of peak concomitant immunity, did endotoxin cause the tumor to undergo complete regression. Direct evidence that the antitumor effect of endotoxin is dependent on concomitant immunity consisted in the demonstration that an SA1 sarcoma growing in TXB recipients can be primed for endotoxin-induced regression by IV infusion of splenic T cells from concomitantly immune donors bearing an endotoxin-susceptible 9-day tumor. Surprisingly, the donor T cells that primed the recipient tumor for endotoxin-induced regression were of the Ly-1+2- phenotype, as evidenced by their susceptibility to treatment with anti-Ly-1 antibody and complement, and their complete resistance to treatment with anti-Ly-2 antibody and complement. They were different, therefore, from the T cells that cause the regression of smaller tumors in gamma-irradiated recipients without the aid of endotoxin. It is suggested that the antitumor function of endotoxin depends on its ability to cause intratumor macrophages to acquire and express tumoricidal function, but only after the macrophages have been activated by Ly-1+2-tumor-sensitized T cells.

Animals↗

Mechanism of immune transfer by RNA extracts. Immune RNA induces the synthesis of idiotype-bearing antigen receptors in noncommitted cells.

Immune RNA (I-RNA) was extracted form lymphoid organs of BALB/c mice immunized with AKR lymphoid cells. Incubation of normal BALB/c spleen cells with this I-RNA (but not with normal RNA) resulted in leukocyte migration inhibition reactions (LMIR) against AKR extracts but not against purified protein derivative or BALB/c sarcoma extracts. This transfer was abolished by pretreating I-RNA with RNAse but not with pronase. The active fraction of I-RNA was retained by and could be eluted from Poly-U Sepharose columns. Normal cells pretreated with I-RNA also reacted in the presence of an anti-idiotypic anti-serum of anti-(BALB/c anti-AKR) specificity. Pretreatment of cells with anti-idiotypic serum plus complement did not inhibit the subsequent transfer of LMIR with I-RNA. Idiotypic receptors were expressed on I-RNA treated cells less than one hour after I-RNA treatment. Using an I-RNA of double specificity, the results suggested that I-RNA entered into and acted on the cells through a nonspecific mechanism. Finally, I-RNA could induce BALB/c anti-AKR idiotypic markers in C57Bl/6 cells, genetically committed for different idiotypes, while RNA extracted from C57Bl/6 immune cells could not induce in BALB/c cells their own genetically acquired idiotypes. This series of data would prove that I-RNA acting as a mRNA is able to induce in normal noncommitted cells the de novo synthesis of antigen receptors similar or identical to those present in the surface of in vivo immunized lymphoid cells of the same strain.

AKR murine leukemia virus↗

Immune impairments and antibodies to HTLVIII/LAV in asymptomatic male homosexuals in Israel: relevance to the risk of acquired immune deficiency syndrome (AIDS).

We have studied 288 Israeli asymptomatic male homosexuals (MHS) to determine the prevalence of antibodies to HTLVI and HTLVIII and their correlation with impairments of the immune system and serum interferon (IFN). Seropositivity for HTLVI, HTLVIII, or both was found in 1.4, 8.3, and 0%, respectively. Significant decreases in the total peripheral T cells, TH cells, and TH/TS ratio as well as elevated alpha IFN serum levels were found in the MHS group in comparison with normal controls. Although no difference in the prevalence of either immune derangements or elevated serum IFN was observed between HTLVIII/LAV-seropositive and HTLVIII/LAV-seronegative MHS, the decreases in total T cells, TH cells, and TH/TS ratios were significantly greater in the seropositive MHS. These results indicate that (a) immune impairments and IFN system activation occur commonly in homosexuals, precede their exposure to HTLVIII/LAV, and probably reflect this group's increased risk for AIDS and (b) HTLVIII/LAV infection of MHS aggravates further their preexisting immune impairments.

Acquired Immunodeficiency Syndrome↗

The immune response in iron-deficient young children: effect of iron supplementation on cell-mediated immunity.

The effects of iron deficiency on immunity remain controversial. This study was designed to assess the impact of iron supplementation on the immune status, in 81 children aged 6 months-3 years, at high risk for iron deficiency, using a longitudinal double blind randomised and placebo-controlled study. Lymphocytes of iron-deficient children produced less interleukin-2 in vitro. Iron supplementation for 2 months increased mean corpuscular volume, serum ferritin and serum transferrin, but had no effect on the parameters of T-cell mediated immunity. The lower interleukin-2 levels in iron-deficient suggest that cell-mediated immunity may be impaired in iron deficiency.

Anemia, Hypochromic↗

Experimental studies on factors causing acute serum sickness glomerulonephritis of immune complex origin. I. The role of immune complexes and the immunological status of the host.

In acute serum sickness glomerulonephritis induced in rabbits by large doses of BSA, the relationship of the host's immunological status and the severity of renal histological changes was studied. It was found that good antibody producers developed more severe renal lesions. The higher avidity of antibodies enhances the inflammatory effect of immune complexes. Kidney is favoured for deposition of immune complexes especially in the case of chronic immune complex formation in the presence of antigen excess. Diminished phagocytic function of leukocytes (probably decreased immune complex saturating capacity) may also contribute to the severity of renal histological alterations.

Acute Disease↗

Cyclic kinetics and mathematical expression of the primary immune response. Cyclic kinetics of antibody-forming cells following immunization with Salmonella typhi O-antigen.

The kinetics of antibody-forming cells (AFC) in the spleen of rats immunized with Salmonella typhi O-antigen was investigated. The number of nucleated cells of spleen and blood serum antibody titres in passive haemagglutination were determined in parallel. Cyclic changes in the number of antibody-forming cells were detected as three peaks on the 4th, 9th, and 13th days following immunization. The fluctuations of their number were not related to the total number of nucleated cells of spleen. The antibody titres reached their peak on the 10th day following immunization, decreased by the 14th day and rose again on the 16th day after immunization. Repeated increases of the number of AFC were probably due to the regular, not accidental, recruitment of committed precursors cells (memory cells).

Animals↗

Glomerular immune complex deposition, circulating immune complexes, and antibodies in experimental insulinopenic diabetes.

Compared with control animals with a normal metabolism, rats with insulinopenic diabetes generally show an increase in glomerular deposition of complement-fixing immune complexes after immunization with bovine albumin and bovine gamma-globulin. Compared with the control group, the serum of the diabetic animals showed a reduction in the titers of IgM-isotype antibodies, which have a lower affinity. The concentration of the circulating immune complexes is the same. The increased frequency of glomular deposits in experimental diabetes can be explained by an increase in capillary permeability and by the formation of qualitatively different immune complexes.

Animals↗