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Leptospirosis in poikilothermic vertebrates. A review.

Autochthanous leptospirosis does occur in the poikilothermic vertebrates, as evidenced by positive serological reactions and by the isolation of pathogenic leptospiral serovars. These findings in aquatic members of this group are of special importance in view of the increased worldwide interest in aquaculture farming. Since 1975, 24 of the 101 (23.7%) reported human cases of leptospirosis in Hawaii have been associated with aquaculture industries (taro farms, prawn farms and watercress farms). Antibody synthesis and persistence in these animals is variable, and seems to depend to some extent on environmental temperatures. Some members of the group apparently lack the capacity for immunological memory, experience a considerable delay (lag-phase) in antibody formation, demonstrate the "paradoxical reaction" found in other animals, and can maintain living pathogenic leptospirae in their organs in the absence of detectable antibody utilizing our present serologic methods. For these reasons, serological studies as the sole source of evidence for leptospiral infection cannot be recommended. The immunologic mechanism of lower vertebrates is not known, some studies suggesting that there may be more than one antibody system active in these animals, especially the turtles, and further investigation at the cellular and subcellular levels is indicated. The growth temperatures and nutritional requirements of leptospirae isolated from other than warm-blooded animals is also poorly understood. Some knowledge has been contributed by various investigators in recent years, but much more work needs to be done in studying the nutritional and metabolic requirements of leptospirae isolated from all sources, including the various fauna resident in and around the fresh water streams and ponds.

Amphibians↗

Decreased IgA1 response after primary oral immunization with live typhoid vaccine in primary IgA nephropathy.

INTRODUCTION: Patients with primary IgA nephropathy (IgAN) have an increased level of immunological memory to certain parenteral recall antigens. We recently found a deficient IgA1 immune response after intranasal challenge with a neo-antigen: cholera toxin subunit B. In the present study, we assessed the specific IgA1 and IgA2 antibody response in plasma, peripheral blood cells and mucosal secretions after primary enteral immunization. METHODS: Twenty eight IgAN patients, 26 patients with non-immunological renal disease and 32 healthy subjects were immunized orally with three sequential doses of live, attenuated, Salmonella typhi Ty21a. The humoral immune response in body fluids and antibody synthesis by circulating B cells was assessed in specific ELISAs and ELIPSAs respectively. RESULTS: Oral immunization resulted in significantly (P<0.0001) increased IgM, IgG, IgA, IgA1 and IgA2 responses in all groups, both in plasma and in circulating B cells in vitro. The IgA1 response in plasma was significantly (P<0.05) lower in IgAN patients, while no significant differences in IgM (P=0.36), IgG (P= 0.79) or IgA2 (P=0.45) responses were found as compared with matched control groups. The amount of IgA1 synthesized by circulating B cells tended to be lower in IgAN patients. No significant IgA response after oral immunization with S. typhi Ty21a was found in saliva (P=0.11) or tears (P=0.10). CONCLUSIONS: These data suggest an IgA1 hyporesponsiveness in patients with IgAN that is not only apparent after primary challenge of the nasal-associated lymphoid tissue but also after presentation to the gut. Previous results after parenteral recall immunization may be explained by assuming that IgAN patients require more frequent and/or longer exposure to IgA1-inducing antigens on their mucosal surfaces before they reach protective mucosal immunity. As a consequence, overproduction of IgA1 antibodies occurs in the systemic compartment, accompanied by an increased number of IgA1 memory cells.

Administration, Oral↗

Development of acquired immunity to Salmonella.

