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PubMed2003

Ocular immune privilege: the eye takes a dim but practical view of immunity and inflammation.

The delicate visual axis that makes precise vision possible is highly vulnerable to the destructive potential of immunogenic inflammation. Immune privilege of the eye is the experimental expression of the way in which evolution has coped with the countermanding threats to vision of ocular infections and ocular immunity and inflammation. Ocular immune privilege has five primary features that account for its existence: blood:ocular barriers, absent lymphatic drainage pathways, soluble immunomodulatory factors in aqueous humor, immunomodulatory ligands on the surface of ocular parenchymal cells, and indigenous, tolerance-promoting antigen-presenting cells (APCs). Three manifestations of ocular immune privilege that have received the most extensive study are the intraocular microenvironment, which is selectively anti-inflammatory and immunosuppressive; the prolonged acceptance of solid tissue and tumor allografts in the anterior chamber; and the induction of systemic tolerance to eye-derived antigens. Anterior chamber-associated immune deviation is known to arise when indigenous, ocular APCs capture eye-derived antigens and deliver them to the spleen where multicellular clusters of these cells, natural killer T cells, marginal zone B cells, and gammadelta T cells create an antigen-presentation environment that leads to CD4(+) and CD8(+) alpha/beta T cells, which as regulators, suppress induction and expression of T helper cell type 1 (Th1) and Th2 immune expression systems. The ways the eye influences local and systemic immune responses to ocular antigens and pathogens carry risks to and benefits for mammalian organisms. As loss of sight is a powerful, negative-selecting force, the benefits of ocular immune privilege outweigh the risks.

Antigen-Presenting Cells↗

PubMed1995

The immune self: a selectionist theory of recognition, learning, and remembering within the immune system.

In this paper, I have briefly explored metaphors shared by the immune and nervous systems and shown that this exercise can lead to the elucidation of common principles of organization, as well as to predictions concerning how the immune system functions. Metaphor itself undoubtedly reflects the way in which we categorize and retrieve information 44], so it is not surprising that the deep processes of language tend to sample information from related data categories. Although the nervous and immune systems are obviously not the same and metaphors are indeed just that, my primary goal has been to suggest that by virtue of their having evolved in parallel over millions of years, the nervous and immune systems currently use the same archetypal principles and strategies to address related challenges in information processing and retrieval. Ultimately, nature is conservative. One need only look at a tree, a river, the airways, or the vascular bed in order to see how a fractal pattern of repetitive dichotomous branching has been used by each, in order to optimize the transport of fluids over large distances [45]. While each system has had to adopt different materials in order to solve the problem, the shape of their solutions is remarkably alike. In the immune and nervous systems, the elements used to produce optimal functional responses are also quite different, but again the solutions have been achieved by comparable strategies. I am certain that these two great systems of information processing, each responding with vastly different kinetics, will prove to be far more integrally interdependent than has been previously recognized. For example, should a swift response by the immune system be required in an overwhelming invasion by microbial pathogens, the immune system may be able to cooperate with the rapidly reacting nervous system to rid the host of the invaders. In this regard, we have shown that the beta-adrenergic hormone epinephrine rapidly increases the traffic of memory T-cells to mucosal sites, presumably representing an immune component of the fight-or-flight response [46]. Neural evolution appears to have as its goal the development of more efficient information processing systems that lead to higher levels of consciousness. However, in modern times, technologic advances in information processing have rapidly outstripped the slower adaptations that can be made by evolution. In order to satisfy his compulsive quest for information, man has recently developed and recruited the aid of computers.(ABSTRACT TRUNCATED AT 400 WORDS)

Association Learning↗

PubMed2006

Immunization with trivalent inactivated influenza vaccine in partially immunized toddlers.

