Immune Response Phenotype Research Articles

A genome-wide association study of immune response traits in Canadian Holstein cattle

BackgroundBreeding for enhanced immune response (IR) has been suggested as a tool to improve inherent animal health. Dairy cows with superior antibody-mediated (AMIR) and cell-mediated immune responses (CMIR) have been demonstrated to have a lower occurrence of many diseases including mastitis. Adaptive immune response traits are heritable, and it is, therefore, possible to breed for improved IR, decreasing the occurrence of disease. The objective of this study was to perform genome-wide association studies to determine differences in genetic profiles among Holstein cows classified as High or Low for AMIR and CMIR. From a total of 680 cows with immune response phenotypes, 163 cows for AMIR (81 High and 82 Low) and 140 for CMIR (75 High and 65 Low) were selectively genotyped using the Illumina Bovine SNP50 BeadChip. Results were validated using an unrelated population of 164 Holstein bulls IR phenotyped for AMIR and 146 for CMIR.ResultsA generalized quasi likelihood score method was used to determine single nucleotide polymorphisms (SNP) and chromosomal regions associated with immune response. After applying a 5% chromosomal false discovery rate, 186 SNPs were significantly associated with AMIR. The majority (93%) of significant markers were on chromosome 23, with a similar peak found in the bull population. For CMIR, 21 SNP markers remained significant. Candidate genes within 250,000 base pairs of significant SNPs were identified to determine biological pathways associated with AMIR and CMIR. Various pathways were identified, including the antigen processing and presentation pathway, important in host defense. Candidate genes included those within the bovine Major Histocompatability Complex such as BoLA-DQ, BoLA-DR and the non-classical BoLA-NC1 for AMIR and BoLA-DQ for CMIR, the complement system including C2 and C4 for AMIR and C1q for CMIR, and cytokines including IL-17A, IL17F for AMIR and IL-17RA for CMIR and tumor necrosis factor for both AMIR and CMIR. Additional genes associated with CMIR included galectins 1, 2 and 3, BCL2 and β-defensin.ConclusionsThe significant genetic variation associated with AMIR and CMIR in this study may imply feasibility to include immune response in genomic breeding indices as an approach to improve inherent animal health.

Engaging adaptive immunity with biomaterials.

Adaptive immune responses, characterized by T cells and B cells engaging and responding to specific antigens, can be raised by biomaterials containing proteins, peptides, and other biomolecules. How does one avoid, control, or exploit such responses? This review will discuss major properties and processes that influence biomaterials-directed adaptive immunity, including the physical dimensions of a material, its epitope content, and its multivalency. Selected strategies involving novel biomaterials designs will be discussed to illustrate these points of control. Specific immunological processes that biomaterials are being developed to direct will be highlighted, including minimally inflammatory scaffolds for tissue repair and immunotherapies eliciting desired B cell (antibody) responses, T cell responses, or tolerance. The continuing development of a knowledge base for specifying the strength and phenotype of biomaterials-mediated adaptive immune responses is important, not only for the engineering of better vaccines and immunotherapies, but also for managing immune responses against newer generations of increasingly biological and biomolecular materials in contexts such as tissue repair, tissue engineering, or cell delivery.

The Specificity of Targeted Vaccines for APC Surface Molecules Influences the Immune Response Phenotype

Different diseases require different immune responses for efficient protection. Thus, prophylactic vaccines should prime the immune system for the particular type of response needed for protection against a given infectious agent. We have here tested fusion DNA vaccines which encode proteins that bivalently target influenza hemagglutinins (HA) to different surface molecules on antigen presenting cells (APC). We demonstrate that targeting to MHC class II molecules predominantly induced an antibody/Th2 response, whereas targeting to CCR1/3/5 predominantly induced a CD8+/Th1 T cell response. With respect to antibodies, the polarizing effect was even more pronounced upon intramuscular (i.m) delivery as compared to intradermal (i.d.) vaccination. Despite these differences in induced immune responses, both vaccines protected against a viral challenge with influenza H1N1. Substitution of HA with ovalbumin (OVA) demonstrated that polarization of immune responses, as a consequence of APC targeting specificity, could be extended to other antigens. Taken together, the results demonstrate that vaccination can be tailor-made to induce a particular phenotype of adaptive immune responses by specifically targeting different surface molecules on APCs.

