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At least 289 records · Page 16Linked to original sources
PubMed2000

Bicarbonate accelerates assembly of the inorganic core of the water-oxidizing complex in manganese-depleted photosystem II: a proposed biogeochemical role for atmospheric carbon dioxide in oxygenic photosynthesis.

The proposed role for bicarbonate (HCO(3)(-)) as an intrinsic cofactor within the water-oxidizing complex (WOC) of photosystem II (PSII) [Klimov et al. (1997) Biochemistry 36, 16277-16281] was tested by investigation of its influence on the kinetics and yield of photoactivation, the light-induced assembly of the functional inorganic core (Mn(4)O(y)Ca(1)Cl(x)) starting from the cofactor-depleted apo-WOC-PSII center and free Mn(2+), Ca(2+), and Cl(-). Two binding sites for bicarbonate were found that stimulate photoactivation by accelerating the formation and suppressing the decay, respectively, of the first light-induced assembly intermediate, IM(1) [apo-WOC-Mn(OH)(2)(+)]. A high-affinity bicarbonate site (K(D) </= 10 microM) stimulates both the rate of recovery of O(2) evolving centers and decreases (by a factor of 1.2-3) t(lag), the time for formation of IM(1). This stimulation involves enhanced binding of the initial Mn(2+) and occurs only at concentrations of Mn(2+) at or below the stoichiometric requirements for water oxidation (</=4 Mn/PSII) and disappears above 4 Mn/PSII. The absence of an effect from added bicarbonate on photoactivation kinetics and yield at saturating concentrations of Mn(2+) and Ca(2+) may be due to the availability of atmospheric bicarbonate dissolved in the buffers (approximately 4 microM at pH 6.0) sufficient for photoactivation. The second bicarbonate site also stimulates the rate of formation of IM(1) but has much lower affinity (K(D) approximately millimolar) and becomes observable only at low concentrations of Ca(2+) that are limiting for photoactivation. This stimulation effect appears to occur by complexation of free Ca(2+), thereby reducing its activity in competing with Mn(2+) in the formation of IM(1). Bicarbonate had no effect on the calcium effector site responsible for the rate-limiting dark step of photoactivation (Ca(2+) binding to IM(1)). Four interpretations of the high-affinity bicarbonate effect may be advanced as testable hypotheses: bicarbonate may (1) act as an integral cofactor within the WOC (possible ligand to the first Mn), (2) act as a Bronsted base to accelerate proton release during formation of either the dark precursor [apo-WOC-Mn(OH)(+)] or IM(1) [apo-WOC-Mn(OH)(2)(+)], (3) directly deliver one or more hydroxide ions during formation of the latter two species (with release of CO(2)), or (4) act as a membrane-soluble anion that electrostatically elevates the local concentration of Mn(2+) in PSII. These results support a possible biogeochemical role for bicarbonate in the evolution of the first oxygenic photosynthetic organism. An improvement in the illumination method for photoactivation is presented in which light flashes of increasing duration are used to extend the pre-steady-state lag phase and to suppress photoinhibition, thereby improving the accuracy of t(lag) determination.

Atmosphere↗
PubMed2001

Alterations in T cell phenotype and human immunodeficiency virus type 1-specific cytotoxicity after potent antiretroviral therapy.

Cytotoxic T lymphocytes (CTLs) are an important defense against human immunodeficiency virus (HIV) type 1 but ultimately fail to control infection. To determine whether more efficient sustained immunity is induced by suppressing replication, the evolution of T cell phenotypes and HIV-specific CD8+ lymphocytes was prospectively investigated in 41 patients initiating combination therapy. Suppression of viremia to <200 copies/mL was associated with increases in naive cells (CD45RA+62L+) and declines in activated T cells (CD95+ cell counts and CD38+ HLA-DR+). HIV-specific tetramer-staining CD8+ T cells were detected in 6 of 10 HLA-A*0201-positive persons, which declined in 5 with treatment. CTL precursor frequencies were markedly consistent before and after treatment. Eight (72%) of 11 recognized > or =1 immunodominant epitope, representing either a new or an increased CTL response after treatment. Thus, activated CD8+ T cells, including those recognizing immunodominant epitopes, decline with combination therapy. However, the overall level of antigen-specific cells that are capable of differentiating into effectors remains stable, and the recognition of new epitopes may occur.

Anti-HIV Agents↗
PubMed1996

Identification of a novel Rac1-interacting protein involved in membrane ruffling.

