Functional Immune Cell Differences Associated With Low Vaccine Responses in Infants

BACKGROUND: We sought to understand why some children respond poorly to vaccinations in the first year of life. METHODS: A total of 499 children (6-36 months old) provided serum and peripheral blood mononuclear cell samples after their primary and booster vaccination. Vaccine antigen-specific antibody levels were analyzed with enzyme-linked immunosorbent assay, and frequency of memory B cells, functional T-cell responses, and antigen-presenting cell responses were assessed in peripheral blood mononuclear cell samples with flow cytometric analysis. RESULTS: Eleven percent of children were low vaccine responders, defined a priori as those with subprotective immunoglobulin G antibody levels to ≥66% of vaccines tested. Low vaccine responders generated fewer memory B cells, had reduced activation by CD4(+) and CD8(+) T cells on polyclonal stimulation, and displayed lower major histocompatibility complex II expression by antigen-presenting cells. CONCLUSIONS: We conclude that subprotective vaccine responses in infants are associated with a distinct immunologic profile

Modeling the Dynamics and Migratory Pathways of Virus-Specific Antibody-Secreting Cell Populations in Primary Influenza Infection

<div><p>The B cell response to influenza infection of the respiratory tract contributes to viral clearance and establishes profound resistance to reinfection by related viruses. Numerous studies have measured virus-specific antibody-secreting cell (ASC) frequencies in different anatomical compartments after influenza infection and provided a general picture of the kinetics of ASC formation and dispersion. However, the dynamics of ASC populations are difficult to determine experimentally and have received little attention. Here, we applied mathematical modeling to investigate the dynamics of ASC growth, death, and migration over the 2-week period following primary influenza infection in mice. Experimental data for model fitting came from high frequency measurements of virus-specific IgM, IgG, and IgA ASCs in the mediastinal lymph node (MLN), spleen, and lung. Model construction was based on a set of assumptions about ASC gain and loss from the sampled sites, and also on the directionality of ASC trafficking pathways. Most notably, modeling results suggest that differences in ASC fate and trafficking patterns reflect the site of formation and the expressed antibody class. Essentially all early IgA ASCs in the MLN migrated to spleen or lung, whereas cell death was likely the major reason for IgM and IgG ASC loss from the MLN. In contrast, the spleen contributed most of the IgM and IgG ASCs that migrated to the lung, but essentially none of the IgA ASCs. This finding points to a critical role for regional lymph nodes such as the MLN in the rapid generation of IgA ASCs that seed the lung. Results for the MLN also suggest that ASC death is a significant early feature of the B cell response. Overall, our analysis is consistent with accepted concepts in many regards, but it also indicates novel features of the B cell response to influenza that warrant further investigation.</p></div

Schematic diagram of ASC migration pathways involving MLN, spleen, and lung following influenza infection.

<p>Schematic diagram of ASC migration pathways involving MLN, spleen, and lung following influenza infection.</p

Point estimates based on the best sub-models (derived from Model 1) selected using AICc and the 95% confidence intervals (insignificant parameter estimates selected by AICc are labelled as dropped).

<p>The lower bound for some highly-skewed parameters are not available and labeled as NA.</p><p>Point estimates based on the best sub-models (derived from Model 1) selected using AICc and the 95% confidence intervals (insignificant parameter estimates selected by AICc are labelled as dropped).</p

ASC disappearance compared with ASC migration from MLN and spleen.

<p>The term migration covers ASC trafficking from MLN to lung or spleen, or ASC trafficking from spleen to lung. Migration pathways reflect assumptions shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104781#pone-0104781-g001" target="_blank">Figure 1</a>. The term disappearance covers ASC death or ASC migration to sites other than the lung or spleen.</p

Visualization of the modeling results for the three types of ASCs, where the solid lines represent statistically significant parameter estimates and the dashed lines are for negligible parameter values.

<p>Visualization of the modeling results for the three types of ASCs, where the solid lines represent statistically significant parameter estimates and the dashed lines are for negligible parameter values.</p

Parameter and variable definitions in Models 1–2 (subscripts for antibody isotypes are not shown).

<p>Parameter and variable definitions in Models 1–2 (subscripts for antibody isotypes are not shown).</p

Rituximab immunotherapy results in the induction of a lymphoma idiotype-specific T-cell response in patients with follicular lymphoma: support for a “vaccinal effect” of rituximab

The incorporation of rituximab, a chimeric anti-CD20 monoclonal antibody, into the therapeutic armamentarium for patients with follicular lymphoma (FL) has significantly improved treatment outcome for such patients. Despite the almost universal application of this therapy, however, its exact mechanism of action has not been completely defined. One proposed mechanism is that of a “vaccinal” effect, whereby FL cell kill by rituximab results in the elicitation of an FL-specific T-cell response. The demonstration that rituximab can even elicit such a response in patients has, to our knowledge, never been shown. We analyzed the response against the immunoglobulin expressed by the FL before and after rituximab monotherapy in 5 FL patients and found an increase in FL idiotype–specific T cells after rituximab in 4 of 5 patients. Our data thus provide “proof of principle” for the ability of passive immunotherapy with rituximab to elicit an active FL-specific cellular response