OBJECTIVE: Children > or = 6 months of age who have previously received 1 dose of trivalent inactivated influenza vaccine are recommended to be given an additional single trivalent inactivated influenza vaccine dose the following fall. Limited data exist documenting the immunogenicity of 2 doses of influenza vaccine given in separate years to young children, and it is not known if the antigen content of each of the 2 doses of vaccine must be identical or similar to optimally immunize children in this age group. In 2004, the A/H3N2 and B antigens contained in trivalent inactivated influenza vaccine were changed from those in the 2003-2004 influenza vaccine, providing the opportunity to assess the effect of such a change on the single-dose recommendation in trivalent inactivated influenza vaccine-experienced toddlers. PATIENTS AND METHODS: We conducted an observational, nonrandomized, open-label study comparing immunogenicity and reactogenicity of 2 doses of trivalent inactivated influenza vaccine in 2 groups of healthy children aged 6 to 23 months. Children who had received 1 dose of 2003 trivalent inactivated influenza vaccine the previous season received 1 dose of 2004 trivalent inactivated influenza vaccine according to current guidelines (group 1). Trivalent inactivated influenza vaccine-naïve toddlers received the standard 2 doses of 2004 trivalent inactivated influenza vaccine 1 month apart (group 2). Blood was obtained 4 weeks after the second dose of trivalent inactivated influenza vaccine. The primary outcome measure was antibody response to the 3 vaccine antigens in the 2004 trivalent inactivated influenza vaccine after 2 doses of vaccine, as determined by hemagglutination-inhibition antibody titers. Noninferiority of the antibody response was based on the proportion of subjects in each group achieving a titer of > or = 1:32 postvaccination to antigens (H1N1, H3N2, and B) contained in the 2004-2005 vaccine. For each antigen, the antibody response was proposed to be noninferior if the upper bound of the 95% confidence interval of the difference between the proportion of children in the 2 groups with postvaccination titers > or = 1:32 was < 15%. Reactogenicity was a secondary outcome and was assessed by parental diaries or telephone follow-up. RESULTS: Fifty six of 58 previously immunized children (group 1) and 63 of 64 vaccine-naïve children (group 2) completed the study. The groups were similar, except group 1 was older at receipt of the second trivalent inactivated influenza vaccine. Reactogenicity did not differ by age or time between doses. Antibody responses to the unchanged influenza A/H1N1 antigen at 4 weeks after the second trivalent inactivated influenza vaccine dose were similar in both groups, with good responses as measured by geometric mean titer (75.2 vs 69.1) and percentage with antibody titers > or =1:32 (82.1% group 1 vs 85.7% group 2). For the A/H3N2 antigen, which changed between 2003 and 2004, there was a significantly higher geometric mean titer in group 1 compared with group 2 (156 vs 53.7), but both groups had very high rates of seroconversion that were not statistically different (91% vs 84%). The antibody response to influenza B was significantly lower in group 1 recipients, who received only a single dose of 2005 vaccine, as measured by both geometric mean titer and percentage with antibody > or = 1:32. The group 1 geometric mean titer was 13.8, and the group 2 geometric mean titer was 49.1. Only 27% of children in group 1 achieved antibody levels > or = 1:32 to influenza B compared with 86% in group 2. Using logistic regression, we also determined that older children had less potentially seroprotective levels to influenza B. Overall, noninferiority of the antibody response for group 1 compared with group 2 was confirmed for influenza A/H3N2, was marginally significant for A/H1N1, and was not confirmed for influenza B. CONCLUSIONS: The assessment of immune responses in children after changes in vaccine composition is important, because influenza vaccines change frequently, affecting not only antibody responses in partially immunized toddlers, but potentially immune responses in more fully immunized individuals. In this study, a change in 2 different vaccine antigens enabled us to assess and compare the impact of the original priming antigens after relatively minor changes in 1 antigen (A/H3N2) or after considerable antigenic changes in another vaccine antigen (B). Our subjects demonstrated relatively good responses to the vaccine antigen change characterized by relatively minor changes (A/H3N2). Circulating virus may have primed infants in both groups to antigen more closely related to the 2004 influenza A/H3N2 strain. The high A/H3N2 antibody response to the second dose of trivalent inactivated influenza vaccine in children who were immunized the previous fall with a different vaccine is consistent with the fact that more children in group 1 were alive during this epidemic and, therefore, were more likely to have experienced priming with natural infection. In contrast, a decreased antibody response to the influenza B antigen was seen in children primed with the earlier 2003 vaccine, suggesting that the major change in B virus lineage in the 2004 vaccine reduced the priming benefit of previous vaccination. Our findings are reminiscent of antibody responses in children seen after immunization with different but novel influenza antigens, such as swine flu vaccine (influenza A/swine/1976/37-like virus). Our results should be taken into account when evaluating new vaccines in young children for novel viruses, such as new pandemic strains of influenza. The need for multiple doses of vaccine to produce potentially protective antibody levels in children needs to be considered, even when vaccine is in short supply.