Salmonella enterica serovar Typhi (S. typhi) causes human typhoid fever, a serious and widespread disease in developing countries. Other Salmonella serovars are associated with food-borne infections. The recent emergence of multi-drug-resistant Salmonella strains highlights the need for better preventive measures, including vaccination. The available vaccines against Salmonella infection do not confer optimal protection. The design of new Salmonella vaccines must be based on the identification of suitable virulence genes and on knowledge of the immunological mechanisms of resistance to the disease. Control and clearance of a vaccine strain rely on the phagocyte oxidative burst, reactive nitrogen intermediates, inflammatory cytokines and CD4(+) TCR-alphabeta(+) T cells and are controlled by genes including NRAMP1 and MHC class II. Vaccine-induced resistance to reinfection requires the presence of Th1-type immunological memory and anti-Salmonella antibodies. The interaction between T and B cells is essential for the development of resistance following vaccination. The identification of immunodeficiencies that render individuals more susceptible to salmonellosis must be taken into consideration when designing and testing live attenuated Salmonella vaccines. An ideal live Salmonella vaccine should therefore be safe, regardless of the immunological status of the vaccinee, but still immunogenic.

Animals↗

[The dynamics of the humoral immune response to mycobacterial antigens in mice].

The main regularities of humoral immune response to mycobacterial antigens have been studied in experiments on BALB/c mice immunized with live and thermoinactivated Mycobacterium tuberculosis, var. bovis. As shown in this study, the maximum level of serum antibodies to mycobacterial antigen is achieved in two weeks after immunization irrespective of the dose and viability or mycobacteria, then follows a decrease in the antibody level. The absence of uniformity in the dependence of primary immune response and the formation of immunological memory on the dose and viability of mycobacteria has been demonstrated.

Animals↗

Neurovascular immunology: a 25-year odyssey.

Small vasoactive neurotransmitter molecules with a long evolutionary history of involvement in biological defense and inflammation play important roles in the up-regulation and down-regulation of the immune response and with similar effects on neuronal and lymphocyte transmembrane signaling molecules and mechanisms. The longest acting of these stimulatory molecules on lymphocyte traffic, substance P and bradykinin, also are transmitters of impulses relating to heat and pain. Heat and pain have been primordial stimuli to learning and memory--immunological as well as CNS.

Animals↗

Immunity in the female sheep reproductive tract.

Immune surveillance in the female reproductive tract is dependent on the interplay of many factors that include the expression of pattern recognition receptors on epithelial cells, resident leukocyte populations and hormones, none of which are uniform. The lower reproductive tract must accommodate the presence of commensal organisms whereas the upper reproductive tract is sterile. However, the upper female reproductive tract has its own immunological challenge in that it must tolerate the presence of a semi-allogeneic fetus if pregnancy is to succeed. So, immune activation and effector mechanisms to control pathogens may be qualitatively and quantitatively different along the reproductive tract. Our knowledge of innate and adaptive immunity in the sheep is less comprehensive than that of human or mouse. Nevertheless, comparative studies suggest that there are likely to be conserved innate immune sensory mechanisms (e.g. Toll-like receptors) and defence mechanisms (anti-proteases, defensins) that combine to limit infection in its early stages while shaping the adaptive response that leads to immunological memory and long-term protection. There are many pathogens that target the reproductive tract, and in particular the placenta, where specialised immunoregulatory mechanisms are operational. Among such pathogens are bacteria belonging to the genera Chlamydia/Chlamydophila that chronically infect the reproductive tracts of sheep and humans and ultimately cause disease through inflammation and tissue damage. An understanding of the immunological microenvironment of the reproductive tract is important for the design of novel control strategies to control chlamydial disease.

Animals↗

Mucosal and systemic anti-HIV responses in rhesus macaques following combinations of intranasal and parenteral immunizations.