The Rac GTP binding proteins are implicated in actin cytoskeleton-membrane interaction in mammalian cells. In fibroblast cells, Rac has been shown to mediate growth factor-induced polymerization of actin to form membrane ruffles and lamellipodia. We report here the isolation of a noval Rac1-interacting protein, POR1. POR1 binds directly to Rac1, and the interaction of POR1 with Rac1 is GTP dependent. A mutation in the Rac1 effector binding loop shown to abolish membrane ruffling also abolishes interaction with POR1. Truncated versions of POR1 inhibit the induction of membrane ruffling by an activated mutant of Rac1, V12Rac1, in quiescent rat embryonic fibroblast REF52 cells. Furthermore, POR1 synergizes with an activated mutant of Ras, V12Ras, in the induction of membrane ruffling. These results suggest a potential role for POR1 in Rac1-mediated signaling pathways.

Adaptor Proteins, Signal Transducing↗
PubMed1983

Sequence homology between Lac and Gal repressors and three sugar-binding periplasmic proteins.

Many proteins consist of several independent folding units or domains, each specifying a different function. Repressor proteins such as Lac or lambda cI carry small N-terminal domains which recognize DNA sequences and larger C-terminal domains which are required for effector recognition and/or oligomerization. The native periplasmic metabolite-binding proteins consist of short membrane-recognizing signal sequences and larger C-terminal metabolite-binding domains which also recognize membrane-bound proteins involved in transport and chemotaxis. The DNA-recognizing domains of many repressors are homologous, as are the sugar-recognizing periplasmic proteins. Here I demonstrate that the sugar-binding domains of the Lac and Gal repressors are homologous with the sugar-binding domains of three periplasmic proteins.

Amino Acid Sequence↗
PubMed1989

Stathmin is a major phosphoprotein and cyclic AMP-dependent protein kinase substrate in mouse brain neurons but not in astrocytes in culture: regulation during ontogenesis.

Stathmin is a ubiquitous soluble protein (Mr approximately 19,000; pI approximately 6.2-5.5) whose phosphorylation is associated with the intracellular mechanisms involved in the regulations of cell differentiation and functions by extracellular effectors. It is present in various tissues and cell types and has several nonphosphorylated and increasingly phosphorylated forms, and it is particularly abundant in brain. Very high concentrations of stathmin were also detected in mouse embryo striatal neurons grown in primary culture, whereas stathmin was barely detectable in astrocytes from the same source. Stathmin appeared in neurons as a major substrate for protein phosphorylation and, in particular, for the cyclic AMP (cAMP)-dependent protein kinase, because its phosphorylation was stimulated by cAMP in cell-free preparations and in intact cells by forskolin, a potent activator of adenylate cyclase. During brain ontogenesis, stathmin was first detected at embryonic day 12; its concentration increased until birth and then decreased from postnatal day 10 to adulthood. In parallel, its molecular forms shifted from the least phosphorylated to the more phosphorylated ones. This result may reflect the evolution of the activity of stathmin during development and the subsequent maturation of the brain. In conclusion, our results substantiate the likely role of stathmin as an intracellular relay of extracellular regulations, as they point out its specific importance related to neuronal functions and brain differentiation.

1-Methyl-3-isobutylxanthine↗
PubMed1990

Quantum mechanics and cellular information processing: the self-assembly paradigm.

Biological cells have greater information processing efficiency than the programmable computers used to model them. In part this is due to the larger number of interactions that can contribute to function. General arguments suggest that systems in which quantum features play a prominent role are more powerful than classical physical-dynamical analogs. A hypothetical model, involving macromolecular self-assembly, is used to illustrate how the parallelism inherent in the quantum mechanical wave function could play a role in cellular pattern processing. Signals impinging on the external membrane of the cell trigger the release of specifically shaped macromolecules. These aggregate into a mosaic shape features that reflect different groupings of the signal input patterns. The shape features are in turn read out and connected to effector actions by adaptor molecules. The self-assembly model fits into a more general hierarchical scheme of biological information processing in which macroscopic signals are transduced to mesoscopic and then microphysical representations, processed largely at the microphysical level, and then amplified for macroscopic action. The physical dynamics are controlled by proteins and other macromolecules that are molded through the evolutionary process of variation and selection. The organizational requirements for evolutionary moldability and for efficient information processing function are completely consistent. They include high dimensionality, multiplicity of weak interactions, and hierarchical-compartmental structure.

