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PubMed1997

Immune versus natural selection: antibody aldolases with enzymic rates but broader scope.

Structural and mechanistic studies show that when the selection criteria of the immune system are changed, catalytic antibodies that have the efficiency of natural enzymes evolve, but the catalytic antibodies are much more accepting of a wide range of substrates. The catalytic antibodies were prepared by reactive immunization, a process whereby the selection criteria of the immune system are changed from simple binding to chemical reactivity. This process yielded aldolase catalytic antibodies that approximated the rate acceleration of the natural enzyme used in glycolysis. Unlike the natural enzyme, however, the antibody aldolases catalyzed a variety of aldol reactions and decarboxylations. The crystal structure of one of these antibodies identified the reactive lysine residue that was selected in the immunization process. This lysine is deeply buried in a hydrophobic pocket at the base of the binding site, thereby accounting for its perturbed pKa.

Animals↗
PubMed1999

The immune system in the elderly: III. Innate immunity.

The capability to cope with infectious agents and cancer cells resides not only in adaptive immune responses against specific antigens, mediated by T and B lymphocytes clonally distributed, but also in natural immune reactions. These innate defence mechanisms include chemotaxis, phagocytosis, natural cytotoxicity, cell interactions, and soluble mediators or cytokines. However, specific and natural immune mechanisms are always closely linked and interconnected, providing the primary defense against pathogens. The Authors discuss the main changes observed with advancing age in granulocytes and natural killer (NK) cell activity, in the expression and function of adhesion molecules, and in the pattern of cytokine production. Since phagocytic function is the primary mechanism through which the immune system eliminates most extracellular pathogenic microorganisms, analysis of this function is of clinical importance. Neutrophils from aged subjects often exhibit a diminished phagocytic capacity, as well as a depressed respiratory burst, notwithstanding an activated state. The activity of NK cells during aging has been studied extensively and different results have been reported. The most consistent data indicate an increase in cells with high NK activity with advancing age. Cells from healthy centenarians can efficiently kill target cells. This finding seems to suggest that innate immunity and in particular NK cell activity, is not heavily deteriorated with age. Conversely, a low NK activity is a predictor of impending morbidity. Immunosenescence is associated with increased expression of several cell adhesion molecules (CAM) resulting in an augmented capacity to adhere. Finally, also the cytokine network, responsible for differentiation, proliferation, and survival of lymphoid cells, undergoes complex changes with age. The main findings are a Th1 to Th2 cytokine production shift and an increased production of proinflammatory cytokines, which could explain many aspects of age-associated pathological events, such as atherosclerosis and osteoporosis.

Aged↗
PubMed1983

Aging of natural and acquired immunity of mice. I. Decreased natural killer cell function and hybrid resistance.

Two "natural resistance" functions, natural killer (NK) cell activity against YAC-1 lymphoma cells and rejection by irradiated mice of parental-strain or H-2 allogeneic bone marrow cell grafts (hybrid or allogeneic resistance) were compared in mice at ages between 10 weeks and 26 months. NK cell numbers, as assessed by target-binding cells, decreased to one-half that of young mouse spleen cells, whereas NK lytic function was much more depressed. Hybrid, but not allogeneic, resistance to marrow grafts was weakened by 17 months of age. The immunogenicity of marrow stem cells of old Fl hybrid mice had not changed. The interferon inducer polyinosinic:polycytidylic acid (pI:pC) restored hybrid resistance to marrow grafts but only weakly boosted NK cell function in old mice. Incubation of spleen cells of old mice with beta interferon resulted in a weak boosting of NK cell activity. No cells capable of inhibiting NK cell function were detected in the spleens of old mice. These findings in old mice were similar to findings in young mice treated with 89Sr, with the exceptions that both hybrid and allogeneic resistance to marrow grafts are defective in 89Sr-treated mice and pI:pC failed to restore hybrid resistance in mice treated with 89Sr. This loss of "natural resistance" by aged mice, perhaps mediated by marrow-dependent effector cells, can partially explain the increased incidence of tumors in aging populations.

Aging↗
PubMed1998

Regulation of adaptive immunity by natural killer cells.

Natural killer (NK) cells are well recognized as cytolytic effector cells of the innate immune system. In the past several years, the structure and function of NK cell receptors for the major histocompatibility complex (MHC) class I molecules and other ligands have been the subject of extensive studies. These studies. These studies have focused largely on the mechanisms of target cell recognition for lysis. Another aspect of NK cell function that seems to be underappreciated is their role in immune regulation. Since NK cells produce a number of immunologically relevant cytokines, it has been suggested that these cells may modulate the development of the adaptive immune response. But, is it the only mechanism by which NK cells interact with cells involved in the induction of antigen-specific responses? This article reviews some older and more recent studies and attempts to place NK cells in the context of potent immune regulators of T cell responses.