There is an urgent need to develop vaccines that can elicit immunological memory responses against HIV. Using the rhesus macaque model and a combination of intranasal (IN) and parenteral immunizations with DNA or protein adsorbed to microparticles or mixed with mucosal adjuvants we sought to induce anti-HIV memory-type immune responses in both the mucosal and systemic compartments. Prime/boost immunizations were performed through five IN immunizations alone with HIV-env oligomeric gp140 (Ogp140) or HIV-gag-p24 mixed with Escherichia coli heat labile-derived mutant adjuvants or two parenteral immunizations with DNA encoding HIV-env or -gag adsorbed to microparticles followed by three IN immunizations with p24 gag protein and the mutant adjuvants. Both modes of immunizations induced anti-gp140 plasma and vaginal IgG and IgA as well as interferon (IFN)-gamma secreting peripheral blood mononuclear cells (PBMC) after HIV-env and -gag peptide restimulation. After a resting period of 4 months, when the levels of humoral and cellular responses had decreased, intramuscular (IM) booster immunizations with p55-gag protein adsorbed to microparticles and Ogp140 in MF59 oil in water emulsion significantly enhanced anti-HIV plasma and vaginal antibody, as well as peripheral blood IFN-gamma responses in all groups of vaccinated macaques. Importantly, plasma neutralization activity against both homologous and heterologous HIV strains was observed in all groups following the IM booster immunizations with protein. These findings show that IN priming alone or combinations of parenteral and IN immunizations followed by IM booster immunizations hold promise to significantly enhance mucosal and systemic memory-type immune responses against HIV-1 antigens.

AIDS Vaccines↗

Lymphocyte migration patterns in organ allograft recipients.

A central tenet of immunology is the observation, made 30 years ago, that lymphocytes recirculate continuously between peripheral blood and lymphoid tissues. In recent years, the subject of lymphocyte migration, both under physiological conditions and in states of alloresponsiveness, has become more enigmatic. It lies outside most current topics of immunological investigations, labelling and tracing techniques are problematic, and many experimental findings are phenomenological and difficult to interpret. Indeed, our overall knowledge of the functional differences between the various host lymphoid compartments and their constituent cell populations remains rudimentary. However, as understanding increases regarding the host immunological events responding to an antigenic stimulus such as a graft, with growing definition of the distinctive and interconnecting roles of lymphocyte subpopulations and their products acting on each other to produce graft destruction, the conceptual importance of lymphocyte migration again is becoming obvious. This role includes many facets of immunity such as the effects of antigen specificity, immunologic memory, differential behavior of recirculating or sessile populations, and local and systemic contact between antigen and effector cells. It has become evident that lymphocytes migrate in a non-random and highly dynamic fashion determined by a range of specific and non-specific factors; in the setting of organ transplantation, patterns are profoundly affected by the interrelated cellular and humoral components of the immunological cascade which may lead either to graft rejection or to its prolongation in untreated and immunologically modified recipients, respectively. Thus, the traffic of lymphocytes throughout host lymphoid and non-lymphoid compartments and their activity within these compartments should be considered an integral part of the host immunomodulation triggered by transplantation of histoincompatible tissue. Gradual filling of the gaps in our current knowledge on the mechanistic aspects of this phenomenon will not only contribute to basic science itself, but also should lead to the development of innovative therapeutic approaches to treat graft rejection.

Animals↗

A concept of immune regulation of somatic cell differentiation.

On the basis of several lines of experimental evidence a hypothesis is advanced on autoimmune regulation of somatic cell differentiation in an immunologically mature organism ("self-anti-self" hypothesis of differentiation). There are supposed to be clones of lymphocytes interacting via their antigen-recognizing receptors with autologous differentiation antigens on various target cells. This interaction would modify the genetically determined rate of cell differentiation. Some implications of the hypothesis are discussed in relation to immunological memory, tolerance etc. In particular, the new concept might imply similarity (or identity) of the genes coding for autologous differentiation antigens and those responsible for the idiotypes of antigen-recognizing lymphocyte receptors.

Animals↗

[A new approach to immunotherapy: the transfer factor].

