Tick-Borne Encephalitis Specific Lymphocyte Response after Allogeneic Hematopoietic Stem Cell Transplantation Predicts Humoral Immunity after Vaccination

Nicole Harrison, Katharina Grabmeier-Pfistershammer, Alexandra Graf, Doris Trapin, Peter Tauber, Judith H Aberle, Karin Stiasny, Ralf Schmidt, Hildegard Greinix, Werner Rabitsch, Michael Ramharter, Heinz Burgmann, Winfried F Pickl, Christina Bahrs, Nicole Harrison, Katharina Grabmeier-Pfistershammer, Alexandra Graf, Doris Trapin, Peter Tauber, Judith H Aberle, Karin Stiasny, Ralf Schmidt, Hildegard Greinix, Werner Rabitsch, Michael Ramharter, Heinz Burgmann, Winfried F Pickl, Christina Bahrs

Abstract

The aim of this prospective study was to assess lymphocyte proliferative and cytokine response prior to and following tick-borne encephalitis (TBE) immunization among patients after allogeneic hematopoietic stem cell transplantation (HSCT). Seventeen adult patients 11-13 months after HSCT and eight unvaccinated healthy adults received up to three TBE vaccinations. Following in vitro stimulation with TBE-antigen, lymphocyte proliferation and cytokine secretion (IL-2, IL-10, IL-13, TNF-alpha, IFN-gamma, GM-CSF) were analyzed by thymidine incorporation assay and the Luminex system. Ten patients (59%) showed significant baseline TBE-specific lymphocyte proliferation (stimulation index (SI) > 3) prior to vaccination, but none of the unvaccinated controls (p = 0.002). All patients with a TBE-specific antibody response after two vaccinations (at least 2-fold increase of neutralization test titers) exhibited a strong TBE-specific lymphocyte proliferative response at baseline (SI > 10). Patients with sibling donors had a significantly stronger baseline TBE-specific lymphocyte proliferative and IL-13 cytokine response than patients with unrelated donors (p < 0.05). In conclusion, a relevant proportion of patients showed TBE-specific lymphocyte proliferative and cytokine responses prior to vaccination after HSCT, which predicted the humoral response to the vaccine. Patients with vaccinated sibling donors were more likely to elicit a cellular immune response than patients with unrelated donors of unknown vaccination status.

Keywords: allogeneic stem cell transplant; cytokine response; humoral responders; interleukin 13; lymphocyte proliferation; sibling donors; tick-borne encephalitis vaccination.

Conflict of interest statement

C.B. received a grant of the Austrian Scient Fund (grant number KLI 372) that enabled to conduct the present study and partly supported employment of N.H. H.B. received a research grant from Pfizer (Project No. WI201689), who performed neutralizing assays and supplied TBE-vaccines and TBE-antigens free of cost. Pfizer had no role in the conceptualization, design of the study or the decision to publish. All other authors report no competing interests related to the present work.

Figures

Figure 1
Figure 1
Boxplots showing the median and distribution of lymphocyte proliferation as detected by thymidine incorporation assay (the stimulation indices are given) at three different time points for healthy controls (orange) and patients (green) after stimulation with TBE antigen. Asterisk marks significant p-value (p = 0.0019).
Figure 2
Figure 2
Boxplots showing the median and distribution of cytokines as detected by Luminex assay at baseline before vaccination for healthy controls (orange) and patients (green) after stimulation with TBE antigen. Asterisk marks significant p-value (IL2: p = 0.03; TNF-alpha: p = 0.03; IL13: p < 0.001; GM-CSF: p = 0.01).
Figure 3
Figure 3
Boxplots showing the median and distribution of lymphocyte proliferation as detected by thymidine incorporation assay (the stimulation indices are given) at three different time points for humoral non-responders (orange) and responders (green) after stimulation with TBE antigen (response was defined as NT ≥ 10 and at least two-fold increase in titer after two vaccinations). Asterisk marks significant p-value (baseline: p < 0.001; 2nd vaccination: p = 0.0019).
Figure 4
Figure 4
Boxplots showing the median and distribution of cytokines as detected by Luminex assay at baseline before vaccination for humoral non-responders (orange) and responders (green) after stimulation with TBE antigen (response was defined as NT ≥ 10 and at least two-fold increase in titer after two vaccinations). Asterisk marks significant p-value (IL2: p < 0.001; IFN-gamma: p = 0.003; TNF-alpha: p = 0.002; IL10: p = 0.04; IL13: p < 0.001; GM-CSF: p = 0.001).
Figure 5
Figure 5
Boxplots showing the median and distribution of lymphocyte proliferation as detected by thymidine incorporation assay (the stimulation indices are given) at three different time points for patients with unrelated (orange) and related donors (green) after stimulation with TBE antigen. Asterisk marks significant p-value (baseline: p = 0.004; 2nd vaccination: p = 0.015; 3rd vaccination: p = 0.002).
Figure 6
Figure 6
Boxplots showing the median and distribution of IL-13 as detected by Luminex assay at three different time points for patients with unrelated (orange) and related donors (green) after stimulation with TBE antigen. Asterisk marks significant p-value (baseline: p = 0.04; after 2nd vaccination: p = 0.01; after 3rd vaccination: p = 0.01).

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