Animals↗
PubMed2003

[Epidemiological study of the hepatitis C virus in our population and vaccine coverage].

OBJECTIVE: Epidemiological study of patients with chronic hepatitis C and its serological status in relation to the hepatitis A (HA) and B (HB) viruses. DESIGN: Descriptive cross-sectional study. SETTING: Two urban health centres. Participants. 291 patients with chronic hepatitis C. MAIN MEASUREMENTS VARIABLES: age, sex, year and reason for diagnosis, personal histories, alcohol intake, serological status of the HA and HB viruses and HIV, and initial level of transaminases. RESULTS: Mean age, 55 +/- 16. Sex, 52% women. Prevalence, 0.98%. Reason for diagnosis, 41% health study, 15% study of hepatic pathology, 18% study of other pathologies. Personal histories, surgical intervention, 37.5%; intravenous drug users, 21.4%; transfusion, 14%; high-risk sexual conduct, 2.4%; health material used more than once, 2.4%; family member HC positive, 1.4%; no personal history recorded, 26.5%. Alcoholism, 17.9%. Mean transaminases: AST, 79.7 +/- 100 (9-920); ALT, 114.8 +/- 160 (6-1640). HB serological status: natural immunity, 22%; chronic, 9%; vaccine immunity, 3%; negative, 44%; not recorded, 21%. HA serological status: natural immunity, 2%; vaccine immunity, 2.5%; negative, 9%; not recorded, 87%. HIV-positive: 4.5%. CONCLUSIONS: Prevalence was below the expected level. Knowledge of serological status needs to be improved, especially for HA. The degree of vaccine coverage in these patients for HA and HB should be increased.

Adult↗
PubMed2005

In pursuit of xenoreactive antibodies: where has it gotten us?

Numerous studies have aimed to overcome the barrier to xenotransplantation posed by xenoreactive antibodies and the antigens they recognize. Whether this work will eventually lead to the widespread clinical application of xenotransplantation remains unknown. However, the benefits of this research are already substantial, with research leading to dramatic new developments in fields other than xenotransplantation. Our understanding of natural immunity, particularly the nature and function of natural antibodies, has taken quantum leaps forward, with far-reaching implications. Our improved understanding of the immune response to xenografts has proven invaluable in the characterization of the human immune reaction to commonly used biological therapeutics of xenogeneic origin. Our understanding of cell surface carbohydrates and our ability to modify these carbohydrates in living animals has advanced substantially, with implications for diseases such as cancer and autoimmunity. With this in mind, it is argued that continued work in xenotransplantation is of great value, not only because of the great potential benefits of xenotransplantation, but also because of the more certain benefits that arise from setting our sights on a difficult challenge.

Animals↗
PubMed2001

Variable immune-driven natural selection in the attachment (G) glycoprotein of respiratory syncytial virus (RSV).

A maximum-likelihood analysis of selection pressures acting on the attachment (G) glycoprotein gene of respiratory syncytial virus (RSV) from humans (HRSV) and bovines (BRSV) is presented. Six positively selected sites were identified in both group A and group B of HRSV, although only one site was common between them, while no positively selected sites were detected in BRSV. All positively selected sites were located within the ectodomain of the G protein and showed some association with positions of immunoglobulin (Ig) epitopes and sites of O-glycosylation. These results suggest that immune (antibody)-driven natural selection is an important determinant of RSV evolution and that this selection pressure differs among strains. The passage histories of RSV strains were also shown to affect the distribution of positively selected sites, particularly in HRSV B, and should be considered whenever retrospective analysis of adaptive evolution is undertaken.

Amino Acid Sequence↗
PubMed1996

Amplification of natural regulatory immune mechanisms for transplantation tolerance.

There is a need to derive donor-specific tolerance in clinical organ transplantation, where potential benefits remain overshadowed by chronic rejection and side effects of continual immunosuppressive therapy. It is known that the mature immune system in mice can be reprogrammed to accept a foreign graft as if it were "self." Here we show that, once generated, this state of operational tolerance becomes self-sustaining, imposing itself on new cohorts of lymphocytes as they arise. These new cohorts retain specificity for the tolerizing antigen and can be selectively amplified to tolerate new antigens that have linked expression with the original tolerogen. Regulation is critically dependent upon the continuous presence of tolerizing antigen and is mediated by the CD4+ lymphocyte population. We propose that such natural mechanisms of immune regulation may eventually be exploited for transplantation tolerance, even in fully immune-competent recipients.

Animals↗
PubMed2006

CD1d expression level in tumor cells is an important determinant for anti-tumor immunity by natural killer T cells.

