Robust Memory Responses Research Articles

Boosting antibody responses toPlasmodium falciparummerozoite antigens in children with highly seasonal exposure to infection

Longitudinal cohort studies are important to describe the dynamics of naturally acquired antibody response profiles to defined Plasmodium falciparum malaria antigens relative to clinical malaria episodes. In children under 7 years of age in The Gambia, serum IgG responses were measured to P. falciparum merozoite antigens AMA1, EBA175, MSP119, MSP2 and crude schizont extract, over a 10-month period. Persistence of antibody responses was measured in 152 children during the dry season when there was virtually no malaria transmission, and 103 children were monitored for new episodes of clinical malaria during the subsequent wet season when transmission occurred. Children who experienced clinical malaria had lower antibody levels at the start of the study than those who remained free from malaria. Associations between dry season antibody persistence and subsequent wet season antibody levels suggested robust immunological memory responses. Mean antibody levels to all antigens were elevated by the end of the wet season in children who experienced clinical malaria; each of these children had a boosted antibody response to at least one antigen. In all children, antibody avidities were lower against MSP2 than other antigens, a difference that did not change throughout the study period or in relation to clinical malaria episodes.

SOCS3 expression induced by PIM2 requires PKC and PI3K signaling

Initiation of proinflammatory host immunity in response to infection represents as a key event in effective control and containment of the pathogen at the site of infection as well as in elicitation of robust immune memory responses. In the current investigation, we demonstrate that an integral cell wall antigen of the mycobacterial envelope, Phosphatidyl-myo-inositol dimannosides (PIM2) triggers Suppressor of cytokine signaling (SOCS) 3 expression in macrophages in a Toll-like receptor 2 (TLR2)-MyD88 dependent manner. Data derived from signaling perturbations suggest the involvement of phosphoinositide-3 kinase (PI3K) and protein kinase C (PKC) signaling pathways during PIM2 induced SOCS3 expression. Further, pharmacological inhibition of ERK1/2, but not of p38 MAP kinase or JNK abrogated the induced expression of SOCS3. The PIM2 induced activation of ERK1/2 was dependent on the activation of PI3K or PKC signaling which in turn regulated p65 nuclear factor -κB (NF-κB) nuclear translocation. Overall, current study delineates the role for PI3K-PKC axis and ERK1/2 signaling as key signaling events during PIM2 induced SOCS3 expression in macrophages.

RNA Interference Inhibits Respiratory Syncytial Virus Replication and Disease Pathogenesis without Inhibiting Priming of the Memory Immune Response

Respiratory syncytial virus (RSV) is a major cause of morbidity in infants, young children, and the elderly worldwide. Currently, there is no effective vaccine, and antiviral drugs to control infection are limited. RNA interference is a powerful tool amenable to development of antiviral drugs. Using small interfering RNA (siRNA) targeting the RSV P gene (siRNA-P), RSV replication can be silenced both in vitro and in a BALB/c model of RSV infection. In this study, we examine the effect of siRNA prophylaxis on the primary and memory immune response to RSV infection in mice. We show that mice prophylactically treated with siRNA-P to decrease but not eliminate RSV replication exhibit reduced pulmonary inflammation and lung pathogenesis and produce a robust anti-RSV memory response when subsequently challenged with RSV. The pulmonary T-cell memory response was characterized by high numbers of CD44(hi) CD62L(lo) CD4(+) and CD8(+) T cells, M2 peptide tetramer(+) CD8(+) T cells expressing gamma interferon, and an RSV-specific antibody response. The results support the hypothesis that siRNAs can be developed as effective antiviral drugs that can be used to reduce the viral load and parameters of pathogenesis without limiting the induction of the memory immune response.

Significant IFNγ production by early effector T cells signifies development into memory

The mechanism underlying transition of T cells from effector to memory remains largely undefined. It is believed that this transition occurs as a result of exposure to residual suboptimal antigen found in lymphoid tissues as the effector phase wanes. This led to the interpretation that memory arises from slightly activated late effectors producing reduced amounts of IFNγ. Herein, an in vivo model suitable for tracking memory transition was developed and shows that highly activated early effector CD4 T cells transit to memory. Moreover, effector T cells that have undergone 4 divisions expressed significant IL‐7R, produced IFNγ and yielded rapid and robust memory responses. Cells that divided three times which had marginal IL‐7R expression and no IFNγ raised base level homeostatic memory while those which have undergone only two divisions and produced IFNγ yielded conditioned memory despite low IL‐7R expression. These findings indicate that highly activated early effectors generated upon exposure to optimal antigen in vivo develop into memory and such transition is dependent on a significant production of the cell's signature cytokine, IFNγ.Research supported by grant 2RO1AI48541‐08 from the NIH. JSE and JJB were supported by training grant DHHS2T32GM08396‐16A1 from the NIGMS.

