These data confirm that there is a correlation between HLA-DRB1*15:01, –DRB1*11:04, DRB1*11:01, –DRB1*04 and –DRB1*07:01 alleles and ABPA–CF susceptibility and suggest that HLA-DQB1*02:01 is an ABPA–CF resistance allele. Cystic fibrosis (MIM 219700) is the most common autosomal recessive disease in Caucasians [1]. Chronic lung disease, pancreatic insufficiency and male infertility

are the most characteristic clinical features. All of these phenotypic abnormalities are caused by mutations in the CFTR gene (MIM 602421). A spectrum of CFTR mutations in patients with CF from the region of Murcia (southeast of Spain) has previously been reported [2, 3]. On the other hand ABPA, a hypersensitivity lung PCI-32765 price disease that affects both patients with CF and those with asthma, is caused by colonization of the airways with the fungus Aspergillus fumigatus [4, 5]. ABPA affects approximately 1–2% of patients with AST and 7–9% of those with CF [6]. The clinical features of ABPA include asthma, pulmonary infiltrates, bronchiectasis and pulmonary fibrosis. The immune and inflammatory responses

against A. fumigatus antigens are characterized by increases in total serum IgE, specific IgE and IgG antibodies and precipitating antibodies and eosinophilia [7]. T cell reactivity in ABPA is characterized by the presence of CD4+ T cells producing IL-4 and IL-5 cytokines [8-10]. Associations between HLA class II antigen purified allergens and IgE responses have previously been reported [11-16]. Indeed, HLA-DRB1 alleles have previously this website been associated with ABPA susceptibility, although HLA-DQB1 allele associations have not been clearly established [17, 18]. Our aim was to study HLA class II allele frequencies in our patients with ABPA–CF and compare

their allele frequencies with those of patients with CF without ABPA, those with AST and healthy subjects to determine the role of various alleles in susceptibility or protection. Patients with ABPA–CF (n = 38), CF without ABPA (n = 46) and AST (n = 306) included in this study were recruited at the University Hospital Virgen de la Arrixaca from the Murcia region, in the southeast of Spain. CF mutational analysis was performed by the genetic service of Sinomenine our hospital, as previously reported [2, 3]. Patients with AST were diagnosed as previously reported [15, 16]. The control group comprised 176 unrelated healthy Caucasoid blood donors (CS) living in the same area. Patients with ABPA fulfilled the criteria for this diagnosis, as outlined by Patterson et al. [17]. ABPA was diagnosed by the presence of recurrent wheezing, chest radiographic infiltrates, peripheral blood eosinophilia, immediate A. fumigatus skin reactivity, positive precipitating antibodies against A. fumigatus antigens, increased serum total IgE concentrations of greater than 1000 IU/mL and IgE and IgG anti-A. fumigatus antibodies.

1A and data not shown). Thus C12Id-expressing B cells comprise a population of cells with heterogeneous specificities. HA-specific check details C12Id+ B cells do not undergo differentiation to Ab secreting cells prior to infection and therefore HA-specific C12Id+ Ab are not part of the natural Ab repertoire to influenza virus in non-influenza infected mice, which we

showed previously to be generated by B-1 cells 33. B cells associated with rapid differentiation to Ab-forming cells are often attributed to certain B-cell subsets, such as B-1 cells and splenic MZ B cells 11, 19, 34. To determine the phenotype of C12Id B cells prior to infection, we compared C12Id+ and C12Id− LN B cells by flow cytometry. C12Id+ LN B cells were indistinguishable from the other LN B cells by phenotype, displaying a homogenous CD23+ CD21int follicular B-cell phenotype AZD6244 (Fig. 2A). They also expressed similar levels of the activation markers CD40, CD86 and CD44 on day 4 after infection with influenza A/PR8 compared to the other B-cell populations in the MedLN (Fig. 2B). This is consistent with our earlier findings that most regional LN B cells from mice early after infection show type I IFN-mediated induction of CD86 and a decrease in CD23 expression 8, 35. Thus, the C12Id+ B cells are similar in their levels or types of activation

compared with the other LN B cells. All C12Id+ and C12Id− B cells from peripheral and regional LN expressed lower levels of CD1 and CD9 compared with splenic CD23lo/− CD21hi MZ B cells (Fig. 2A, right panels) and similar levels compared with splenic follicular B cells (data not shown). Both regional LN C12Id+ and C12Id− B cells showed slightly higher expression of CD1 compared with B cells in peripheral LN (Fig. 2A, right panel). We conclude that C12Id LN B cells do not belong Thiamet G to a previously identified CD1hi follicular B-cell subset 36. Instead, and despite their rapid responses, they are phenotypically indistinguishable from other follicular B cells.