Biological Evolution↗
PubMed2026

Integrative single-cell and genomic analysis reveals NMB as a driver of metastatic adaptation in esophageal squamous cell carcinoma via metabolic rewiring and immune evasion.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) has high mortality, and metastasis is the leading cause of patient death. Neuromedin B (NMB) promotes tumor development in various cancers, yet its role in ESCC metastasis remains unclear. METHODS: We integrated single-cell transcriptomic data from matched primary and metastatic ESCC lesions (GSE309392) with bulk transcriptomic cohorts from TCGA and GSE53624. In silico gene perturbation, ligand-receptor communication analysis, and single-cell prognostic model construction were performed, followed by functional validation through siRNA-mediated NMB knockdown in TE-1 and KYSE30 cell lines. RESULTS: NMB was identified as a key gene enriched in metastatic ESCC lesions, and its high expression was associated with coordinated upregulation of oxidative phosphorylation pathway genes and aldo-keto reductase family antioxidant enzymes (AKR1C1, AKR1C2, AKR1B10). Genomic analysis revealed that NMB-high tumors carried a higher clonal mutation burden and a markedly increased frequency of NFE2L2 activating mutations (23% vs. 8%, P = 0.04). In silico knockout and correlation analysis identified AKR1C1 as a downstream effector of NMB. NMB expression was negatively correlated with CD8+ T cell and activated NK cell infiltration. CellChat analysis revealed communication between NMB-positive cells and monocytes via the TGM2-ADGRG1 axis, and specifically detected IFNG signaling. In the single-cell prognostic model, NMB-positive cells accounted for 50% of the high-risk group but only 20% of the low-risk group. TCGA-based survival analysis demonstrated that high NMB expression was associated with shorter overall survival (HR = 2.98, P = 0.03). In vitro NMB-targeted RNA interference markedly inhibited proliferation, colony formation, and migration in TE-1 and KYSE30 cells. CMap screening identified the endothelin-PDE5-cGMP axis as a potential therapeutic target. CONCLUSION: NMB serves as a key driver of metastatic adaptation in ESCC, conferring a survival advantage to tumor cells during metastatic colonization through genomic evolution and immune remodeling, with metabolic adaptation as a downstream consequence of genomic alterations.

NMB↗
PubMed1995

Nitric oxide: an ancestral immunocyte effector molecule.

The presence and the role of nitric oxide synthase (NOS) were investigated in the molluscan hemocytes by immunocytochemical, biochemical and functional approaches. Using an anti-NOS polyclonal antibody, immunoreactivity was observed in the hemocytes, and this reactivity increased after stimulation of the animals with Escherichia coli, indicating that this enzyme is inducible. The NOS inducibility was also histochemically demonstrated by detection of NADPH-diaphorase activity. Biochemical studies show that the enzyme is 70% cytoplasmatic and 30% membrane bound and that the inducible form is mainly cytoplasmatic. The nitrite + nitrate and citrulline formation, the inhibition by N omega-nitro-L-arginine, the Km value for arginine, the calcium and co-enzyme dependence show that the molluscan NOS shares the same properties as the NOS isoenzymes so far studied. However, it cannot be identified with any of these enzymes. It appears to be in some way similar to an inducible form of human hepatocyte NOS. Also cytokines are able to induce NOS. In vitro studies have shown that hemocytes produce nitric oxide (NO), a bactericide substance, and that there is a relationship between the NO system and phagocytosis. The presence of NO in the invertebrate hemocyte demonstrates that critical molecules have been conserved over the course of evolution.

Animals↗
PubMedDate not supplied

Adrenergic receptors: structure and function.

Adrenergic receptors are cell surface glycoproteins that recognize and selectively bind the catecholamines, norepinephrine and epinephrine, which are released from sympathetic nerve endings and the adrenal medulla. By transducing the external catecholamine stimulus into an intracellular signal, these receptors mediate the actions of the sympathetic nervous system, including a variety of responses such as arteriolar smooth muscle contraction and cardiac contraction, while are critically involved in cardiac function and blood pressure homeostasis. Activation or blockade of these receptors is, thus, a major therapeutic approach for the management of a number of cardiovascular disorders, including hypertension, angina pectoris, and cardiac arrhythmias. Additionally, alterations in these receptors or in their coupled intracellular effectors may contribute to or underlie the pathogenesis of cardiovascular diseases such as cardiac hypertrophy, congestive heart failure, and hypertension. Over the past few years, major insights have been gained into the physiology and pharmacology of these receptors, particularly in relationship to the molecular mechanisms involved in their ability to mediate "transmembrane signalling." These insights, which will be reviewed here, have resulted from the isolation and characterization of adrenergic receptors, from the determination of their deduced primary and secondary structures, and from structure-function studies using classical biochemistry and pharmacology as well as recombinant DNA techniques.