The transfer factor is a tiny molecule capable of transferring the function of the T lymphocytes (immunological memory and retarded hypersensitivity) from a sensitized to a non-sensitized individual. The exact structure and action modalities of the molecule have not yet been precisely established. The difficulties involved in the study of the transfer factor are aggravated by the lack of any suitable experimental model. The attention of immunologists is attracted by this factor which opens up new prospects for the treatment of cancer, immunological deficiencies and certain infectious and autoimmune diseases. More profound research would appear useful to evaluate if and in what cases a potentiation of the immune mechanism can represent an alternative to immunosuppression.

Arthritis, Rheumatoid↗

[Immunological status of people inoculated with various types of inactivated vaccine against tick-borne encephalitis].

As compared with cellular immunity tests, serological tests more frequently detect virus-specific immune response in humans immunized with concentrated purified vaccine (CV) against tick-borne encephalitis. Combined determination of cell reactions and antibody production after a single injection of the vaccine increases the rate of detection of specifically responding persons. The duration of the inactivated vaccine-induced immunity is determined not only by the level of serum antibodies but also by the state of immunological memory detectable by the capacity of the host to produce antibodies after another injection of the specific antigen. At 14 and 30 days after a single immunization with CV IgG antibody is found in the blood of the vaccinees. In the course of 3 vaccinations, the concentration of serum immunoglobulins, chemotaxic activity of leukocytes, and blood lymphocyte reactivity to mitogens do not change. The role of some immunological values as criteria for the evaluation of the effectiveness of vaccine purification from impurities is discussed.

Adolescent↗

Immunotherapeutic approaches for hematologic malignancies.

The immune system has two complementary arms: one is older and seemingly more primitive, called the innate immune system, found in both plants and animals. The second (already many millions of years old!) is the adaptive or antigen-specific immune system, limited to vertebrate animals. The human innate immune system has many cellular elements that include granulocytes, monocytes, macrophages, natural killer (NK) cells, mast cells, eosinophils, and basophils. Receptors for these cells are non-clonal, fixed in the genome, requiring no rearrangement, and recognize conserved molecular patterns that are specific to pathogens. The adaptive immune system (B cells and T cells) have receptors with great variation, able to recognize an almost an unlimited number of highly specific pathogens through rearrangement of receptor gene segments, and can also provide immunological memory so critical for vaccination. As the immune system has evolved to recognize non-self, malignant transformation of self can likely escape immune surveillance with relative ease. Contributors to this chapter are utilizing distinct components of either the innate or adaptive immune system that recognize non-self, in combination with what we know about differences between malignant and normal self, in an effort to develop novel and effective immunologic approaches against hematologic malignancies. In Section I, Dr. Andrea Velardi reviews the benefits of NK cell alloreactivity in mismatched hematopoietic transplantation, provides updates on current clinical trials, and discusses further therapeutic perspectives emerging from murine bone marrow transplant models. In Section II, Dr. David Scheinberg reviews novel leukemic antigens being targeted by humanized monoclonal antibodies as well as mechanisms by which antibody-mediated cytotoxicity occurs in vivo. In Section III, Dr. Ivan Borrello reviews vaccine and adoptive T cell immunotherapy in the treatment of hematologic malignancies. Specifically, he discusses the various vaccine approaches used as well as strategies aimed at augmenting the tumor specificity of T cell therapies.

Animals↗

Immune transfer studies in canine allogeneic marrow graft donor-recipient pairs.