Antibody Formation↗

PubMed1991

Lymphocytes involved in cell-mediated immune responses and methods to assess cell-mediated immunity.

With increasing need for the development of vaccines against many poultry diseases, it is important to understand host immune mechanisms involved in protection against diseases. Because of increasing evidence suggesting a role of cell-mediated immunity in disease resistance against many poultry disease, investigation of immune systems involved in cell-mediated immunity is crucial for the development of immunological control strategies. Recent advances in hybridoma technology and cellular immunology have facilitated the understanding of the ontogeny, structure, and function of the avian immune system. Isolation and flow cytometric analysis of single lymphoid cells now enables researchers to dissect various components of the avian immune system and to investigate the role of subpopulations of lymphocytes in disease processes. In vitro assays are used to asses the host cellular response based upon antigen-specific lymphoproliferation, specific cellular effector function, and lymphokine secretion. These various assays can be used to quantify and qualify host immune responses and to better understand host immunity.

Animals↗

PubMed2026

Cancer Immune Responsiveness and MHC Class I Antigen Presentation: Mechanisms of Immune Escape and Immunotherapy Resistance in Gastrointestinal Cancers.

The Antigen Processing and Presentation Machinery (APM) is essential for immune surveillance by enabling the presentation of antigenic peptides to T lymphocytes and facilitating the elimination of infected or transformed cells. In cancer, the integrity of this process influences cancer immune responsiveness (CIR), defined as a tumour's capacity to be recognised by the immune system and respond to immunotherapy. Tumours with intact antigen presentation pathways are more likely to generate effective antitumour responses, whereas APM defects promote immune escape and therapeutic resistance. Cancer cells frequently evade immune detection through altered antigen processing or reduced expression of major histocompatibility complex (MHC) class I molecules, limiting tumour antigen presentation to cytotoxic T lymphocytes. These alterations are increasingly recognised as determinants of response to immune checkpoint inhibitors and potential predictive biomarkers. APM defects may be reversible or irreversible. Interferon-mediated signalling can restore MHC class I expression and T-cell cytotoxicity in some tumours, whereas permanent genomic alterations affecting human leukocyte antigen (HLA) class I genes, β2-microglobulin (β2-m), or interferon-γ (IFN-γ) pathway components can severely impair antigen presentation. Emerging evidence highlights four mechanistic levels of APM perturbation: peptide generation, peptide loading, MHC class I integrity, and epigenetic regulation. Each contributes to distinct patterns of immune evasion. This review examines how MHC class I alterations influence CIR and contribute to immune evasion and immunotherapy resistance in gastrointestinal malignancies, while discussing therapeutic strategies to restore or bypass APM deficiencies.

Humans↗

PubMed2000

Genetic immunization with lung-targeting macroaggregated polyethyleneimine-albumin conjugates elicits combined systemic and mucosal immune responses.

Genetic immunization is a novel form of vaccination in which transgenes are delivered into the host to produce the foreign protein within host cells. Although systemic immune responses have been relatively easy to induce by genetic immunization, the induction of regional and mucosal immunity has often been more challenging. To address the problem of eliciting mucosal immunity in the lung, we utilized macroaggregated albumin to target plasmid DNA to the lung. Macroaggregated albumin is trapped in the lung after i. v. injection, and it is routinely used in radiolabeled form as an imaging modality to evaluate pulmonary blood flow. To couple DNA to this targeting agent, polyethyleneimine (a polycation that binds DNA and enhances transfection) was conjugated to serum albumin, and the conjugate was aggregated by heating to produce particles of 25-100 microm. The resulting particles bound plasmid DNA avidly, and when injected i.v. in mice, the particles distributed in the peripheral lung tissue in the alveolar interstitium. Particle-bound luciferase plasmid transfected a variety of cell lines in vitro, and after i.v. injection, gene expression was detected exclusively in the lung. Using human growth hormone as the encoded foreign Ag for immunization, i.v. injection of the particle-bound plasmid elicited both pulmonary mucosal and systemic immune responses, whereas naked DNA injected either i.v. or i.m. elicited only systemic responses. Thus, particle-bound plasmid DNA may have utility for genetic immunization by intravascular delivery to the lung and potentially to other organs and tissues.