To determine the distribution of the C12Id+ B cells within the activated regional LN, we performed immunohistochemistry and double immunofluoresence staining using anti-C12Id and anti-CD138 (Syndecan) on MedLN harvested on day 10 after influenza infection. Large C12Id+ B cells with morphological appearance of plasma cells were found predominantly in the medullary cords. Their plasma cell phenotype was confirmed by staining for CD138 (Fig. 3A). Extrafollicular foci responses in LN are found in the medullary areas 11, thus indicating that C12Id B cells rapidly differentiate via the extrafollicular pathway of B-cell activation. This is also consistent with previous reports showing that this pathway is responsible for much of the early Ab response to pathogens 11, 37. Next, we performed FACS analysis on resting and non-infected peripheral LN and compared the frequency and phenotype of C12Id+ and C12Id− B cells to that of MedLN from day 7 and day 14 infected mice.

43 It remains to be determined which recovery technique (CVL, tampon, or swab) most accurately reflects antimicrobial levels in the lower FRT. Whether upper FRT secretions, which contain elevated levels of antimicrobials at mid-cycle, mix with vaginal fluid to mask cycle-dependent differences remains to be determined. Furthermore,

it is important to accurately identify the cycle stage from which samples are recovered. Thus, self-reporting based upon the idealized 28-day cycle, while useful in some cases, can be replaced by direct measurement of serum estradiol and progesterone. Within the upper FRT, HBD1–4 mRNA levels peak in endometrial tissue at different times during the menstrual cycle with HBD4 highest during the proliferative phase and HBD2 peaking at menstruation. Similar to HBD2, Elafin increases late in the cycle,44 while HBD1 is highest during the

mid-secretory stage. In buy RAD001 contrast, HBD3 is maximal at early and late secretory, with a transient decline at mid-secretory. SLPI mRNA and protein also peak during the secretory phase.45 In the Fallopian tube, SLPI and Elafin mRNA expression remain constant across the cycle.46 The reason behind this exquisite regulation of upper FRT antimicrobial expression may reside either in their unique antimicrobial activities or in non-antimicrobial functions related to fertility that remain to be determined. Over 90% of sexually active women in the United States have used some form of contraception at least once.47 Given its widespread use, the effect of hormonal click here contraceptives on antimicrobial levels is understudied. In a seminal study, Schumacher48 demonstrated that sequential oral contraceptives suppress the cyclic changes of a spectrum of proteins including IgG, IgA, and lysozyme. In other studies with a combination oral contraceptive, no effect on antimicrobial expression 2-hydroxyphytanoyl-CoA lyase was observed except for a significant decrease in HBD3 when compared to the secretory phase.49 In the upper FRT, women taking the combined oral contraceptive had decreased SLPI in

luminal epithelial secretions compared to women in the proliferative phase.50 Future studies need to separate the different classes of oral contraceptives to determine their effects on the innate immune system throughout the FRT. Traditionally, pregnancy has been defined as a general state of immune suppression. However, this notion has been challenged recently with an evolution of our understanding; pregnancy seems to be both a pro-inflammatory and an anti-inflammatory state depending on the stage of gestation (reviewed by Ref. 51). The trophoblast, which is the cellular unit of the placenta, acts as an immune-regulatory interface between the maternal and fetal units. The placenta can recognize microorganisms and initiate response by producing cytokines, chemokines, and antimicrobials. Specifically, trophoblastic cells have been shown to produce HBDs, SLPI, and IFNβ in response to pathogenic stimuli.