Invariant natural killer T (iNKT) cells are thought to regulate anti-tumor immunity. Human iNKT (i.e. Valpha24+ NKT) cells have been reported to recognize CD1d on target cells and show cytotoxicity directly on the target cells in vitro. However, the anti-tumor effect of mouse iNKT (i.e. Valpha14+ NKT) cells has been repeatedly reported to be dependent on the activity of natural killer (NK) cells via interferon-gamma, with no evidence of direct cytotoxicity. In the present study, we report that in vitro cytolysis of EL-4 mouse lymphoblastic lymphoma cells by Valpha24+ NKT cells and in vivo eradication of these cells are both dependent on the level of CD1d expression on the tumor cell surface. These observations possibly suggest that direct cytotoxicity of tumor cells by iNKT cells is common to both humans and mice, and that the high expression level of CD1d may be a predictor whether the tumor is a good target of iNKT cells.

Animals↗
PubMed1998

Adjuvant treatment of breast cancer: a pilot immunochemotherapy study with CMF, interleukin-2 and interferon alpha.

Immune responses, including natural immunity (NI), potentiate the antitumor effects of chemotherapy. Since interferons and interleukin-2 (IL-2) augment NI, a pilot study was conducted to assess the tolerability and the effects on host immunity of adjuvant chemotherapy associated with IL-2 + interferon alpha (IFN) in breast cancer patients after surgery. Ten patients underwent alternating 28-day cycles of chemoimmunotherapy [cyclophosphamide + methotrexate + 5-fluorouracil (CMF, days 1, 8) + IL-2 (days 15 19) + IFN (day 22)] and chemotherapy alone (CMF). With this regimen each patient was considered to be a reasonable "control" of herself. Blood cell count and natural killer cell activity (NKA) were tested on days 1, 8, 15, 22, and 23. Preliminary in vitro studies indicated that IL-2 or IFN antagonized the severe inhibition of NKA induced by hydroxy-peroxy-cyclophosphamide (in vitro active derivative of cyclophosphamide), alone or associated with methotrexate + 5-fluorouracil. Nine patients completed all six alternating cycles, whereas one patient proved to have metastatic lesions after four cycles. The protocol was well tolerated, although leukopenia (CMF alone) and leukopenia with fever and moderate or minimal flu-like symptoms (CMF + IL-2 + IFN) were generally observed. Treatment with IL-2 facilitated complete recovery of white cell counts and NKA after the nadir on day 15. In conclusion, the present protocol appears to be well tolerated and amenable to administration on an outpatient basis. Therefore, further investigations should be performed to verify whether CMF + IL-2 + IFN would be superior to CMF alone for adjuvant treatment after surgery in breast cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

[Natural cellular immunity as the effector mechanism in tumor defense].

According to the immunosurveillance theory, the immune system plays an important role in the control of tumor development. Besides of specific cytotoxic T-cells, natural killer (NK) cells have gained recently in attention as effectors of the aforementioned function. They are lymphoid cells, and lyse tumor cells after having recognized them through a variety of membrane properties. Lymphokines can increase NK cell activity and enlarge their spectrum to previously NK-insensitive targets. Several clinical trials are being conducted at present in order to test the potential of lymphokine activated killer cells to function within this new biologic set-up.

Humans↗
PubMed1988

Alteration of non-specific resistance to infection with Listeria monocytogenes.

The experimental infection of murine hosts with Listeria monocytogenes is often used as a model for cell-mediated immunity. However, the natural immunity or non-specific resistance to listeriosis can be influenced by the parasite itself and also by a wide array of endogenous and exogenous host factors. The most important host factor in inbred mouse strains is their genetically determined susceptibility or resistance to Listeria monocytogenes. Secondly, the age of the mice is crucial for the outcome of infection. Resistance is only slowly developed by newborn mice, while aged mice possess an increased non-specific resistance as compared to young adult animals. Resistance is further influenced by the nutritional status, by pregnancy or by a simultaneous second antigenic stimulation. Regarding exogenous factors, macrophage blocking agents can totally abolish the resistance to listeriosis, while a lot of immunomodulating agents, such as BCG, killed Bordetella pertussis or Propionibacterium acnes organisms, lipopolysaccharides, suramin etc., can either increase or decrease the resistance. The mononuclear phagocyte system seems to be the main target of all these immunomodifiers. The timing between listeria infection and application of the immunomodulator determines the effect on non-specific resistance. A simultaneous injection of parasite and immunomodulator results in a decrease of resistance, while the application of immunoadjuvants several days before infection can dramatically increase the resistance to listeriosis. The delicate equilibrium of the mononuclear phagocyte system must therefore be taken into account, when infection with Listeria monocytogenes is used to test for immune-modifying agents, which are intended for use in humans or animals.