Amino Acid Sequence↗

PubMed2006

Neonatal immunization with a Sindbis virus-DNA measles vaccine induces adult-like neutralizing antibodies and cell-mediated immunity in the presence of maternal antibodies.

Infants younger than age 9 mo do not respond reliably to the live attenuated measles vaccine due the immaturity of their immune system and the presence of maternal Abs that interfere with successful immunization. We evaluated the immune responses elicited by Sindbis virus replicon-based DNA vaccines encoding measles virus (MV) hemagglutinin (H, pMSIN-H) or both hemagglutinin and fusion (F, pMSINH-FdU) glycoproteins in neonatal mice born to naive and measles-immune mothers. Despite the presence of high levels of maternal Abs, neonatal immunization with pMSIN-H induced long-lasting, high-avidity MV plaque reduction neutralization (PRN) Abs, mainly IgG2a, that also inhibited syncytium formation in CD150(+) B95-8 cells. IgG secreting plasma cells were detected in spleen and bone marrow. Newborns vaccinated with pMSINH-FdU elicited PRN titers that surpassed the protective level (200 mIU/ml) but were short-lived, had low syncytium inhibition capacity, and lacked avidity maturation. This vaccine failed to induce significant PRN titers in the presence of placentally transferred Abs. Both pMSIN-H and pMSINH-FdU elicited strong Th1 type cell-mediated immunity, measured by T cell proliferation and IFN-gamma production, that was unaffected by maternal Abs. Newborns responded to measles DNA vaccines with similar or even higher PRN titers and cell-mediated immunity than adult mice. This study is the first demonstration that a Sindbis virus-based measles DNA vaccine can elicit robust MV immunity in neonates bypassing maternal Abs. Such a vaccine could be followed by the current live attenuated MV vaccine in a heterologous prime-boost to protect against measles early in life.

Aging↗

PubMed1986

Site requirements and kinetics of immune-dependent elimination of intravascularly administered lung stage schistosomula in mice immunized with highly irradiated cercariae of Schistosoma mansoni.

Experiments were performed to compare the migration and survival of 75Se-labeled schistosomes, introduced by percutaneous cercarial exposure or by intravascular administration of 7-day-old lung stage schistosomula, in control and irradiated cercaria-immunized mice. Schistosomula were intravascularly introduced into the lungs, systemic organs and liver by injection via the femoral vein (FV), left ventricle (LV), and superior mesenteric vein (SMV), respectively. The fate of challenge larvae was examined by autoradiography of host tissues and by recovery of adult worms. It was found that both normal and immune elimination were site-dependent. In control mice 45%-60% of cercarial penetrants and lung schistosomula injected into the FV and LV were recoverable as adult worms, while a significantly greater number (70%-85%) were recoverable when lung schistosomula were injected into the SMV. In immunized mice, parasites introduced as either cercariae or FV-injected schistosomula were both highly sensitive to immune elimination. LV-injected schistosomula were also sensitive but to a slightly lesser degree. In contrast, schistosomula placed directly in the liver by SMV injection were totally insensitive to immune elimination. It was concluded that elimination of schistosomula in irradiated cercaria-immunized mice occurs in the lungs and/or in the systemic organs, but not in the liver. Also, it was concluded that immune elimination is not a rapid process, since more than 7 days were required after intravascular challenge for the development of demonstrable differences between control and immunized mice.

Animals↗

PubMed1993

[Stress-induced immune changes, and brain-immune interaction].

It is commonly known that psychosocial stress influences the immune system. Recent progress in neuroscience and immunology has elucidated the mechanism of stress induced immune changes, as well as brain-immune interactions. Numerous studies suggest that psychosocial stress increases the susceptibility to bacterial and viral infections. Stressful life events, inappropriate coping behavior and disturbed emotional states are associated with decreased phagocytosis, reduced lymphocyte response to mitogen, diminished natural killer cell activity, and with the risk of developing neoplasm. There is increasing evidence for a bidirectional communication system between the immune system and the brain through common receptors and biologically active substances such as cytokines and neuropeptides. Research has demonstrated the direct regulatory effect of the autonomic nervous system on the immune system, as well as the hypothalamic-pituitary-adrenal axis. It has also been shown that immune and allergic reactions can be classically conditioned, cytokines have an effect on the central nervous system, and that lymphocytes can produce neuropeptides. In this article, stress induced immune changes and brain-immune interactions are reviewed and discussed using pertinent literature, including studies by the authors.