Currently, decisions about acceptance onto dialysis are usually made by agreement between the patient, their family and health professionals involved in dialysis treatment. There is also an earlier decision point, which involves the decision to refer a patient to a dialysis service, which involves the general practitioner, or other health professionals not directly associated with dialysis services. These guidelines apply to that earlier decision point as well. Primary among the considerations for acceptance onto

dialysis should be the wishes of the patient and immediate family members. In the situation when the patient is unable to give informed consent (i.e. the patient is a minor, or incapable of understanding the issues due to illness, or mental incapacity), it is important that other appropriate Fluorouracil in vivo individuals or agencies be involved. When there is the possibility of failure to understand the issues involved because of language difficulties, a qualified interpreter must be employed to assist with the consent process. There are very few circumstances when temporary

dialysis cannot be instituted because it is unclear if the individual or their family has sufficient ability to make their wishes known regarding long-term dialysis. The institution of temporary dialysis measures allows individuals and their families sufficient time to evaluate dialysis as a treatment option. Physicians and health professionals have a responsibility to educate and advise the patient and their family/carers, and to present all the facts

available at the time in a manner that assists in making a decision regarding dialysis. When the physician, Selleckchem C59 wnt other health professionals, the patient and/or the family disagree about acceptance onto a dialysis programme, mechanisms should be available for access without difficulty to second opinions, referral to other units or physicians of the patient’s choosing, or to involvement of appointed patient advocates. Many issues affect the decision-making process. These include the patient’s age, comorbid factors such as diabetes, cardiovascular disease, respiratory disease, malignancy, neurological status, dementia, and other chronic illnesses that may predict poor outcomes. The possibility that length or quality of life will not be improved by Non-specific serine/threonine protein kinase dialysis may be a relevant factor for patient and caregivers in making decisions about whether or not to start dialysis. Databases searched: MeSH terms and text words for kidney disease and predialysis were combined with MeSH terms and text words for renal replacement therapy, dialysis and ethics, and then combined with the Cochrane highly sensitive search strategy for randomized controlled trials. The search was carried out in Medline (1966–April, Week 3, 2004). The Cochrane Renal Group Trials Register was also searched for trials not indexed in Medline. Date of search/es: 29 April 2004.

OD was measured with a microplate reader (detection wavelength: 570 nm; reference wavelength: 630 nm), and the tumouricidal activity was determined. Tumouricidal activity

(%) = [1−(ODexperiment–ODeffector cells)/ODtarget cells] × 100%. Statistical analysis.  Analysis was performed using spss 11.5 statistics software (SPSS inc., Chicago, IL, USA), and data were expressed as mean ± SD. Group comparisons were carried out by t-tests. The significance level was set at the P-value of 0.05. Pearson correlation coefficient was selected for bivariate correlation analysis. Correlations between variables were evaluated using Spearman’s correlation coefficient (rho). selleck Flow cytometry plots of T cells, Th cells, NK cells and B lymphocytes from PBMCs were shown in Fig. 1. There were no marked differences

in the absolute numbers of https://www.selleckchem.com/products/R788(Fostamatinib-disodium).html peripheral blood T lymphocytes, NK cells or B lymphocytes among the three groups (P > 0.05 for each). In addition, there were no significant differences in T lymphocyte subsets or CD4+/CD8+ ratios noted among the three groups (Table 1) (P > 0.05 for each). As described in Methods, T lymphocytes were obtained from peripheral blood samples from 10 randomly selected members of each of the three subject groups. MTT assays were used to determine T cell proliferation. The stimulation index (SI) was the highest in group C (5.7 ± 1.9) and the lowest in group A (11.9 ± 2.8), and that in group B was 8.6 ± 2.6. There were significant differences in SI among the three groups (Table 2 and Fig. 2A) (P < 0.05). Bivariate correlation analysis revealed that the decrease in T lymphocyte stimulation index (SI) was age dependent, with a significant decrease in Tyrosine-protein kinase BLK individuals aged above 70 years, compared with the lower-age groups (r = −0.75; P < 0.0001) (Fig. 3A). As also described in Methods, CIK cells were prepared from PBMC samples of 10 randomly selected subjects from each of the three groups. These CIK cells were assessed for their tumouricidal activities. CIK tumouricidal activity was the highest in group C

(67.8 ± 10.1%) and the lowest in group A (43.8 ± 11.7%), and that in group B was 57.4 ± 10.3%. There were significant differences among the three groups (P < 0.05); CIK tumouricidal activity decreased with an increase in subject age (Table 2 and Fig. 2B). Bivariate correlation analysis revealed that the decrease in CIK tumouricidal activity was age dependent, with a significant decrease in individuals aged above 70 years, compared with the lower-age groups (r = −0.59; P < 0.001) (Fig. 3B). Ageing populations will present great challenges in the 21st century, and changes in immune function with increased age are closely related to senescence. In studies of immune-related senescence, various diseases, medical interventions, unhealthy lifestyles and other factors, except for ageing, that can affect immune function should be excluded.