Massive Transcriptional Perturbation in Subgroups of Diffuse Large B-Cell Lymphomas

Based on the assumption that molecular mechanisms involved in cancerogenesis are characterized by groups of coordinately expressed genes, we developed and validated a novel method for analyzing transcriptional data called Correlated Gene Set Analysis (CGSA). Using 50 extracted gene sets we identified three different profiles of tumors in a cohort of 364 Diffuse large B-cell (DLBCL) and related mature aggressive B-cell lymphomas other than Burkitt lymphoma. The first profile had high level of expression of genes related to proliferation whereas the second profile exhibited a stromal and immune response phenotype. These two profiles were characterized by a large scale gene activation affecting genes which were recently shown to be epigenetically regulated, and which were enriched in oxidative phosphorylation, energy metabolism and nucleoside biosynthesis. The third and novel profile showed only low global gene activation similar to that found in normal B cells but not cell lines. Our study indicates novel levels of complexity of DLBCL with low or high large scale gene activation related to metabolism and biosynthesis and, within the group of highly activated DLBCLs, differential behavior leading to either a proliferative or a stromal and immune response phenotype.

Immune response phenotype of allergic versus clinically tolerant pigs in a neonatal swine model of allergy

The prevalence of childhood food allergy and the duration of these allergies, particularly those considered to be transient, like egg and milk allergy, are increasing. The identification of allergic individuals using minimally invasive, non-anaphylaxis-threatening methods is therefore of increasing importance. In this experiment, correlates were sought of an allergic immune response (IR) phenotype in pigs. Using pigs pre-treated with heat-killed bacteria or bacterial components before allergic sensitization with the egg white protein ovomucoid (Ovm), differences were determined in IR phenotype of pigs in the categories treated-allergic, treated-tolerant, control-allergic (CA) and control-tolerant. Phenotype was established by measuring immunoglobulin (Ig)-associated antibody activity (AbA), cytokine profiles and the proportion of blood T-regulatory cells (T-regs) and observing late-phase allergen-specific skin tests (ST). Although 100% of pigs became sensitized to Ovm, only 33% of pigs had clinical signs of allergy after oral challenge with egg white. Pigs without clinical signs were classified as clinically tolerant. Sixty-seven percent of allergic pigs had a positive, late-phase ST classified as very strong or strong, while 84% of clinically tolerant pigs did not have late-phase ST. Treated-allergic pigs and CA pigs had greater total antibody IgG (H+L), IgE and IgG1 AbA than clinically tolerant pigs. Cytokine profiles of allergic pigs and the proportion of circulating T-regs, did not differ significantly between allergic and clinically tolerant pigs. Therefore, measurement of allergen-specific IgG, IgG1 and/or IgE activity and evaluation of late-phase ID ST may be useful in identifying allergic IR phenotypes in swine models of food allergy, which may be extended toward human use.

Phenotypic Differences in Virulence and Immune Response in Closely Related Clinical Isolates of Influenza A 2009 H1N1 Pandemic Viruses in Mice