Adjuvants, Immunologic↗
PubMed2006

Variability and gender differences in memory T cell immunity to varicella-zoster virus in healthy adults.

Latent varicella zoster virus (VZV) can reactivate and cause zoster, the prevention of which relies upon cellular immunity to VZV. To assess temporal variation of VZV cell-mediated immunity in healthy naturally immune adults, we evaluated VZV-specific responder cell frequencies (RCF) longitudinally over 1 year in each of 25 adults. VZV-specific CD4+ T cells were detected (p < 0.003) and showed minimal variability in RCF. Additional analysis of VZV T cell RCF revealed differences between genders, with only males (p < 0.005) having detectable VZV-specific memory CD4+ T cell responses by this method. Taken together, results suggest that further studies regarding immunization of younger adults and females with the modified, high-potency live attenuated VZV vaccine may be warranted.

Adult↗
PubMed2000

Reconstitution of NK cell activity in HIV-1 infected individuals receiving antiretroviral therapy.

We studied natural immunity mediated by natural killer (NK) cells in 62 HIV-1 infected individuals, 54 HIV-1 infected individuals receiving highly active antiretroviral therapy (HAART) for more than one year and 8 HIV-1 infected individuals without antiretroviral therapy. 22 individuals had a complete suppression of viral replication characterized by viral load values <50 copies/ml, whereas 32 individuals presented with persistent viral replication. The 8 untreated patients had an indication to start antiretroviral treatment. Lytic activity of NK cells was measured in a 51chromium release assay. In patients with persistent viral replication under HAART NK cell activity was significantly decreased compared to patients with effective control of HIV viremia. Patients with complete suppression of HIV replication displayed a similar NK activity to healthy control persons. Differences in antibody-dependent cellular cytotoxicity (ADCC) were not observed. Further studies will investigate whether decreased NK cell activity is a reason for or the consequence of persistent viral replication.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1975

Passive immunity against Junín virus in mice.

Passive immunity, naturally acquired from immune mothers or artificially induced by the administration of homologous hyperimmune serum, conferred on suckling mice a high degree of resistance against infection with Junín virus. Maternal antibodies in the circulating blood of the young were not detectable in the first days after birth, but rised rapidly from the 8th to the 20th day of lactation. By cross-foster nursing experiments it was shown that the greater part of the transmission of passive immunity occurred after birth, although there was transmission of a significant, though small part, before birth. The virus passage from mothers to offspring was excluded, since Junín virus was not recovered from brains, livers, spleens and kidneys of uninfected young, born from infected mothers.

Animals↗
PubMed1989

Effects of systemic etretinate treatment on natural cytotoxicity, immune angiogenesis and neutrophil adherence in patients with various forms of psoriasis.

The effects of etretinate treatment on natural killer cell activity, on angiogenic capability of peripheral blood mononuclears and on neutrophil adherence were studied in 20 patients with various forms of psoriasis. In all forms of active psoriasis, etretinate was found to affect first the angiogenic reaction and PMN adherence, whereas NK cell activity usually normalized only after a long-term therapy. The earliest normalization of all three parameters was noticed in pustular psoriasis, and it was correlated with the clinical improvement. In two cases of palmo-plantar pustular psoriasis, in 5 cases of arthropathic variety, and in 5 cases of common psoriasis, the normalization preceded clearing of the skin lesions.

Adult↗
PubMed1994

pH-dependent LAK cell cytotoxicity.

In the microenvironment of many solid tumors the pH is considerably lower (mean pH between 6.6 to 7.2) than the pH in normal tissue (pH 7.0-7.5). Therefore, the influence of acidic pH on the cytotoxic activity of lymphokine-activated killer cells (LAK cells) after different culture periods was tested. K-562 human erythroleukemia cells were selected as target cells. Cell killing was measured using a two-color flow cytometric method. At physiological pH of 7.4, LAK cell-mediated cytotoxicity ranged from 15 to 48% (E:T ratio = 50:1). The specific lysis of target cells was considerably reduced (up to 70% inhibition of specific lysis) under acidic conditions (pH 6.8, 6.3, 5.8). This effect was independent of donors, duration of the culture period, and the E:T ratio in the cytotoxic assay. As pH gradients surrounding tumor cells may reach values below pH 6.0 at the cell surface, the pH-dependence of LAK cell cytotoxicity could at least partially explain the inhibition of the natural immune response in solid tumors. Therapeutic immunological strategies concerning the enhancement of the natural immune response like LAK cell and IL-2 immunotherapy including IL-2 gene therapy may only be successful if a simultaneous inhibition of the acidification process and an elevation of tumor pH is achieved.

Cell Line↗