Animals↗
PubMed1999

Moe1, a conserved protein in Schizosaccharomyces pombe, interacts with a Ras effector, Scd1, to affect proper spindle formation.

In fission yeast, Scd1/Ral1 is a putative guanine nucleotide exchange factor for Cdc42sp and also acts as a Ras1 effector necessary for the regulation of cytoskeleton organization. In this study, we have characterized a protein, Moe1, that binds directly to Scd1. A moe1 null (Delta) mutant exhibits numerous phenotypes indicative of abnormal microtubule functioning, including an abnormality in the spindle. moe1Delta mutants are resistant to microtubule destabilizing agents; moreover, moe1Delta rescued the growth defects of tubulin mutants containing unstable microtubules. These results suggest that Moe1 induces instability in microtubules. Biochemical and subcellular localization studies suggest that Moe1 and Scd1 colocalize in the nucleus. Furthermore, loss of function in Scd1 or Ras1 also induced abnormality in the spindle and is synthetically lethal with moe1Delta producing cells that lack a detectable spindle. These data demonstrate that Moe1 is a component of the Ras1 pathway necessary for proper spindle formation in the nucleus. Human and nematode Moe1 both can substitute for yeast Moe1, indicating that the function of Moe1 in spindle formation has been conserved substantially during evolution.

Carrier Proteins↗
PubMed2000

Modulation of host signaling by a bacterial mimic: structure of the Salmonella effector SptP bound to Rac1.

Salmonella spp. utilize a specialized protein secretion system to deliver a battery of effector proteins into host cells. Several of these effectors stimulate Cdc42- and Rac1-dependent cytoskeletal changes that promote bacterial internalization. These potentially cytotoxic alterations are rapidly reversed by the effector SptP, a tyrosine phosphatase and GTPase activating protein (GAP) that targets Cdc42 and Rac1. The 2.3 A resolution crystal structure of an SptP-Rac1 transition state complex reveals an unusual GAP architecture that mimics host functional homologs. The phosphatase domain possesses a conserved active site but distinct surface properties. Binding to Rac1 induces a dramatic stabilization in SptP of a four-helix bundle that makes extensive contacts with the Switch I and Switch II regions of the GTPase.

Aluminum Compounds↗
PubMedDate not supplied

The evidence for G-protein-coupled receptors and heterotrimeric G proteins in protozoa and ancestral metazoa.

In higher eukaryotes G-protein-coupled signal transduction pathways are a common mechanism used to detect an extracellular message and transmit a signal, via a membrane-bound receptor and a heterotrimeric G protein, to second messenger producing enzymes and effector proteins. The techniques used to identify components of these pathways are increasingly being applied to protozoa and ancestral metazoa. Many of the organisms studied do seem to express functional homologues of those found in higher eukaryotes and increasingly genes encoding these proteins are being cloned. Sequence analysis of the isolated alpha-subunits of heterotrimeric G proteins shows that these proteins have extensive homology to their mammalian counterparts, and often show absolute sequence identity in functionally significant regions. The receptor clones isolated clearly establish that protozoa and early metazoa express proteins with seven transmembrane spanning domains. Comparisons with mammalian receptors indicate that these proteins are likely to be regulated by phosphorylation and dephosphorylation events, although the pathways which control these are yet to be identified. The postulated regulatory mechanisms and the number of homologous clones isolated from some protozoa suggest that a highly regulated system of transmembrane signalling appeared at a relatively early stage in evolution.

Animals↗
PubMed1992

Correlation between destruction of malarial parasites by polymorphonuclear leucocytes and oxidative stress.

The role of reactive oxygen species (ROS) generated by polymorphonuclear leucocytes (PMNs) in the host response against malaria was investigated. Non-activated human PMNs were added to cultures of P. falciparum in microtitre cells. Parasite viability was evaluated by the incorporation of radioactive hypoxanthine. Using PMN/RBC = 1/150 (starting parasitemia was 1%) the incorporation on the second day in culture was only 61% of the control cultures. An effect could be observed already after two hours of incubation (30% reduction at a 1/50 PMN/RBC ratio). A direct contact between the effector and target cells was obligatory for the expression of the damage. Parasites within G6PD-deficient erythrocytes were more sensitive to the PMNs than normal parasitized erythrocytes. This difference could be attributed to the production of reactive oxygen intermediates in the experimental system, since G6PD-deficient erythrocytes are generally more sensitive to oxidant stress. Salicylic acid was used as a scavenger and reporter molecule for hydroxyl radical fluxes. It is converted to the corresponding dihydroxybenzoic acid derivatives, which could be detected by HPLC. Uninfected NRBC or parasitized erythrocytes containing young ring forms could trigger the PMNs to produce much less ROS than the mature forms of the parasites. Other factors associated with PMNs may inactivate the parasites, such as phagocytosis, lysosomal enzymes or degradation toxic products of the PMNs. However our results indicate that increased oxidative stress induced by PMNs interfere with the growth of P. falciparum and could play a role in human evolution of abnormal erythrocytes.

