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PubMed1985

[Preliminary study in female rats of the immunoregulatory effect of estradiol, progesterone and pituitary prolactin on natural killer-like cell mediated cytotoxic activity].

A spontaneous non-immune natural killing-like cytotoxic activity is induced in cyclic non mated virgin F/344 females by progesterone + oestradiol or progesterone alone treatment after bilateral ovariectomy. Many indications attribute this cytotoxic response to the absence of the mating stimulated pituitary prolactin release which normally rescues the corpora lutea from regression, and brings about the necessary progesterone for pregnancy or pseudopregnancy.

Animals↗
PubMed2003

Evolution of naturally acquired hepatitis B immunity in the long-term hemodialysis population.

BACKGROUND: Although the natural history of vaccination-induced hepatitis B virus (HBV) antibodies (Abs) is becoming clearer, little is known about naturally acquired immunity. Some assume that these patients never lose their Abs. METHODS: To document the natural history of HBV immunity, we prospectively followed up all naturally immune patients initiating hemodialysis (HD) therapy at St Michael's Hospital (Toronto, Canada). Patients presenting with Ab to hepatitis B surface antigen (HBsAb) who had no history of vaccination had a core Ab level measured to confirm natural immunity. When HBsAb titer decreased to less than 10 IU/L, patients were administered a single dose of 40 microg of Engerix B vaccine (Smith Kline Beecham Pharma Inc, Oakville, Ontario, Canada) intramuscularly as a booster dose. RESULTS: We identified 29 patients beginning HD therapy with natural immunity. Nine patients (30%) subsequently lost immunity (defined as Ab titer decreasing to < 10 IU/L) during follow-up. They were older and had a lower Ab titer at initiation of HD therapy. Four of 5 patients with a low response to the booster dose were 75 years or older. Two patients with a low peak Ab titer after the booster dose again had their Ab titer decrease to less than 10 IU/L after 6 and 10 months. Both patients were switched to intradermal vaccination. All other patients were still immune after a median of 26 months. CONCLUSION: Individuals who are naturally immune against HBV may experience a decrease in Ab titer. Their responses to booster vaccinations varied widely. It is possible that elderly patients with natural immunity require closer surveillance. We provide recommendations for surveillance in these patients.

Aged↗
PubMed2003

Experimental vaccines against measles in a world of changing epidemiology.

Vaccination with the current live attenuated measles vaccine is one of the most successful and cost-effective medical interventions. However, as a result of persisting maternal antibodies and immaturity of the infant immune system, this vaccine is poorly immunogenic in children <9 months old. Immunity against the live vaccine is less robust than natural immunity and protection less durable. There may also be some concern about (vaccine) virus spread during the final stage of an eventual measles eradication program. Opinions may differ with respect to the potential threat that some of these concerns may be to the World Health Organisation goal of measles elimination, but there is a consensus that the development of new measles vaccines cannot wait. Candidate vaccines are based on viral or bacterial vectors expressing recombinant viral proteins, naked DNA, immune stimulating complexes or synthetic peptides mimicking neutralising epitopes. While some of these candidate vaccines have proven their efficacy in monkey studies, aerosol formulated live attenuated measles vaccine are evaluated in clinical trials.

Animals↗
PubMed2004

Influenza virus: immunity and vaccination strategies. Comparison of the immune response to inactivated and live, attenuated influenza vaccines.

Influenza virus is a globally important respiratory pathogen which causes a high degree of morbidity and mortality annually. The virus is continuously undergoing antigenic change and thus bypasses the host's acquired immunity to influenza. Despite the improvement in antiviral therapy during the last decade, vaccination is still the most effective method of prophylaxis. Vaccination induces a good degree of protection (60-90% efficacy) and is well tolerated by the recipient. For those at risk of complications from influenza, annual vaccination is recommended due to the antigenic changes in circulating strains. However, there is still room for improvement in vaccine efficacy, long-lasting effect, ease of administration and compliance rates. The mucosal tissues of the respiratory tract are the main portal entry of influenza, and the mucosal immune system provides the first line of defence against infection. Secretory immunoglobulin A (SIgA) and IgM are the major neutralizing antibodies directed against mucosal pathogens. These antibodies work to prevent pathogen entry and can function intracellularly to inhibit replication of virus. This review describes influenza virus infection, epidemiology, clinical presentation and immune system response, particularly as it pertains to mucosal immunity and vaccine use. Specifically, this review provides an update of the current status on influenza vaccination and concentrates on the two main types of influenza vaccines currently in use, namely the cold-adapted vaccine (CAV) given intranasally/orally, and the inactivated vaccine (IV) delivered subcutanously or intramuscularly. The commercially available trivalent IV (TIV) elicits good serum antibody responses but induces poorly mucosal IgA antibody and cell-mediated immunity. In contrast, the CAV may elicit a long-lasting, broader immune (humoral and cellular) response, which more closely resembles natural immunity. The immune response induced by these two vaccines will be compared in this review.