To capture the possible genotypic and phenotypic differences of the 2009 influenza A virus H1N1 pandemic (H1N1pdm) strains circulating in adult hospitalized patients, we isolated and sequenced nine H1N1pdm viruses from patients hospitalized during 2009–2010 with severe influenza pneumonia in Kentucky. Each viral isolate was characterized in mice along with two additional H1N1 pandemic strains and one seasonal strain to assess replication and virulence. All isolates showed similar levels of replication in nasal turbinates and lung, but varied in their ability to cause morbidity. Further differences were identified in cytokine and chemokine responses. IL-6 and KC were expressed early in mice infected with strains associated with higher virulence. Strains that showed lower pathogenicity in mice had greater IFNγ, MIG, and IL-10 responses. A principal component analysis (PCA) of the cytokine and chemokine profiles revealed 4 immune response phenotypes that correlated with the severity of disease. A/KY/180/10, which showed the greatest virulence with a rapid onset of disease progression, was compared in additional studies with A/KY/136/09, which showed low virulence in mice. Analyses comparing a low (KY/136) versus a high (KY/180) virulent isolate showed a significant difference in the kinetics of infection within the lower respiratory tract and immune responses. Notably by 4 DPI, virus titers within the lung, bronchoalveolar lavage fluid (BALf), and cells within the BAL (BALc) revealed that the KY/136 replicated in BALc, while KY/180 replication persisted in lungs and BALc. In summary, our studies suggest four phenotypic groups based on immune responses that result in different virulence outcomes in H1N1pdm isolates with a high degree of genetic similarity. In vitro studies with two of these isolates suggested that the more virulent isolate, KY/180, replicates productively in macrophages and this may be a key determinant in tipping the response toward a more severe disease progression.

Identification of Leishmania Spp. in the Infected Foot Wounds of Patient with Mycobacterium Fortuitum

A common intramacrophage niche for leishmanial and mycobacterial pathogens, and a similar spectrum of immune response and disease phenotypes, led to the prediction that the same genes/candidate gene regions might be responsible for genetic susceptibility to mycobacterial infections. There are several reports of atypical cutaneous presentation of leishmaniasis such as paronychial, whitlow, lid, scar, palmoplantar and chancriform in immunocompetent patients. Numerous Leishmania organisms were observed within the histiocytes and extracellular in patient suffering from swelling, pain and itching. An unknown strain of mycobacterium was also isolated from biopsy specimen of the patient. Phenotypic and molecular tests carried out for identification of the strain based on standard methods. The susceptibility of the strain to anti-mycobacterial agents was performed by CDC standard Method. Numerous Leishmania organisms were observed within the histiocytes and extracellular space. PCR amplifications tests for detection of leishmania have been positive. Acid-fast staining and culture tests have been positive. PCR amplifications tests for detection of M. tuberculosis and M. avium have been negative. Phenotypic tests mainly including, positive result for growth at 25°C and 37؛C and PNB test, growth on MacConkey agar without crystal violet, arylsulphatase, urease, iron uptake and 68؛C and 22؛C catalase and negative for tween 80 hydrolysis, tolerance to 5% NaCl, niacin production and nitrate reduction test provided evidences that the strain belong to M. fortuitum species. Our findings show that M. fortuitum however rare its incidence may be is capable of causing infection in immune-compromised patients and could be co-infection in the human population.

Effect of Heat-Killed Escherichia coli, Lipopolysaccharide, and Muramyl Dipeptide Treatments on the Immune Response Phenotype and Allergy in Neonatal Pigs Sensitized to the Egg White Protein Ovomucoid

Predisposition to food allergies may reflect a type 2 immune response (IR) bias in neonates due to the intrauterine environment required to maintain pregnancy. The hygiene hypothesis states that lack of early environmental stimulus leading to inappropriate development and bias in IR may also contribute. Here, the ability of heat-killed Escherichia coli, lipopolysaccharide (LPS), or muramyl dipeptide (MDP) to alter IR bias and subsequent allergic response in neonatal pigs was investigated. Three groups of three litters of pigs (12 pigs/litter) were given intramuscular injections of E. coli, LPS, MDP, or phosphate-buffered saline (PBS) (control) and subsequently sensitized to the egg white allergen ovomucoid using an established protocol. To evaluate change in IR bias, immunoglobulin isotype-associated antibody activity (AbA), concentrations of type 1 and 2 and proinflammatory cytokines released from mitogen-stimulated blood mononuclear cells, and the percentage of T-regulatory cells (T-regs) in blood were measured. Clinical signs of allergy were assessed after oral challenge with egg white. The greatest effect on IR bias was observed in MDP-treated pigs, which had a type 2-biased phenotype by isotype-specific AbA, cytokine production, and a low proportion of T-regs. LPS-treated pigs had decreased type 1- and type 2-associated AbA. E. coli-treated pigs displayed increased response to Ovm as AbA and had more balanced cytokine profiles, as well as the highest proportion of T-regs. Accordingly, pigs treated with MDP were more susceptible to allergy than PBS controls, while pigs treated with LPS were less susceptible. Treatment with E. coli did not significantly alter the frequency of clinical signs.