Transfer of immunity occurring with bone marrow grafting was studied using the dog as a preclinical model. Allogeneic bone marrow transplantation (BMT) was performed between DLA-identical beagle litter-mates. The donors were immunized with tetanus toxoid (TT) or sheep red blood cells (SRBC), and their humoral response was monitored by hemagglutination. The recipients of bone marrow from TT-immunized donors showed a marked increase of antibody titer one week posttransplantation, while in the recipients of marrow from SRBC immunized donors the antibody titers were considerably lower. Within the following 60 days the antibody titers in both groups diminished gradually to pregrafting levels. Control experiments in which cell-free plasma from donors immunized with TT and SRBC respectively was transfused indicated that the initial rise of specific antibody titers after marrow grafting is likely to be due to a passive transfer of humoral immunity. A single challenge of these marrow graft recipients with the respective antigen 15-18 weeks posttransplantation led to a secondary type of humoral immune response. In addition, it could be demonstrated that transfer of memory against TT or SRBC was independent from the actual antibody titer and the time of vaccination of the donor. One dog was immunized with TT after serving as marrow donor. When the donor had shown an antibody response, a peripheral blood leukocytes (PBL) transfusion was given to his chimera. Subsequent challenge of the latter resulted in a secondary type of specific antibody response. This indicates that specific cellular-bound immunological memory can be transferred after BMT from the donor to his allogeneic bone marrow chimera by transfusion of peripheral blood leukocytes. The data presented may be of importance in clinical BMT to protect patients during the phase of reduced immune reactivity by transfer of memory cells from histocompatible immunized donors.

Animals↗

Immunological features in multiple sclerosis.

A clinical and laboratory profile of the immunological system of patients with multiple sclerosis (MS) strongly suggested that many specific immune deficiencies exist in MS. The immunological history showed that patients with MS had had more tonsillectomies, appendicectomies, and childhood infections than matched controls, which suggested that there had been problems in controlling various types of childhood infections. The cell-mediated immune response and the circulating antibody titres were specifically impaired against a variety of antigens. Patients with MS had significantly lower serum antibody titres than controls against many naturally occurring antigens-namely, diptheria and tetanus toxoids, adenovirus, and mumps viruses. Raised serum antibody titres were found against measles and varicella zoster viruses while no difference was found towards other antigens. The delayed hypersensitivity reaction and the immunological memory of patients with MS were also greatly reduced against the mumps skin test antigens. There were normal amounts of circulating T and B lymphocytes, and the phytohaemagglutinin, concanavallin A, pokeweed mitogen, and encephalitogens lymphocyte transformation was not different from that in controls. These results indicated that patients with MS have more infectious problems than normal people and that both their T and B cell systems cannot mount a fully normal immunological response to some viral and bacterial antigens, while they give an increased response to others.

Adult↗

Bone marrow-derived dendritic cells pulsed with tumor homogenate induce immunity against syngeneic intracerebral glioma.

To evaluate the efficacy and toxicity of dendritic cell (DC) based therapy for intracerebral gliomas, we utilized a cell line derived from an astrocytoma that arose spontaneously in a VM/Dk mouse. This astrocytoma mirrors human gliomas phenotypically, morphologically and secretes transforming growth factor (TGF)-betas, immunosuppressive cytokines secreted by human gliomas. Systemic vaccination of mice with DCs pulsed with tumor homogenate followed by intracranial tumor challenge produced a > 160% increase in median survival (p = 0.016) compared with mice vaccinated with PBS or unpulsed DCs (p = 0.083). Fifty percent of mice treated with pulsed DCs survived long-term. Immunologic memory was demonstrated by survival of mice rechallenged with tumor. Both cell-mediated and humoral immunity was induced. On histological examination only focal areas of demyelination at the tumor implantation site were present. There was no evidence that autoimmune encephalomyelitis was induced by DC vaccination. Therefore, in a murine model, vaccination with DCs pulsed with glioma tumor homogenate is a safe and effective therapy against a syngeneic glioma located in the immunologically privileged central nervous system (CNS).

Animals↗

Adjuvant action of bacterial lipopolysaccharide in induction of delayed-type hypersensitivity to protein antigens. II. Relationships of intensity of the action to that of other immunological activities.