Administration, Intranasal↗
PubMed2004

Effects of neurointermediate pituitary lobectomy on humoral and cell-mediated immune responses in the rat.

OBJECTIVE: Chronic stress is characterized by an increased activity of the hypothalamic-pituitary-adrenocortical axis and decreased humoral and cell-mediated immune responses. In the rat, corticosterone is the principal natural immune suppressor. Neurointermediate pituitary lobectomy (NIL) in rats induces diabetes insipidus and protracted increases in basal adrenocorticotropin and corticosterone plasma levels, a situation that resembles chronic stress. In this paper, we evaluated the effects of NIL on humoral (hemagglutinin titers and footpad swelling to sheep red blood cells--SRBC) and cell-mediated immune responses (contact hypersensitivity to dinitrochlorobenzene). METHODS: The studies were conducted on NIL Wistar rats (body weight 150-200 g) 3 weeks after surgery. For comparisons, nonoperated control rats were used. RESULTS: NIL resulted in an increased water intake. Body weight gain and adrenal, thymus, and spleen weights were within the range of nonoperated controls. Eight days after SRBC immunizations a second SRBC injection into the footpad resulted in a decreased swelling response in NIL rats. The hemagglutinin titers were also reduced in the NIL rats. CONCLUSIONS: These results indicate that: (1) NIL reduces humoral immune responses and decreases the cell-mediated immune response; (2) the immune alterations are most likely due to the increased activity of the hypothalamic-pituitary-adrenocortical axis induced by NIL, and (3) NIL animals constitute a valuable paradigm to study hypothalamic-pituitary-immune interactions.

Animals↗
PubMed2003

The interaction of human dendritic cells with yeast and germ-tube forms of Candida albicans leads to efficient fungal processing, dendritic cell maturation, and acquisition of a Th1 response-promoting function.

T helper cell type 1 (Th1) cell-mediated immunity plays a critical role in protection against the opportunistic pathogen Candida albicans. Virulence of the fungus is closely associated with its ability to form germ-tubes (GT), the early phase of the dimorphic transition from the commensal yeast (Y) to the more invasive hyphal (H) form. In this study, we examined the functional outcome of the interaction of Y or GT forms with human dendritic cells (DCs), professional antigen-presenting cells, which are pivotal for initiation and modulation of T cell responses. DCs phagocytosed and killed Y and GT cells with a comparable efficiency, becoming able to trigger strong proliferative responses by Candida-specific, autologous T cell clones. Both fungal forms induced DC maturation, as indicated by up-regulation of CD83, CD80, CD86, CD40, and major histocompatibility complex classes I and II surface antigens. Chemokine receptors were also modulated in Candida-DCs, which showed increased CCR7/CXCR4 and decreased CCR5 expression. Y- and GT-activated DCs differed in the pattern of cytokine expression. In particular, GT cells, in common with fully differentiated H cells, induced significantly more elevated levels of interleukin (IL)-10 than Y cells. Nevertheless, Y-, GT-, or H-pulsed DCs secreted comparable amounts of IL-12p70. In addition, irrespective of the fungal form triggering DC activation, Candida-DCs acquired the ability to prime naive T lymphocytes with a defined Th1 phenotype. Overall, our findings highlight the induction of substantially similar functional patterns in human DCs encountering the different forms of growth of C. albicans, both seemingly activating the Th1-type immunity which is characteristic of the healthy human subjects, naturally immunized and protected against the fungus.

Antigen-Presenting Cells↗
PubMed1982

Utilization of monoclonal antibodies in the treatment of leukemia and lymphoma.