Many more studies have been done on the human T-cell responses to viral infections in mice with reconstituted human immune system components, particularly on CD8+ T-cell responses. In both HIV and EBV infection of reconstituted mice viral antigen-specific T-cell responses were detected, but their frequency as assessed by IFN-γ production usually did not exceed 0.1%, despite the fact that a substantial proportion of the expanded CD8+ T-cell population could be detected by MHC class I/viral peptide tetramer staining [5, 38, lambrolizumab 40, 64, 68]. This inability of most expanded antiviral CD8+ T cells to secrete cytokines might result from infection-induced

differentiation of these cells and concomitant upregulation of the inhibitory receptor PD-1. Indeed, PD-1 blockade was able to rescue proinflammatory cytokine secretion in HIV-infected reconstituted mice [69]. However, this terminal differentiation of the expanded CD8+ T cells might not negatively affect their cytotoxicity, and indeed significant perforin and granzyme B upregulation as well as cytolytic activity was found in expanded CD8+ T cells after HIV and EBV infection [38, 64, 68, 70]. Nevertheless, the viral peptide

epitopes that were recognized by these responding T cells seemed to strongly depend on the MHC class I context, in which the CD8+ T-cell repertoire Quizartinib clinical trial is educated in the thymus. In mice with human thymic transplants, the reconstituted CD8+ T-cell compartments can readily recognize immunodominant dengue virus and HIV Cytidine deaminase derived epitopes [49, 64]. In reconstituted mice, in which the T-cell repertoire gets selected through the mouse thymus, these immunodominant epitopes are only recognized if the murine host transgenically expresses the respective HLA class I molecules [38, 50, 70]. In the absence of these HLA class I molecules from the murine thymic stroma, presumably unusual and in humans subdominant epitopes are recognized

by the expanding CD8+ T cells. However, this has only been documented for one clonal EBV specificity so far [38]. Although the epitope specificities of the expanding CD8+ T-cell response are still being unraveled in reconstituted mice, this adaptive immune response clearly exerts protective immune control. HIV, for example, accumulates escape mutations in response to primed CD8+ T cells [71]. Moreover, the presence of the protective HLA-B57 molecule on the reconstituted human immune system components and on the thymic transplant allowed better HIV-specific immune control and restricted CD8+ T-cell responses similar to those found in human patients [71].

Of the seven species that affect the poultry industry, E. maxima is considered as the most immunogenic (56). Early studies therefore concentrated on the E. maxima model and much work was focused on better understanding the basis of immunity and the lifecycle stages that are predominantly involved in immune responses (56–58). In addition, E. maxima was selected as the model species for initial work on development GS-1101 in vivo of a subunit vaccine as its gametocytes are very large in size and relatively easily visualized and purified (59). The induction

of immunity using the E. maxima model was first demonstrated by Rose (56), who showed that a single low dose of E. maxima oocysts could protect chickens against a challenge with high doses of oocysts of the homologous strain, and that one

cycle of infection was enough to stimulate this protective immunity. It was further demonstrated that sera taken 14 days post-infection with E. maxima can give passive protection 3-deazaneplanocin A ic50 to naive chickens against a challenge (57,58). However, it was first thought that the asexual stages of the lifecycle of Eimeria were predominantly responsible for the immune response invoked in chickens. Analysis of convalescent sera taken 14–20 days after an E. maxima infection, which was shown to passively protect naive birds, demonstrated that the early stages of development have a strong immunogenic effect, and the Avelestat (AZD9668) later sexual stages were poorly immunogenic in E. maxima,