Immune response phenotype induced by controlled immunization of neonatal pigs varies in type 1:type 2 bias

Immune response (IR) of pigs varies by litter and by individual such that ratios of type-1 and type-2 IR differ. Estimates of heritability for antibody and cell-mediated IR suggest that genotype and the environment contribute approximately 20% and 80% to this variation. It is hypothesized that the IR phenotype of outbred neonatal pigs is immature and variable progressing with age from type-2 bias to a more balanced phenotype. To test this, pigs were IR phenotyped by a standardized protocol using two intramuscular injections of the combined type-1 and type-2 antigens (Ag) Candida albicans (CA) and hen egg white lysozyme (HEWL). Immune response was measured by wheal and flare reaction to HEWL and double skin fold thickness (DSFT) response to each Ag injected intradermally at 35 days of age. Blood was collected at 14 and 35 days of age to measure immunoglobulin IgG1, IgG2 and IgE isotype-relatedness of antibody (Ab) to CA and HEWL. Comparison was made between two different groups of pigs (A) and (B), from the same herd tested separately at an interval of two and a half years. An unexpected group difference in IR bias was observed. Bias in IR was not consistently toward type-2. Increase in DSFT to CA, an indicator of type-1 IR, was greater in A while frequency of wheal and flare to injection of HEWL, a type-2 IR correlate, was greater in B. Frequency of individuals with positive serum Ab activity to both Ags was greater in B than A for most isotypes. Ratios of Ab activity by type-1 and 2 isotypes and DSFT to type-1 and 2 Ags indicate diminished type-1 relative to type-2 biased IR response in B. We conclude that in normal neonatal pigs under standard husbandry IR bias is not invariably toward type-2. Phenotype varied between groups in type-1:type-2 bias with implications for protective and immunopathogenic IR. While the etiology was not pursued it is possible that unidentified environmental variables may have induced this change in IR phenotype.

Genetic Diversity in Cytokines Associated with Immune Variation and Resistance to Multiple Pathogens in a Natural Rodent Population

Pathogens are believed to drive genetic diversity at host loci involved in immunity to infectious disease. To date, studies exploring the genetic basis of pathogen resistance in the wild have focussed almost exclusively on genes of the Major Histocompatibility Complex (MHC); the role of genetic variation elsewhere in the genome as a basis for variation in pathogen resistance has rarely been explored in natural populations. Cytokines are signalling molecules with a role in many immunological and physiological processes. Here we use a natural population of field voles (Microtus agrestis) to examine how genetic diversity at a suite of cytokine and other immune loci impacts the immune response phenotype and resistance to several endemic pathogen species. By using linear models to first control for a range of non-genetic factors, we demonstrate strong effects of genetic variation at cytokine loci both on host immunological parameters and on resistance to multiple pathogens. These effects were primarily localized to three cytokine genes (Interleukin 1 beta (Il1b), Il2, and Il12b), rather than to other cytokines tested, or to membrane-bound, non-cytokine immune loci. The observed genetic effects were as great as for other intrinsic factors such as sex and body weight. Our results demonstrate that genetic diversity at cytokine loci is a novel and important source of individual variation in immune function and pathogen resistance in natural populations. The products of these loci are therefore likely to affect interactions between pathogens and help determine survival and reproductive success in natural populations. Our study also highlights the utility of wild rodents as a model of ecological immunology, to better understand the causes and consequences of variation in immune function in natural populations including humans.