Animals↗
PubMed2000

The uncoupling protein-3 gene is transcribed from tissue-specific promoters in humans but not in rodents.

Uncoupling protein-3 (UCP3), a mitochondrial membrane transporter, is a candidate effector of thermogenesis. Even though mice with targeted disruption of the UCP3 gene are not obese, indirect evidence suggests that this protein contributes to the control of energy expenditure in humans. We therefore characterized the human UCP3 gene and compared it with its rodent homologues with respect to tissue-specific expression and regulatory regions. Like rodent UCP3, human UCP3 was expressed in skeletal muscle and brown adipose tissue (BAT). The short mRNA isoform, UCP3(S), which is absent in rodents, was relatively more abundant in human skeletal muscle in comparison to human BAT. Two tissue-specific transcription start sites for each skeletal muscle and BAT were delineated for human UCP3. Tissue-specific transcript initiation was maintained in both tissues and cultured cells over a wide range of expression levels. In contrast, rodent transcripts were initiated at the same site in BAT and muscle tissue. Comparison of human and rodent promoters indicated a rapid phylogenetic evolution suggesting functional diversification. The transcription from tissue-specific promoters in humans is a novel finding that may provide the basis for therapeutic interventions aimed at regulating energy expenditure in a tissue-specific fashion.

Adipose Tissue, Brown↗
PubMed1994

Pulmonary microvascular injury following intestinal reperfusion.

Multiple organ failure is the most common cause of death in critically ill patients in the United States. Acute respiratory failure is the most important single component of this clinical scenario, with a mortality risk > 50%. Key pathophysiologic events occur in the pulmonary microvasculature at the interface between circulating elements and the external environment. In particular, the response of the alveolar capillary endothelial cell is of fundamental importance in this injury process. A variety of clinical stimuli initiate a systemic inflammatory response that contributes to acute microvascular lung injury. Sepsis, trauma, thermal injury, acute pancreatitis, and ischemia-reperfusion injury are among these stimuli. The particular emphasis of this review is on events associated with intestinal ischemia-reperfusion, a common and important clinical event. The pathogenic mechanisms that lead to acute lung injury in this setting are not completely understood, although it is clear that neutrophil-endothelial interactions regulated by both humoral and local mediators are crucial. Oxygen-derived free radicals, proteases, cytokines, eicosanoids, endotoxin, complement activation products, and probably platelet activating factor and nitric oxide are involved as either signalling or effector molecules. The key cellular participants during the acute phase of injury are the polymorphonuclear neutrophil (PMN) and the microvascular endothelial cell. Each of these participants is considered with regard to phlogistic behavior and the potential for therapeutic intervention. Adherence of the neutrophil to the endothelium creates a microenvironment in which PMN-derived oxidants, proteases, and cationic proteins are discharged under conditions that lead to cellular injury. Loss of microvascular integrity results and pulmonary dysfunction follows. At present, we offer only nonspecific supportive care for patients with this problem. However, investigations into relevant molecular and cellular regulatory events offer important opportunities for directed therapy. We are now approaching the threshold for utilization of several new and specific approaches. While no single pharmacologic therapy is likely to be curative for this complex problem, it is probable that certain approaches will be of clinical benefit in the near future. This review is designed to provide a basis for understanding this evolution.

Animals↗
PubMed1992

Intra-operative electron beam radiotherapy and abdomino-pelvic surgery for cancer: influence on immunological parameters.