E. necatrix and E. tenella (58,60). Kouwenhoven and Kuil (61) also reported that sera taken from chickens infected with E. tenella showed no reaction with sexual stages or first generation schizonts, indicating that gametocytes had poor immunizing capabilities in chickens. Later studies, however, contradicted these earlier findings (62,63). The antigenicity of sexual stages of Eimeria was first demonstrated when a monoclonal antibody to an E. tenella gametocyte antigen was shown to inhibit fertilization in vitro (64). In 1989, Pugatsch et al. (62) developed a method to isolate and purify gametocytes by enzymatic digestion of the infected mucosa with hyaluronidase, followed by size separation. They showed that whole gametocytes were highly antigenic both in the course of an infection and when injected into rabbits/mice. During the same year, convalescent sera from E. maxima immune chickens were found to recognize two immunodominant macrogametocyte antigens of 56 and 82 kDa in size (63). When these two proteins were administered to a variety of hosts in the form of a crude extract, they were found to be highly immunogenic (63). Following this discovery, it was hypothesized that these macrogametocyte antigens may play a role in conferring protective immunity to the host (63).

Unless otherwise noted, such pairwise comparisons were made between infected pregnant and uninfected pregnant; and between infected pregnant and infected non-pregnant mice within strains; and between infected pregnant mice and infected non-pregnant mice across strains. Pregnancy outcome data were analysed by Fisher’s exact test or chi-squared test as appropriate. Differences with P < 0·05 were considered significant. In agreement with previous studies of virgin mice (15,24), pregnant A/J mice were susceptible to a lethal infection with P. chabaudi AS, whereas B6 mice were resistant (20). Among A/J mice, 100% of infected pregnant mice died by experiment day

12 (n = 7; Figure 1a) whereas B6 mice were resistant, with only 1 of 6 mice succumbing by experiment day 12 (Figure 1a). Because the interest of the study was to evaluate mid-gestational pregnancy outcome in both strains, serial sacrifices were subsequently performed up PLX4032 chemical structure to experiment day 11. In A/J mice, a maximum peripheral parasite density of 39 ± 2% (mean ± SEM; n = 21) was observed Daporinad solubility dmso in the infected pregnant group at experiment day 11, while the peak parasitemia for infected pregnant

B6 mice occurred on experiment day 10 at 25 ± 3% (n = 16; Figure 1b), a level significantly lower than in A/J mice. Consistent with previous reports (25,26), parasitemia was also significantly higher in infected non-pregnant A/J mice on experiment

day 9 through 11 relative to infected non-pregnant B6 mice (data not shown). Moreover, peripheral Parvulin blood parasite density was significantly higher in pregnant A/J mice relative to non-pregnant mice at experiment day 6 (0·5 ± 0·2% (n = 64) vs. 0·1 ± 0·0% (n = 104), respectively; P = 0·03) and at peak parasitemia (39·1 ± 1·9% (n = 21) vs. 33·4 ± 1·8% (n = 27), respectively; P = 0·04; Figure S1), suggesting that, as in B6 mice (20), pregnancy increases the susceptibility of A/J mice to malaria. While anaemia was not observed in uninfected pregnant A/J and B6 mice, haematocrit was substantially reduced over time in infected pregnant (Figure 1c) and infected non-pregnant (Figure S1 and data not shown; (20) mice of both strains. On experiment day 11, haematocrit in infected pregnant A/J mice was significantly lower than in infected pregnant B6 mice (Figure 1c). As expected in normal pregnancy, uninfected pregnant A/J and B6 mice gained weight over the course of the experiment (Figure 1d). In contrast, infected pregnant mice of both strains did not experience significant weight gain, and starting at experiment day 9, body weights fell steadily with reductions to below starting body weight at experiment day 11 (Figure 1d) (20). From experiment days 9 through 11, mean body weight was significantly lower in infected pregnant relative to uninfected pregnant mice for both strains (P < 0·05).

Severe fungal infestation by Aspergillus terreus was documented in the otic region but not in any other site of the body. Adjacent to the promontorium, massive accumulation of fibrinous secretion and infiltration of clusters of inflammatory cells were present. Newly formed cysts and vessels replaced the round window membrane location, reminiscent of granulation tissue. Inflammatory cells and a severe fibrin net were noted within the perilymphatic spaces of scala tympani and scala vestibuli, indicative of an

acute fibrinous otitis. Inflammatory reactions have probably been caused by this fungal organism. The basilar membrane was solely covered by a simple cuboidal epithelium. Complete Ivacaftor mouse absence of sensory cells of the Organ of Corti characterised a further severe phenomenon, which possibly led to the animal’s poor nutritional status and stranding. Potential portals of entry are being discussed. “
“Fungaemia diagnosis could be improved by reducing the time to identification of yeast from blood cultures. This study aimed to evaluate three rapid methods for the identification of yeast direct from blood cultures; Gram’s stain analysis, the Tipifarnib nmr AdvanDX Peptide Nucleic Acid in Situ Hybridisation Yeast Traffic Light system (PNA-FISH YTL) and Bruker Sepsityper alongside matrix-assisted laser desorption ionisation time of flight mass spectrometry (MALDI-TOF MS). Fifty blood cultures spiked with a known single yeast