Abstracts from AIDS Vaccine 2011Bangkok, Thailand12–15 September, 2011

Background: Microneedles have previously been shown to enhance transdermal delivery of drugs and macromolecules. Their ability to effectively penetrate the dermis over a relatively large surface area offers potential use as minimally-invasive and painless replacements for more conventional parenteral vaccine regimens. In this study we compared the immune responses to HIV CN54gp140 using microneedles alone or a microneedle prime followed by mucosal boosting with monophosphoryl lipid A adjuvanted protein.Methods: Polymeric microneedle arrays that dissolve after piercing the skin were fabricated from poly(methylvinylether/ maleic acid) (Gantrez AN139) using laser-engineered siliconemicromould templates. Three groups of 8 BALB/c mice were primed using microneedles containing CN54gp140 and monophosphoryl lipid A. Three boosts were performed at two week intervals, using either the same microneedle formulation or vaginal or nasal administration of an antigen/adjuvant solution. Another group received four subcutaneous immunisations. Mice were sampled (serum and vaginal wash) prior to each vaccinationand two weeks post final immunization. Antigen-specific IgG and IgA production was assessed in the sera and mucosal lavage samples by quantitative ELISA. Splenocytes were harvested at necropsy and analysed for lymphocyte proliferation.Results: CN54gp140-specific serum IgG and lymphocyte proliferation responses were elicited in the subcutaneous immunization group and in those animals that were primed using microneedle delivery and boosted mucosally via the nasal route. Only the microneedle prime / intranasal boost group mounted a robust IgA response. In this group, IgG1 and IgG2a subtype quantification revealed a strong bias toward IgG2a.Conclusion: We have demonstrated that using a novel microneedle device to prime immunity followed by an intranasal boost elicits significant antigen-specific immune responses. This regimen generated similar serum IgG levels to the subcutaneous inoculations, but in contrast IgA was significantly elevated. This vaccination modality also induced a strong bias toward the IgG2a subtype suggesting a Th1 skewing of the immune response phenotype.

Deletion of cannabinoid receptors 1 and 2 exacerbates APC function to increase inflammation and cellular immunity during influenza infection

We and others have reported that simultaneous targeted deletion of CB(1) and CB(2) resulted in exacerbation of immune reactivity, suggesting a role of endocannabinoids in down-regulating immune function. In this study, we demonstrate that APC function is enhanced specifically in the absence of CB(1) and CB(2) signaling, resulting in an exacerbated immune response phenotype. After influenza infection, CB(1)(-/-)CB(2)(-/-) mice showed more pronounced pulmonary damage, increased inflammatory cell infiltrate, inflammation, and a greater cellular immune responses compared with WT mice, as evidenced by transcriptome analysis, more robust T cell activation, and effector cell cytokine production. After direct activation in vitro, there were no differences in the percentages of cytokine-producing CD4(+) T cells between CB(1)(-/-)CB(2)(-/-) and WT mice. However, untreated CB(1)(-/-)CB(2)(-/-) mice routinely had fewer naïve T cells compared with WT, suggesting dysregulation of APC immune homeostasis. Moreover, bmDCs and AM isolated from CB(1)(-/-)CB(2)(-/-) mice exhibited a more mature phenotype, with and without TLR stimulation, and bmDCs elicited T cells more robustly than WT mice. Collectively, these findings implicate a role for CB(1) and CB(2) on APCs in regulating immune responses and immune homeostasis.

Primary response against cytomegalovirus during antiviral prophylaxis with valganciclovir, in solid organ transplant recipients

Antiviral prophylaxis has proved successful for prevention of cytomegalovirus (CMV) disease in solid organ transplant (SOT) patients; though emerging data suggest that antiviral agents interfere with immunity, and may inhibit immune priming. In this context, we investigated levels and phenotype of primary CMV-specific immune responses that developed during antiviral prophylaxis in a cohort of CMV seronegative recipients (R(-) ) of a SOT from a seropositive donor (D(+) ). We longitudinally monitored CMV viral load, antibodies and levels of the negative immuno-modulator IL-10. PBMC were stimulated with CMV-specific peptide libraries to measure CD137 activation marker on CMV-specific T-cells and levels of PD-1 receptor, which is over expressed on exhausted T-cells. Unexpectedly, the majority (13/18) of D(+) R(-) patients who developed a primary CMV response showed early post-transplant CMV-specific responses, though levels of PD-1 on CMV-specific T-cells remained elevated throughout prophylaxis. A strong inverse association was found between levels of plasma IL-10 and CMV-specific cellular immune responses. Our study suggests that during prophylaxis, subclinical CMV infection might have occurred in the D(+) R(-) patients, and primary CMV-specific responses were detected early post-transplant when levels of plasma IL-10 were low. Extended prophylaxis or antiviral treatment did not appear to suppress CMV-specific antibodies or T-cells, which, however, showed exhaustion phenotypes.

