Abstract
Objective: Monitoring of immune responses is essential in the care of immunosuppressed individuals, including rheumatic patients. Evaluation of cellular immunity is essential for confirming virus-specific effector cell functions, but it is poorly standardized, and suffers from technical limitations and inaccurate results. There is, therefore, a need for reliable techniques for assessing cell-mediated immunity. In this study we compared the cell-mediated immunity response to influenza vaccine between a population of rheumatoid arthritis (RA) patients and healthy subjects by three methods. Methods: Trivalent influenza subunit vaccine was administered to 18 RA patients who were taking disease-modifying antirheumatic drugs and to 18 healthy controls. Peripheral blood mononuclear cells (PBMCs) and sera were obtained immediately before and ~28 days after vaccination. Cell-mediated immunity responses to vaccination were evaluated by (1) flow cytometric analysis of IL-2/IFN-γ production in activated CD4/CD8 T-cells, (2) enzyme-linked immunosorbent assay for the analysis of IFN-γ secretion, and (3) Granzyme B activity assay. Humoral response was evaluated by the hemagglutination inhibition assay. Results: Vaccination induced a significant increase in PBMC IFN-γ secretion and Granzyme B activity in the RA patients. Granzyme B activity also significantly increased in the controls, but there was no change in the levels of secreted IFN-γ. No group differences in the frequencies of IFN-γ/IL-2-producing activated CD4/CD8 T-cells were observed by flow cytometry. The geometric mean of hemagglutination inhibition antibody titers increased significantly for the H1N1/H3N2 influenza strains in both groups. Conclusions: Granzyme B activity assay was the only method to detect a significant cell-mediated immunity response in both groups while significant increase in IFN-γ secretion was demonstrated only in RA patients. Flow cytometric analysis failed to show IL-2 and IFN-γ production in both groups. Currently available methods for measuring cellular responsiveness to influenza vaccination are inconsistent and limited in their ability to reflect acquired cellular immunity.
Highlights
Patients with autoimmune inflammatory rheumatic diseases, such as Rheumatic Arthritis (RA), have approximately twice the risk of infectious diseases compared with the normal population [1,2]
The European League against Rheumatism (EULAR) recommends that the administration of inactivated influenza vaccination should be strongly considered for patients with rheumatic disease [6], even those who are treated with DMARDs or tumor-necrosis factor (TNF) inhibitors
In most trials upon which the recommendations were based, efficacy was assessed by humoral responsiveness, which is currently considered the gold standard for seasonal influenza vaccines
Summary
Patients with autoimmune inflammatory rheumatic diseases, such as Rheumatic Arthritis (RA), have approximately twice the risk of infectious diseases compared with the normal population [1,2]. This increased susceptibility may be attributed to both disease-associated immunoregulatory imbalances, as well as to chronic use of immunosuppressive drugs [3]. The European League against Rheumatism (EULAR) recommends that the administration of inactivated influenza vaccination should be strongly considered for patients with rheumatic disease [6], even those who are treated with DMARDs or tumor-necrosis factor (TNF) inhibitors (with the exclusion of the B-cell depleting agent, rituximab). In the case of virus-related illnesses, such as influenza, cellular immunity is another important pathway of response, since the ability of vaccines to induce cell-mediated immunity (CMI) is believed to be important in preventing severe disease and in enabling long-term immunological memory [7]
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