The generation of murine monoclonal antibodies reactive with human leukemia and lymphoma cells has recently led to clinical trials that have begun to evaluate the use of these reagents in the treatment of various leukemias and lymphomas. Several of these studies have demonstrated that infusion of monoclonal antibody can cause the rapid and specific clearance of leukemic cells from the peripheral blood. Intravenously administered antibody also rapidly binds to bone marrow lymphoblasts, and in one instance, has resulted in the partial regression of tumor cell infiltrates in lymph nodes and skin. Unfortunately, clinically significant responses have not in general been achieved, but these clinical studies have identified specific factors that result in the development of resistance to antibody-mediated lysis in vivo. These factors include the presence of circulating antigen, antigenic modulation, reactivity of monoclonal antibody with normal cells, immune response to murine antibody, and the inefficiency of natural immune effector mechanisms. Current research is now being directed towards developing methods to circumvent each of these obstacles. Future clinical studies utilizing antibodies in vitro or with different specificity may demonstrate greater therapeutic efficacy. In addition, monoclonal antibodies can be used as carriers of other cytotoxic agents and in conjunction with other agents that will reduce the total load. Monoclonal antibodies represent new and powerful reagents that may in the near future become an additional therapeutic modality for patients with malignant disease.

Animals↗
PubMed1986

Enhancement by interferon of chicken splenocyte natural killer cell activity against Marek's disease tumor cells.

A non-immune natural killer-type cell population (NK) from 6-to 12-week old chickens was able to kill MSB-1 Marek's disease (MD) tumor cells in vitro; as measured by the 51Cr-release cytotoxicity assay. Removal of T cells, B cells, adherent cells, or any combination of the three populations of cells did not result in diminished levels of cytotoxicity of the remaining spleen cells against MSB-1 cells. The cytotoxicity of chicken NK cells could be rapidly augmented by polyinosinic-polycytidylic acid (poly I:C) and by the Cal 11914 strain of Newcastle disease virus (NDV), but not by the TCND strain of NDV which is not an interferon (IFN) inducer, indicating that IFN play a role in augmentation of the NK activity in chickens.

Animals↗
PubMed1999

The Th1/Th2 nature of concurrent immune responses to unrelated antigens can be independent.

We tested the independence hypothesis, namely that the Th1/Th2 nature of concurrent immune responses, generated in the same secondary lymphoid organ to non-cross-reacting Ags, can be independently determined. Some infectious agents and some adjuvants contain modulatory molecules that affect the Th1/Th2 nature of immune responses in a non-Ag-specific manner. We therefore excluded infectious agents as Ags and the use of adjuvants to generate immune responses. We first show that the dose of xenogeneic RBC administered i.v. determines the Th1/Th2 nature of the splenic immune response. Low doses generate a virtually exclusive Th1 response, whereas a higher dose induces either a mixed Th1/Th2 or a predominantly Th2 response, and stimulates the production of specific Abs. We immunized individual mice simultaneously with a low dose of one kind of xenogeneic RBC and with a higher dose of another non-cross-reacting xenogeneic RBC and assessed the Th1/Th2 nature of the immune responses generated in the spleen to each kind of RBC. The Th1/Th2 nature of the response to each RBC in doubly immunized mice was indistinguishable from that of the corresponding immune response in singly immunized mice. We discuss the significance of our findings for understanding immune class regulation, and the possible reasons why such independence is not always seen.

Adjuvants, Immunologic↗
PubMed1990

Human immune responses against sexual stages of malaria parasites: considerations for malaria vaccines.

Studies on the natural immune responses to the sexual stages of malaria parasites have been reviewed in the context of human malaria transmission-blocking vaccines. Antibodies against the sexual stages of the malaria parasite, gametocytes and gametes, are readily evoked by natural malaria infections. These antibodies that suppress infectivity at high concentrations can, at low concentrations, enhance the development of the parasite in the mosquito; however, because enhancing antibodies are prevalent during natural malaria infections, it is likely that a vaccine would rapidly boost these antibodies to blocking levels. The immunogenicity of sexual stage antigens appears to be constrained in the human host, probably due to T epitope polymorphism and MHC restriction in humans. These constraints apply mainly to those antigens that are sensitive targets of host immunity such as the gamete surface antigens and not to internal gamete antigens, indicating that antigenic polymorphism may have evolved in response to immune selection pressure. Evidence for immunosuppression of the host by exposure to endemic malaria is presented and its consequences on vaccine development are discussed.

Animals↗
PubMed2006

Manufacturing immunity to disease in a test tube: the magic bullet realized.