Practical immunoregulation: Neonatal immune response variation and prophylaxis of experimental food allergy in pigs

The importance of environment in immune response is identified and the increase in prevalence of allergic, autoimmune and chronic inflammatory diseases reviewed. In particular, altered opportunity to acquire evolutionarily anticipated commensal microbiota is associated through the “hygiene hypothesis” with defective developmental and response signals to the innate and adaptive immune systems. Evidence of the detrimental effects of such environments is reviewed as is evidence for remediation using controlled exposure to bacteria or their active components such as LPS or peptidoglycan ligands for TLR and NOD-like receptors. Occurrence of major environmentally associated changes in porcine immune response phenotype are described. The prophylactic effects of heat-killed Escherichia coli given intramuscularly or of oral Lactococcus lactis on experimental ovomucoid-induced allergy in piglets are described in the context of altered immune response bias favouring reduced type-2 phenotypes. The high frequency of clinical tolerance to developing allergic signs even in the face of classical sensitization indicates possible function in this pig model of regulatory effectors such as Treg cells.

Complement regulation of T-cell alloimmunity.

The purpose of this review is to summarize recent findings implicating complement as an important regulator of T-cell immune responses. We then provide perspective for how these newly described mechanisms apply to allograft injury and how they could ultimately influence therapy. In addition to known effects of serum complement as an effector arm of antibody-initiated injury, T cells and antigen-presenting cells produce complement proteins and up-regulate complement receptors following cognate interactions. The locally released and activated, immune cell-derived complement signals predominantly through C3a and C5a binding to their receptors expressed on both partners to induce immune cell activation and differentiation. Complement deficiency or blockade limits T-cell-mediated autoimmunity and transplant rejection, whereas removal of the complement regulatory protein decay accelerating factor can enhance T-cell immunity and accelerate graft rejection. Emerging data indicate that immune cell-derived complement physiologically regulates immune cell survival and proliferation, modulating the strength and phenotype of adaptive T-cell immune responses involved in transplant rejection. The recognition of the diversity through which complement participates in allograft injury supports the need for continued design and testing of complement inhibitors in human transplant recipients.

Targeted Deletion of Cannabinoid Receptors 1 and 2 Results in Enhanced Inflammation and Exacerbated Immune Response Phenotype to Influenza Challenge (92.10)

Abstract In previous studies, mice lacking cannabinoid receptors 1 and 2 (CB1-/-CB2-/-) showed reduced lung viral burden after a single instillation of mouse-adapted A/PR8/34 influenza compared to C57Bl/6 (WT) mice. In this study we investigated potential mechanisms involved in the differences in viral burden. In a kinetic study, CB1-/-CB2-/- and WT mice were challenged with A/PR8/34 and 1, 3, 5 and 7 days post infection (dpi) several immune parameters were assessed. In the bronchoalveolar lavage fluid, increases in neutrophils and macrophages were observed in response to viral challenge, and both populations were increased in CB1-/-CB2-/- mice as compared to WT at 3 dpi. Furthermore, increases in T cell activation as assessed by CD69 and IFNγ production were observed in CD4+ and CD8+ T cells from CB1-/-CB2-/- compared to WT as early as 3 dpi. To determine potential factors involved in modulating the outcome of the T cell response we performed a low density mouse immune panel gene array on lung RNA 1 and 3 dpi. Differences in chemokine and inflammatory cytokine levels, with enhancement in CB1-/-CB2-/- compared to WT were observed. In a repeat study we observed CD4+NK1.1+CD44- and NK1.1+CD4-CD8- producing significant amounts of IL-17 in CB1-/-CB2-/- over WT at 3 dpi. Overall, these studies suggest an enhanced inflammatory response in CB1-/-CB2-/- leading to faster T cell kinetics and a more robust immune response, thereby limiting viral replication.