Early Effector T Cells Producing Significant IFN-γ Develop into Memory

Currently, transition of T cells from effector to memory is believed to occur as a consequence of exposure to residual suboptimal Ag found in lymphoid tissues at the waning end of the effector phase and microbial clearance. This led to the interpretation that memory arises from slightly activated late effectors producing reduced amounts of IFN-gamma. In this study, we show that CD4 T cells from the early stage of the effector phase in which both the Ag and activation are optimal also transit to memory. Moreover, early effector T cells that have undergone four divisions expressed significant IL-7R, produced IFN-gamma, and yielded rapid and robust memory responses. Cells that divided three times that had marginal IL-7R expression and no IFN-gamma raised base level homeostatic memory, whereas those that have undergone only two divisions and produced IFN-gamma yielded conditioned memory despite low IL-7R expression. Thus, highly activated early effectors generated under short exposure to optimal Ag in vivo develop into memory, and such transition is dependent on a significant production of the cell's signature cytokine, IFN-gamma.

Coadministration of the Hexavalent Combination Vaccine Infanrix hexa™ and the Pneumoccoccal Conjugate Vaccine Prevenar™ Provides Early and Comprehensive Vaccination Coverage in Children after Related and Unrelated Allogeneic Hematopoietic Stem Cell Transplantation.

Recipients of allogeneic hematopoietic stem cell transplantion (alloHSCT) lose protective immunity to vaccine-preventable disease and thus are at increased risk of developing infections, in particular with encapsulated bacteria such as pneumococci and Haemophilus influenzae. However, several important issues on reimmunization after alloHSCT remain unresolved due to the lack of clinical studies especially in the pediatric setting. Here we report the results of the prospective, multicenter vaccination trial IKAST (NCT 00169728) and show for the first time that coadministration of the hexavalent tetanus, diphtheria, acellular pertussis, poliomyelitis, Haemophilus influenzae type B and hepatitis B combination vaccine Infanrix hexa™ (6vCV; GlaxoSmithKline Pharma) along with the heptavalent pneumococcal conjugate vaccine Prevenar™ (PCV7; Wyeth Pharma) provides early protective antibody responses against a broad range of vaccine antigens in the vast majority of pediatric HSCT recipients. Following alloHSCT from related (n=37) or unrelated (n=40) donors a total of 77 children (median age 8.3 (1.4–17.0) years) were immunized with a primary series of three monthly doses of 6vCV in conjunction with PCV7 starting as early as 6 months after transplantation irrespective of immunosuppressive therapy and graft-versus-host-disease, with a subsequent booster dose at 18 months. Immunogenicity was analysed by assessment of antibody concentrations, adverse events were monitored by a standardized diary and physician's assessment. Prior to vaccination only 8.2% and 12.8% of patients exhibited protective antibodies towards 6vCV and PCV7 vaccine antigens, respectively. As a result of a highly significant increase in mean antibody concentrations (p<0.001) protection to all 6vCV and PCV7 vaccine antigens was achieved in 85.1% and 89.8% of patients after primary immunization within the 1st year after alloHSCT, and this was independent of patient age, donor type, in vitro/in vivo T cell depletion, stem cell source, and conditioning (p>0.05). Although nine months later, prior to booster vaccination, 63.8% and 83.7% of patients retained protective antibody levels, mean antibody concentrations had dropped by a factor of 1.9–4.8 (p<0.001) except for one pneumococcal serotype, underlining the need for subsequent vaccination. Following booster immunization, antibody concentrations increased 2.4-19.1 fold (p<0.001) indicating robust memory responses, and 100% and 91.5% of patients achieved protective antibody levels against all 6vCV and PCV7 antigens, respectively. Vaccination was generally well tolerated with no vaccine-related serious adverse events. Our data show that early immunization of pediatric alloHSCT recipients according to our simple and convenient revaccination schedule is safe and provides early and comprehensive vaccination coverage during the first 2 years following stem cell transplantation.