Animals↗

PubMedDate not supplied

Tumor necrosis factor alpha and human immunodeficiency virus-specific functional immune responses after immunization with Gp120-depleted, inactivated HIV-1 in incomplete Freund's adjuvant (REMUNE) in HIV-1-seropositive subjects.

OBJECTIVE: We examined the relation between tumor necrosis factor-alpha (TNF-alpha) levels and human immunodeficiency virus type 1 (HIV-1)-specific functional immune responses, as measured by HIV-1 antigen-stimulated lymphocyte proliferation and beta-chemokine production after immunization with gp120-depleted, inactivated HIV-1 in incomplete Freund's adjuvant (i.e., HIV-1 Immunogen; REMUNE, The Immune Response Corporation, Carlsbad, CA, U.S.A.). STUDY DESIGN/METHODS: HIV-1-seropositive subjects who enrolled in an open-label study were immunized with REMUNE every 12 weeks and monitored for 60 weeks. HIV-1 antigen-stimulated lymphocyte proliferation and RANTES production were measured in peripheral blood mononuclear cells (PBMCs). TNF-alpha levels were measured in serum. RESULTS: TNF-alpha (P = 0.0003) significantly decreased and HIV-1 antigen-stimulated RANTES production (P = 0.002) and lymphocyte proliferation (P = 0.07) increased after immunization with REMUNE. TNF-alpha levels negatively correlated with HIV-1 antigen-stimulated RANTES production (r = -0.71; P = 0.0002) and lymphocyte proliferation (r = -0.37; P = 0.09). CONCLUSIONS: This study demonstrated decreased TNF-alpha levels with a concomitant augmentation of HIV-specific functional immunity in subjects immunized with REMUNE. Because TNF-alpha has been implicated in the induction of anergy in HIV-1 infection, the ability to decrease TNF-alpha may allow the immune system to respond to HIV and non-HIV antigens. Larger studies are being conducted to confirm the clinical utility of REMUNE in combination with potent antiviral drugs.

AIDS Vaccines↗

PubMed1975

The effect of maternal immunity, age at vaccination and doses or live vaccines on immune response to Newcastle disease.

The short life span of domestic fowls necessitates the use of early vaccination, but the response is affected by the immaturity of the immune mechanism and by the presence ofmaternal immunity: this results in an uneven immunity of the large and continually changing poultry population. This paper compares the response of groups of chicks from vaccinated and non-vaccinated hens after vaccination at various ages with Newcastle Disease vaccines of different pathogenicity (lentogenic and mesogenic strains). The results show that: 1. maternal immunity has a great effect on the pathogenicity of the vaccine viruses and the subsequent immune response; 2. the older the chicks are at the time of vaccination, the better is their immune response; 3. for vaccines of low pathogenicity the immune response can be enhanced by increasing the dose of the virus irrespective of the presence of maternal immunity.

Age Factors↗

PubMedDate not supplied

[Immune response in adult immunized with adsorbed DT-M anatoxin with reduced antigen content and Imovax-DT-adulte vaccine].

The comparative study of immune response after immunization of adults with adsorbed DT toxoid with reduced antigen content and Imovax-DT-adulte vaccine, as well as the safety of these preparations, was made. The study revealed that immunization of adults with adsorbed DT toxoid having reduced antigen content, made in two injections, and the injection of Imovax-DT-dulte vaccine, as well as the successive injection of these preparations, produced the same the levels of antitetanus immunity. Antidiphtheria immunity, evaluated by the number of seroconverted to diphtheria persons following two injections immunization was similar for the two preparations, while the level of antidiphtheria antibodies was higher in persons immunized with adsorbed DT toxoid. The immune stratum index was rather high among persons aged 16-29 years. This age group exhibited the highest number of persons, seropositive to both diphtheria and tetanus. Both vaccine preparations, adsorbed DT toxoid with reduced antigen content and Imovax-DT-adulte vaccine, were found to be equally capable of inducing autoimmune reactions in the vaccinees, detected by laboratory methods.