X-Linked Variation in Immune Response in Drosophila melanogaster

This study quantifies the effects of naturally occurring X-linked variation on immune response in Drosophila melanogaster to assess associations between immunity genotypes and innate immune response. We constructed a set of 168 X-chromosomal extraction lines, incorporating X chromosomes from a natural population into co-isogenic autosomal backgrounds, and genotyped the lines at 88 SNPs in 20 X-linked immune genes. We find that genetic variation in many of the genes is associated with immune response phenotypes, including bacterial load and immune gene expression. Many of the associations act in a sex-specific or sexually antagonistic manner, supporting the theory that with the selective pressures facing genes on the X chromosome, sexually antagonistic variation may be more easily maintained.

Macroimmunology and Immunotherapy of Cancer

Cytotoxic T lymphocytes (CTLs), associated with Th1 responses, are the most important mediators of resistance against most tumors. We argue that most murine tumors grow progressively when a significant Th2 component to their immune response develops, which is associated with the downregulation of the CTL response. We outline recent evidence that strongly supports this Th2-skewing hypothesis as the prevalent mechanism of tumor escape in murine systems. We describe the conceptual grounds and evidence for the 'threshold hypothesis' that proposes how the Th1/Th2 phenotype of an immune response generated against 'nonliving' antigens is determined. We suggest that this threshold hypothesis also accurately describes how the Th1/Th2 phenotype of murine antitumor immune responses is determined, as this hypothesis can account for the critical and known features of these immune responses. The efficacy of several manipulations that prevent or arrest progressive tumor growth in murine models, through their effects on the antitumor immune response, can be understood within the context of the threshold hypothesis. Indirect evidence supports the view that similar relationships between cancers and the immune system are present in humans. We propose means by which these insights can be employed to optimize the harnessing of protective Th1 CTL immunity against tumors.

IL‐4‐mediated fine tuning of IL‐12p70 production by human DC

IL-4 is expressed at high levels in allergic diseases and dominates the early phases of multiple acquired immune responses. However, the precise role of IL-4 during early inflammation and its impact on the differentiation of newly recruited DC precursors remains elusive. In order to characterize the impact of IL-4 on the differentiation of human DC, we investigated the role of IL-4 on the differentiation of monocytes into DC. Human DC were differentiated from peripheral blood precursors under either low or high concentrations of IL-4. We analyzed their cytokine profile and capacity to polarize T-cell differentiation. Concentrations of 5 (low) and 50 (high) ng/mL IL-4 induced two distinct types of DC. DC differentiated under low-dose IL-4 (5 ng/mL) produced almost no IL-12p70, and primed naïve CD4+ T cells allowing IL-4 secretion and Th2 induction. In contrast, DC generated under high concentrations of IL-4 (50 ng/mL) produced large amounts of IL-12p70, low IL-10 and primed naïve CD4+ T cells to become Th1 cells. Thus, we demonstrate that the Th2 cell cytokine IL-4 decisively determines the phenotype of ongoing immune responses by orchestrating the functional phenotype of newly immigrating DC precursors.

Personalized vaccines: the emerging field of vaccinomics

The next ‘golden age’ in vaccinology will be ushered in by the new science of vaccinomics. In turn, this will inform and allow the development of personalized vaccines, based on our increasing understanding of immune response phenotype: genotype information. Rapid advances in developing such data are already occurring for hepatitis B, influenza, measles, mumps, rubella, anthrax and smallpox vaccines. In addition, newly available data suggest that some vaccine-related adverse events may also be genetically determined and, therefore, predictable. This paper reviews the basis and logic of personalized vaccines, and describes recent advances in the field.