Although it took over one hundred years, Ehrlich's concept of the magic bullet is now a reality. Today, therapeutic antibodies are, arguably, the most important class of new drugs for the treatment of illnesses ranging from Alzheimer's disease to cancer. The emergence of therapeutic antibodies had to wait for advances in immunochemistry that allowed construction of antibodies in vitro. The centerpiece of the new technology is the combinatorial antibody library, which essentially allows one to synthesize an artificial immune system with a diversity that exceeds that of the natural repertoire. The construction of such libraries was perceived to be difficult because, if the natural immune system was to be used as the starting material, construction of the libraries would entail protocols that are the opposite of usual cloning. In gene cloning one starts with complexity and reduces it to a singularity. In the generation of diversity by construction of combinatorial antibody libraries, one starts with a collection of clones, randomly expands their complexity, and then returns them to recoverable singularities. The methods developed to accomplish this seemingly formidable task now allow construction of antibodies in a test tube to any antigen. These synthetic antibodies may be qualitatively and quantitatively superior to those of nature.

Antibodies↗
PubMed1984

Influence of naturally occurring human immune complexes on monocyte movement in vitro.

The influence of naturally occurring immune complexes (IC) on monocyte motility has been investigated. Both chemokinesis and chemotaxis have been measured, using modified Boyden chambers, in response to sera containing IC and to the same sera depleted of IC with 2% polyethylene glycol. Chemokinetic activity was markedly increased in the presence of IC-containing sera, and this increased activity was largely abolished, following IC depletion. The chemotactic activity of the IC-containing sera was largely independent of the IC content, since IC depletion only resulted in a modest decrease in stimulated movement. The chemotactic response to a standard chemoattractant (zymosan-treated sera) was significantly increased with the cells in the presence of IC-containing sera, and this effect was abolished following IC depletion. There was no relationship between the total IC concentration and changes in monocyte movement. These results indicate that circulating IC may markedly alter monocyte locomotion in such a way that more cells may be attracted more rapidly to an inflammatory focus.

Antigen-Antibody Complex↗
PubMed2000

Natural anti-carbohydrate IgM in mice: dependence on age and strain.

Natural anti-carbohydrate antibodies in humans play a key role in natural immunity and in recognition of allogeneic and xenogeneic antigens. Presumably, natural anti-carbohydrate antibodies in mice have similar functions; but these antibodies have not been extensively characterized. An assay was developed and used to screen for anti-carbohydrate IgM in the serum of BDF-1 mice. Among the natural anti-carbohydrate IgM identified, anti-betaGlcNAc IgM were the most abundant. Anti-betaGlcNAc IgG was not detected. Levels of anti-betaGlcNAc IgM were very low in 3-week-old BDF-1 mice and increased until 5 to 7 months of age. Levels of serum anti-betaGlcNAc IgM similar to those in BDF-1 mice were found in the serum of some strains related to the BDF-1 strain (DBA and C57BL/6) and in BDF mice lacking the galactosyl transferase gene. However, in two strains unrelated to the BDF-1 strain (FVB and SJL), levels of anti-betaGlcNAc IgM were less than one-tenth of those found in BDF-1 mice. These results provide considerable insight into the effect of age on the production of natural anti-carbohydrate antibodies in mice and indicate that production of those antibodies is strongly dependent on the strain of mouse. These studies will help in future development of murine models for studying the biological and medical roles of natural anti-carbohydrate antibodies.

Acetylglucosamine↗
PubMed1992

Experimental studies of immunotoxicity of a photosensitizing agent (Photofrin II) in mice.

Immunotoxicity studies have been performed on the photosensitizing agent Photofrin II (PHFR), a porphyrin derivative used in photodynamic therapy. Hybrid CD2F1 (H-2d/H-2d) or inbred C57Bl/6 (H-2b) male mice were injected with graded doses of the agent (from 1.2 to 12 mg/Kg ip) on day -5, -3 and -1 before assays. The animals, or spleen cells collected from them on day 0 with respect to PHFR treatment, were tested for: a) competence of producing GVHD upon cell transfer into allogeneic, immunosuppressed recipients; b) graft response against challenge with allogeneic lymphoma cells; c) delayed-type hypersensitivity (DTH) against sheep red blood cells; d) in vitro response to mitogens; e) NK cell activity; f) in vitro generation of alloreactive cytotoxic T lymphocytes (CTL); g) resistance against the challenge of a sublethal dose of Pseudomonas aeruginosa. Moreover the LD50 of the drug given ip has been determined in male CD2F1 mice. The results show that PHFR, even at the highest doses used, does not affect most of the immunological parameters studied, except for a marginal inhibition of CTL generation and increment in proliferative responses to Con A or LPS. These data along with parallel studies performed by our group on human models in vitro, showing increased susceptibility of PHFR-treated tumors to NK or LAK effector cells, point out that PHFR, in the absence of systemic photoactivation, is essentially non-immunotoxic in vivo and could render tumor cells more susceptible to natural immunity.