Adolescent↗

PubMedDate not supplied

Systemic immune response of young chickens orally immunized with bovine serum albumin.

The efficacy of oral immunization, with and without commercial adjuvants, to mount a systemic immune response in young chickens was studied. Bovine serum albumin (BSA) mixed with a pegylated C8/C10 mono/di-glyceride, (Softigen), or Cholera toxin B-subunit (CTB), administered orally by gavage to 15-day-old chickens resulted in circulating immunospecific anti-BSA IgG, IgM and IgA antibodies. Continuous 5-day oral administration of BSA without adjuvant also resulted in immunospecific IgM and IgA antibodies in the circulation of chickens first immunized at 15 days of age; and immunospecific antibodies of all three classes in chickens first immunized when they were 22 days old. IgG and IgM serum concentrations were more than 4 to 10 times higher, respectively, in CTB- and Softigen-treated chickens as compared to chickens immunized without adjuvants. The IgA response in the orally immunized chickens seemed unaffected by CTB and Softigen. The antibody concentrations in chickens immunized subcutaneously with BSA emulsified in Freund's Incomplete Adjuvant (FIA) were approximately 10 times higher than those of the chickens orally immunized using CTB and Softigen.

Administration, Oral↗

PubMed1977

Experimental immune complex glomerulonephritis in the mouse with two types of immune complexes.

Immune complex glomerulonephritis was induced in three groups of mice by long-term immunization. Two antigens of similar molecular weight were used. The first group was immunized with ferritin (mol wt 480,000). In altered glomeruli deposits of immune complexes were seen in the subendothelial and subepithelial spaces of the glomerular basement membrane (GBM) and in the mesangium. The immune complex deposits were formed by amorphous matrix with marked dense molecules of ferritin. The second group was immunized with human fibrinogen (mol wt 450,000). The immune complex deposits were present in the intramembranous, subepithelial and subendothelial spaces of the GBM and in the mesangium. These deposits were relatively less electron-dense and had a fine granular structure. The third group of mice were immunized with both ferritin and fibrinogen simultaneously. Two types of deposits situated subendothelially in the GBM and in the mesangium were seen in one animal of this group. One type of deposit resembled structurally the ferritin-antiferritin complex deposits, the other resembled the fibrinogen-antifibrinogen complex deposits. The individual deposits in the GBM and in the mesangium formed discrete homogeneous masses. The two types of deposit were occassionally in direct contact with one another, but were more often completely separate and were never mixed. It can be assumed that in at least some phase of the experiment both types of complex were present in the circulating blood simultaneously. However, since none of the complexes deposited in the GBM or in the mesangium were mixed, it seems probable that each type of complex is deposited separately in the form of "clusters" composed of a single type of complex. The phagocytic activity of mesangial cells of animals with complex glomerulonephritis was not increased when compared with control animals.

Animals↗

PubMedDate not supplied

[Effect of tumor necrosis factor DNA on immune response to DNA immunization against herpes simplex virus].

A study was made of the adjuvant effect of the mouse tumor necrosis factor alpha (mTNF alpha) on DNA immunization against the herpes simplex virus type 1 (HSV1). The HSV1 gD gene (pDNAgD) served as an immunogen; mTNF alpha or its gene cloned in an eukaryotic expression vector (pDNAmTNF) were used to modulate the immune response. Double immunization with pDNAgD led to a sixfold increase in the in vitro T-cell response, a high (1:2000) titer of anti-HSV1 antibodies (including virus-neutralizing antibodies), an increase in IgG2a/IgG1 (suggesting a shift of the immune response to the Th1 type), and no change in CD4/CD8 T-cell ratio. A single injection of mTNF alpha along with inactivated HSV1 allowed a twice higher antibody titer and a fourfold higher T-cell response as compared with immunization with HSV1 alone. Double immunization with both pDNAgD and pDNAmTNF increased the titer of anti-HSV1 antibodies and the T-cell response by factors of 8 and 1.5, respectively, as compared with immunization with pDNAgD alone. However, the protective effect was significantly lower with the two plasmids than with pDNAgD (73 vs. 100%). Thus, DNA immunization with pDNAgD induced both B- and T-cell responses and completely protected mice from a lethal doze of HSV1. The adjuvant properties of mTNF alpha and pDNAmTNF need further investigation.