Broad cellular immunity with robust memory responses to simian immunodeficiency virus following serial vaccination with adenovirus 5- and 35-based vectors

Adenovirus serotype 35 (Ad35) is a promising vaccine platform for human immunodeficiency virus (HIV) infection and emerging infectious diseases as it is uncommon in humans worldwide and is distinct from Ad5, the major vaccine serotype for which many individuals have pre-existing immunity. The immunogenicity of a first-generation, replication-competent Ad35-based vaccine was tested in the simian immunodeficiency virus (SIV) rhesus macaque model by evaluating its capacity to boost immunity generated by Ad5-based vectors. A series of four immunizations with replication-defective Ad5 vectors expressing SIVmac239 gag induced high-frequency responses mediated by both CD8(+) and CD4(+) T cells directed against several epitopes. Ad5-specific neutralizing antibody responses that did not neutralize Ad35 were rapidly induced but waned over time. Subsequent immunization with Ad5-based vectors was minimally effective, whereas immunization with Ad35-based vectors generated a strong increase in the frequency of Gag-specific T cells with specificities that were unchanged. While this boosting response was relatively transient, challenge with the distinct pathogenic isolate SIV/DeltaB670 generated robust and selective recall responses to Gag with similar specificities as induced by vaccination that were elevated for 25 weeks relative to controls. Vaccination had measurable albeit minor effects on virus load. Unexpectedly, regional hypervariability within the Gag sequence of SIV/DeltaB670 was associated with mutation of the conserved CD8(+) T-cell epitope CM9 without concurrent flanking mutations and in the absence of immune pressure. These findings support the further development of Ad35 as a vaccine vector, and promote vaccine regimens that utilize serial administration of heterologous adenoviruses.

Costimulatory ligand 4-1BBL (CD137L) as an efficient adjuvant for human antiviral cytotoxic T cell responses.

Effective adjuvants capable of inducing strong cytotoxic T cell responses in humans are lacking. In this study, we tested 4-1BBL as an adjuvant for activation of human memory antiviral CD8 T cell responses ex vivo. A recombinant replication-defective 4-1BBL adenovirus was used to convert autologous monocytes into efficient antigen-presenting cells after overnight incubation, bypassing the need to generate dendritic cells. Together with viral peptides, 4-1BBL led to robust memory responses of human Epstein-Barr virus- and influenza virus-specific cytotoxic T cells, with expansion of peptide-specific CD8 effector cells; up-regulation of Bcl-x(L), granzyme A, and perforin; enhanced cytotoxic activity; and increased cytokine production. The response was significant even at a 100-fold lower peptide dose, compared with responses obtained with control adenovirus. Adenovirus-delivered B7.1 also expanded and activated virus-specific CD8 T cells, but 4-1BBL was more effective in driving the T cells toward a more fully differentiated CD27(-) effector state. Thus, 4-1BBL is a promising adjuvant for human memory CD8 T cells and will likely be most effective in the boost phase of a prime-boost strategy.

Neue Vakzinierungsstrategien in der Immundermatologie und Allergologie

Classical vaccination regimens play an important role against the spread of infectious agents or for the treatment of existing malignancies. The common goal of these vaccination efforts is to induce and maintain antigen-specific immunity including a robust memory response. However, in the recent years vaccination strategies have been developed, which aim to modulate and regulate immune responses. A growing body of evidence exists that different vaccination methods can even be used to suppress an ongoing immune response. These data built the rationale for the new development of immunosuppressive therapies for a safe, effective and well-tolerated treatment of organ-specific autoimmune diseases in dermatology and other clinical fields. Dendritic cells play a prominent role in this context since they not only activate but are also able to modulate and regulate the effector function ofT cells. Dendritic cells have already been successfully used for the experimental treatment of autoimmune diseases in animal models. Dendritic cells can induce, stimulate and expand regulatory/suppressor T cells, which in turn actively inhibit effector T cells. Moreover, dendritic cells have been recently used in vivo to modulate an anti-viral immune response in humans. Therefore, dendritic cells appear to be promising tools for the development of new vaccination strategies which target the downregulation of (auto)immunity. In this article the latest experimental data on the use of dendritic cells for the induction of immunotolerance and the regulation of immunity are discussed in light of the recent literature.