Animals↗
PubMed1984

The future of measles in highly immunized populations. A modeling approach.

Little is known about how an intensive measles elimination program changes the overall immune status of the population. A computer model was created to study the effect of the measles elimination program in the United States on the number of susceptibles in the population. The simulation reveals that in the prevaccine era, approximately 10.6% of the population was susceptible to measles, most of whom were children less than 10 years of age. With the institution of the measles immunization program, the proportion of susceptibles in the population fell to 3.1% from 1978 through 1981, but then began to rise by approximately 0.1% per year to reach about 10.9% in the year 2050. The susceptibles at this time were distributed evenly throughout all age groups. The model did not consider the potential effect of waning immunity. The results of this study suggest that measles elimination in the United States has been achieved by an effective immunization program aimed at young susceptibles combined with a highly, naturally immunized adult population. However, despite short-term success in eliminating the disease, long-range projections demonstrate that the proportion of susceptibles in the year 2050 may be greater than in the prevaccine era. Present vaccine technology and public health policy must be altered to deal with this eventuality.

Adolescent↗
PubMed1981

Preliminary demonstration of human tuberculoimmunity in vitro.

In this paper a method for studying human tuberculoimmunity in vitro is described. Results from its use support an explanation for human tuberculoimmunity that is like that for mouse tuberculoimmunity: that immune lymphocytes are stimulated by being cultured with immunizing antigen to make a lymphokine which enables syngeneic macrophages to kill intracellular tubercle bacilli. This method uses antigen-responding lymphocytes and effector monocytes taken in the same original 20-ml sample of venous blood. These cells are cultured separately, the lymphocytes for 72 h with antigen to make immune lymphokine and the monocytes for 7 days to become macrophages. The macrophages are then infected with attenuated or virulent tubercle bacilli and cultured for 7 days more in medium with or without the immune lymphokine. Without it they are unable to control intracellular replication of the bacilli, whereas with it they do. This lymphokine was produced only by lymphocytes of immune subjects, of whom there were three kinds: tuberculin positive naturally immunized, Mycobacterium bovis BCG immunized, and trypsin-extracted bacillary antigen immunized. This method for detecting human tuberculoimmunity in vitro should be useful for comparing experimental vaccines and for studying cellular and molecular mechanisms of human tuberculoimmunity under better controlled conditions than hitherto have been possible.

BCG Vaccine↗
PubMed2000

Architecture for an artificial immune system.

An artificial immune system (ARTIS) is described which incorporates many properties of natural immune systems, including diversity, distributed computation, error tolerance, dynamic learning and adaptation, and self-monitoring. ARTIS is a general framework for a distributed adaptive system and could, in principle, be applied to many domains. In this paper, ARTIS is applied to computer security in the form of a network intrusion detection system called LISYS. LISYS is described and shown to be effective at detecting intrusions, while maintaining low false positive rates. Finally, similarities and differences between ARTIS and Holland's classifier systems are discussed.

Animals↗
PubMed2003

[Cohorts and bio-libraries for studying malaria in tropical areas].

The relationship between Plasmodii transmission, infection, morbidity, genetic susceptibility and acquisition of natural immunity is studied among two cohorts in the Senegalese villages of Dielmo (300 inhabitants) and Ndiop (350 inhabitants) where malaria is holoendemic (about 200 P. falciparum infective bites/person/year) and mesoendemic (about 20 P. falciparum infective bites/person/year), respectively. The populations are under a daily active clinical survey. Blood samples are collected at least once per month. Plasma and red blood cells are stored in bio-libraries that allow longitudinal studies of the immune responses against plasmodial antigens and the investigation of the natural history of P. falciparum infections by molecular genotyping methods.

Animals↗