Antibodies, Viral↗

PubMed2004

Superior therapeutic efficacy of alphavirus-mediated immunization against human papilloma virus type 16 antigens in a murine tumour model: effects of the route of immunization.

In our efforts to develop a strong, effective immune response against cervical carcinoma and premalignant disease, we study the use of recombinant Semliki Forest virus (SFV) encoding the oncoproteins E6 and E7 from high-risk human papilloma viruses (HPVs). Optimal immunization conditions are required for immunotherapeutic treatment of cervical cancer as it has been postulated that cervical cancer patients are immune-suppressed and/or immunologically tolerant for HPV. We previously generated an optimized construct encoding a fusion protein of HPV16 E6 and E7 and a translational enhancer (enhE6,7). Immunization of mice with SFV-enhE6,7 was shown to induce cytoxic T cell (CTL) responses and resulted in the eradication of established tumours. We now demonstrate, using HPV16-specific MHC class I tetramers, that high pCTL frequencies can be induced. However, this induction is strongly influenced by the route of immunization applied. Whilst in bulk CTL assays, requiring in vitro restimulation, CTL activity can be observed upon s.c., i.p., i.v. and i.m. immunization, detectable pCTL frequencies, without in vitro restimulation, are only induced upon i.m. and i.v. immunization. The route of immunization also strongly influences the dose of viral vector needed to induce CTLs and tumour therapy. As few as 5x10(4) SFV-enhE6,7, primed and boosted i.v., are needed to eradicate tumours in six out of seven mice treated. Furthermore, exponentially growing tumours of approximately 500 mm3 in size were seen to completely resolve and even tumours as large as 1500 mm3 decreased to one-third of their size. Apart from this potency, SFV vectors can safely be used for the expression of oncoproteins such as E6 and E7, since the viral RNA is not integrated in the host genome. Thus SFV-enhE6,7 meets with the criteria that a vaccine against cervical cancer should be safe and induce a very strong, long-lasting CTL response, strong enough to eradicate existing tumours.

Animals↗

PubMed2006

[Immune response induced by combinant immunization of different HBsAg vaccines in mice].

AIM: To investigate the specific humoral and cellular immune response induced by prime-boost immunization of HBsAg protein vaccine (P), recombinant vaccinia virus vaccine (V) and DNA vaccine (D) in mice. METHODS: Groups of BALB/c mice were primed by one of the three vaccines P, V or D and boosted by another vaccine at 2, 5, 8 and 11 week later, thus 9 immune combinations were made: PP, PV, PD, VP, VV, VD, DP, DV and DD. Serum samples were collected at week 2, 5, 8 and 11 and levels of anti-HBsAg IgG antibodies and their sub-isotypes were determined. Seven days after every boost, spleen cells of vaccinated mice were separated and the specific CTL lysis ratio of P815S cells were determined. RESULTS: Among the three HBsAg vaccines P, V and D, V could induce the quickest humoral immune response. The memory humoral immune response induced by P was the strongest. D induced the weakest antibody titer. The ratio of specific IgG1/IgG2a indicated that antibody induced by PP was more polarized to Th2. The other groups induced balanced Th1/Th2 immune response. Among all the groups, VD and DV induced the strongest CTL response, and the specific lysis ratio of P815S cells was 71% and 64%, respectively. CONCLUSION: The experimental results suggested that among all the immune combinations, PV, PD, VP and VD can induce better humoral immune response while DV and VD can induce stronger CTL response in BALB/c mice.

Animals↗

PubMed1991

[Variability of immune response in mice immunized at different time intervals after total or partial removal of organs with different reparative capacity].

The antibody response on sheep erythrocytes in the murine spleen at different time intervals after has been studied in one of the following operations: liver resection (70%), unilateral nephrectomy or sialadenectomy, or castration and bilateral sialadenectomy or castration. It was shown, that the liver and kidney surgery enhance the immune response if immunization was performed immediately or 24 h after the operation. Analogous changes of the immune response were observed under the immunization during 3 days after unilateral nephrectomy. The unilateral sialadenectomy evokes the contrary changes in immune response: immunization immediately or 24 h after the operation is accompanied by decrease of the above, the immunization on 3-7 days after the operation gets the increase of antibody genesis. Unilateral and bilateral castration as well as bilateral sialadenectomy evoke no changes of the immune response.

Animals↗