Evolution of some immunological parameters was observed during the first month in 20 patients with different abdomino-pelvic cancers who underwent surgery with intra-operative radiation therapy (IORT) (mean dose of 19.44 Gy, range 15, 25). Observed parameters before (DO-) and after procedure (DO+), on seventh (D7) and fourteenth (D14) days and fifth week (D30) were: lymphocyte count, lymphocyte subsets (CD19, CD3, CD4, CD8, CD56), natural killer (NK) activity, immunoglobulins, C3 and C4b fractions of complement, soluble receptor for interleukin 2 (sIL2-R). Results showed a decrease of circulating lymphocytes (DO-: 1189 +/- 168 cells/mm3; D7: 889 +/- 91; P = 0.011), of absolute number of CD3 lymphocytes (DO-: 785 +/- 114 cells/mm3; D7: 563 +/- 86; P = 0.025), of CD4 lymphocytes (DO-: 441 +/- 70 cells/mm3; DO+: 299 +/- 43; P = 0.013) and of CD8 lymphocytes (DO-:361 +/- 50 cells/mm3, D7:250 +/- 44; P = 0.006). All values returned towards preoperative levels by D30. Absolute number of NK cells was unchanged but NK activity was significantly diminished (effector target ratio 5:1 DO-:33 +/- 5%; DO+:44 +/- 7%; D7:18 +/- 3%; D14:21 +/- 4%; D30:25 +/- 4%). sIL2-R was significantly enhanced from D7 to D30. All these impairments are moderate and these observations provide some evidence of satisfactory tolerance to IORT for abdomino-pelvic cancers during the immediate postoperative period.

Abdominal Neoplasms↗
PubMedDate not supplied

An evolutionary conserved target cell antigen along with MHC class I molecules influences susceptibility to murine NK cell lysis.

We have previously characterized a novel monoclonal antibody (mAb), termed 18C2, which binds to and inhibits the lysis of target cells by human natural killer (NK) cells. We now show that the anti-target cell mAb 18C2 also recognizes a similar structure on the murine NK sensitive target cell YAC-1, as well as on NK resistant target cells P815 and EL-4, as observed by flow cytometry. Functional studies demonstrated that the mAb 18C2 inhibited the lysis of both NK sensitive YAC-1 target cells, as well as NK resistant target cell lines P815 and EL-4 by freshly-isolated nylon wool nonadherent (NWNA) NK cells, 5-day lymphokine activated killer (LAK) cells and adherent lymphokine activated killer (ALAK) cells. The inhibitory activity of the mAb 18C2 occurred at the target cell level only. Single cell conjugate assays as demonstrated that the structure recognized by the mAb 18C2 was involved in recognition between NK cells and NK target cells, as the mAb inhibited conjugate formation between a variety of effector cells and various target cell lines tested. Further, the role of major histocompatibility complex (MHC) class I antigens in NK cell cytotoxicity was examined. We observed that target cells expressing low levels of MHC class I antigens in association with the novel target cell antigen were more sensitive to NK cell lysis, as compared to cells that co-express higher levels of MHC class I antigen and the target cell antigen. Further, the presence of this antigen across different species suggests this target cell antigen/structure to be highly evolutionarily conserved.

Animals↗
PubMed1996

Characterization of the immunological memory state generated in mice susceptible to Leishmania major following exposure to low doses of L. major and resulting in resistance to a normally pathogenic challenge.

BALB/c mice are susceptible to a high-dose infection of the protozoan Leishmania major, which induces a parasite-specific antibody, Th2-like response, exclusive of a significant and protective cell-mediated Th1 component. We have shown, in contrast, that infection with a low number of parasites induces cell-mediated immunity exclusive of antibody production, and results in resistance to substantial subsequent high-dose infection. Low-dose exposure thus constitutes effective vaccination. In the present study, we analyze lymphokine production by parasite-specific T cells from those low-dose exposed, resistant mice and from normal, susceptible mice following high-dose infection. Two findings stand out. First, the parasite-specific T cells in mice rendered resistant appear not to be in an activated, effector state at the time of parasite challenge, as assessed by lack of lymphokine production on short-term stimulation with parasite antigens, but to be rather in a memory state. Second, the ratio of parasite antigen-dependent production of interferon-gamma to that of interleukin-4 by spleen cells of low-dose exposed and normal mice upon high-dose challenge takes a dramatically different course. This ratio is similar in both groups of mice shortly after challenge, but increases dramatically in the resistant and declines dramatically in the control mice over a period of weeks, such that these ratios differ by about 60-fold 12 weeks after the high-dose challenge. In addition, we show that a similar state of resistance occurs following low-dose infection with a more virulent strain of L. major. In toto, our observations suggest that resistance may be generally achievable by low-dose exposure and may be associated with a memory state which, when activated by parasite challenge, results in the evolution of the response over weeks such that the protective, Th1 component becomes ever more dominant over the Th2 component.

Animals↗