Various kinds of lipopolysaccharides (LPS) isolated from different bacterial strains exhibited more or less an adjuvant action in induction of delayed-type footpad response to ovalbumin (OA) in mice when antigen was injected subcutaneously together with LPS. There was a wide diversity in strength of the adjuvant action of LPS, and the action of the 03 antigen isolated from the culture supernatant fluid of Klebsiella was the most potent of eleven kinds of LPS tested. Besides this substance, LPS extracted from Escherichia coli 08, 09 and 0128, and Salmonella typhosa exhibited relatively strong action. The difference in strength of the action of the high and low active LPS in induction of delayed-type hypersensitivity could be observed at any doses of OA and LPS. The strength of the adjuvant activity of LPS in induction of delayed-type hypersensitivity roughly correlated with that of their adjuvant activity in augmenting immunological memory for the secondary antibody response to OA and also their ability to enlarge the regional lymph node, whereas it did not apparently correlate with that of their activity to stimulate B cells polyclonally and their ability to enlarge the spleen.

Adjuvants, Immunologic↗

Immunogenicity and toxicity testing of an experimental HIV-1 vaccine in nonhuman primates.

A highly purified saponin from Q. saponaria (QS-21) was tested in juvenile rhesus macaques for adjuvant activity and toxicity. The QS-21 was tested alone or as part of an experimental subunit HIV-1 vaccine containing a truncated recombinant HIV-1 envelope protein (gp160D) adsorbed to alum. Antibody responses were measured using ELISA and cell-mediated immunity was measured using cellular proliferation assays. Potential toxicity was monitored by standard clinical pathology testing using peripheral blood and urine samples. No toxic effects were observed, even after the administration of the experimental vaccines three times at monthly intervals. The QS-21 saponin adjuvant enhanced total antibody production levels by greater than 100-fold and broadened the specificity of the response so that additional epitopes were recognized, when compared with alum-adsorbed HIV-1 gp160D formulation. Low-level, antigen-specific proliferative responses to HIV-1 recombinant gp160 were induced by either vaccine formulation. Proliferative responses were induced by a sham challenge with soluble recombinant HIV-1 gp160 for all of the animals that had been vaccinated. However, those that received the HIV-complete vaccine formulation containing QS-21 responded significantly better. These data demonstrated that the QS-21 adjuvant augmented both antibody responses and cell-mediated immunity and established immunological memory. The potent adjuvant activity and lack of toxicity suggest that this adjuvant should be safe and effective for use in HIV-1 vaccines.

AIDS Vaccines↗

Antibodies against Entamoeba histolytica in human milk and serum in Kenya.

A modified enzyme-linked immunosorbent assay (ELISA) technique has been developed for the detection of secretory immunoglobulin A (SIgA) antibodies against Entamoeba histolytica. By substituting phosphate-buffered saline-Triton for phosphate-buffered saline-Tween as the antibody incubating buffer, unspecific absorption of SIgA was avoided. As revealed by chessboard titrations, the optimal amount of antigen for coating was higher in SIgA than in IgG ELISA. A purified antigen from the membrane pellet fraction of E. histolytica gave equally good reactivity with SIgA and IgG antibodies and was used throughout. A total of 283 milk and 232 serum samples from three areas in Kenya were tested. The samples were collected in maternity hospitals on one of days 1 to 3 after parturition. All milk samples were tested for total SIgA. In one of the study areas (Machakos), the mean level of SIgA was significantly lower than in the other two areas (Mombasa and Nairobi). Eighty-seven of the milk samples (31%) were reactive in the test. The rate of positives was higher in Mombasa, where the SIgA levels were highest. Since both the frequency and the level of serum antibodies were similar in the three study areas, it is likely that the higher milk reactivity in Mombasa was mainly due to the higher SIgA concentrations observed. Antibodies were detected in 32 (14%) of the sera, mostly in low or moderate titers. Surprisingly few mothers had detectable antibodies in both milk and serum. In fact, the majority of positives were reactive in either milk or serum, with a predominance of milk positives. The background for this is probably complex, containing components such as differences in immunoglobulin concentrations in the samples, diversities in local and systemic antigenic stimulation responses, and level of immunological memory.

Amebiasis↗