Parvulin strain were analysed by blinded operators experienced in each method. Identifications were compared with MALDI-TOF MS CHROMagar Candida culture and ITS rRNA sequence-based identifications. On first attempt, success rates of 96% (48/50) and 76% (36/50) were achieved using PNA-FISH YTL and Gram’s stain respectively. MALDI-TOF MS demonstrated a success rate of 56% (28/50) when applying manufacturer’s species log score thresholds and 76% (38/50) using in-house

parameters, including lowering the species log score threshold to >1.5. In conclusion, PNA-FISH YTL demonstrated a high success rate successfully identifying yeast commonly encountered in fungaemia. Sepsityper™ with MALDI-TOF MS was accurate but increased sensitivity is required. Due to the misidentification of commonly encountered yeast Gram’s stain analysis demonstrated limited utility in this setting. “
“Severe Candida infections are increasing and are associated with considerable morbidity and mortality. Rapid and accurate differentiation of Candida albicans from non-C. albicans species is essential for therapeutic decisions. We therefore developed a fluorescence in situ hybridisation (FISH) assay comprising previously described probes and a newly designed specific C. albicans probe/competitor probe combination. The FISH probes were first evaluated using 99 selected fungal strains covering 31 species, and a specificity between 96% and 100% and a sensitivity of 100%.

DENV isolates passed serially from brain to brain led to increased neurovirulence and neurotropism in mice[44] and a clear attenuation in human volunteers.[45] However, viral encephalitis is not a major clinical symptom in human dengue disease, as nervous system involvement in DENV infections is

rare and few cases are reported.[46] The IFN system is critical to the host antiviral response, which led to the use of AG129 mice, which are type I and II IFN-R-deficient 129 mice, immune deficient and highly susceptible.[47] Intraperitoneal infection with the mouse-adapted neurotropic DENV-2 strain, New Guinea C, led to 100% lethality in AG129 mice, all of them presenting paralysis.[48] The neuroinflammatory changes led to alterations in motor behaviour and muscle tone and strength in DENV-3-infected mice. The neuroinflammatory process was marked by up-regulation of the chemokines LY2157299 CCL2, CCL5, CXCL1 and CXCL2, and of the cytokines TNF-α and IFN-γ, which occurs in parallel with increased leucocyte rolling and adhesion in meningeal vessels and infiltration of immune cells into the brain.[49] In summary, even if these models were used to study antiviral compounds or behaviour, the major limitation involving immune-compromised mice is that paralysis is not a major clinical observation in DENV infection. Initial tropism studies using the

AG129 (IFN type I and II receptor-deficient) model demonstrated that clinical isolates from all four DENV serotypes replicate LY2606368 concentration efficiently in spleen, lymph node, bone marrow and muscle.[50] Negative-strand

viral RNA was detected in dendritic cells and macrophages of the lymph node and spleen.[50] To develop an experimental model where viral encephalitis was not the major clinical observation, Shresta et al.[47] infected AG129 mice intravenously with the DENV-2 strain PL046. Infected AG129 mice succumbed to DENV infection, Chlormezanone presenting increased levels of TNF-α and vascular leakage syndrome. AG129 mice are able develop cross-reactive and long-lasting antibody responses to DENV.[51] Sequential DENV infection in AG129 mice results in decreased viral load of the second serotype and full protection against lethal infection. AG129 and other mouse strains have been used to study ADE by passive transfer of anti-DENV monoclonal antibodies, cross-reactive immune serum, or diluted homotypic serum before infection.[52, 53] Mortality was associated with vascular leakage syndrome, high levels of TNF-α and thrombocytopenia, similar to the clinical findings observed in DHF/DSS in humans. No memory response was observed in mice receiving passive transfer of serum or antibody. Hence, models of sequential DENV infection may be useful to study ADE in the presence of a cellular memory immune response.